Dopamine Reviews: 2002
(395 References)
(2002). "Drugs to treat autonomic dysfunction in Parkinson's disease." Mov Disord 17 Suppl 4: S103-11.
(2002). "DA agonists -- non-ergot derivatives: ropinirole: management of Parkinson's disease." Mov Disord 17 Suppl 4: S98-102.
(2002). "DA agonists -- non-ergot derivatives: pramipexole: management of Parkinson's disease." Mov Disord 17 Suppl 4: S93-7.
(2002). "DA agonists -- non-ergot derivatives: piribedil: management of Parkinson's disease." Mov Disord 17 Suppl 4: S90-2.
(2002). "DA agonists -- non-ergot derivatives: apomorphine: management of Parkinson's disease." Mov Disord 17 Suppl 4: S83-9.
(2002). "DA agonists -- ergot derivatives: pergolide: management of Parkinson's disease." Mov Disord 17 Suppl 4: S79-82.
(2002). "DA agonists -- ergot derivatives: lisuride: management of Parkinson's disease." Mov Disord 17 Suppl 4: S74-8.
(2002). "DA agonists -- ergot derivatives: dihydroergocryptine (DHEC): management of Parkinson's disease." Mov Disord 17 Suppl 4: S72-3.
(2002). "DA agonists -- ergot derivatives: cabergoline: management of Parkinson's disease." Mov Disord 17 Suppl 4: S68-71.
(2002). "DA agonists -- ergot derivatives: bromocriptine: management of Parkinson's disease." Mov Disord 17 Suppl 4: S53-67.
(2002). "Aripiprazole. Abilitat, OPC 14597." Drugs R D 3(1): 25-7.
Adachi, N. (2002). "[Cerebral ischemia and histamine]." Nippon Yakurigaku Zasshi 120(4): 215-21.
Cerebral ischemia induces excess release of glutamate and an increase in the intracellular Ca2+ concentration, which provoke catastrophic enzymatic processes leading to irreversible neuronal injury. Histamine plays the role of neurotransmitter in the central nervous system, and histaminergic fibers are widely distributed in the brain. In cerebral ischemia, release of histamine from nerve endings has been shown to be enhanced by facilitation of its activity. An inhibition of the histaminergic activity in ischemia aggravates the histologic outcome. In contrast, intracerebroventricular administration of histamine improves the aggravation, whereas blockade of histamine H2 receptors aggravates ischemic injury. Furthermore, H2 blockade enhances ischemic release of glutamate and dopamine. These findings suggest that central histamine provides beneficial effects against ischemic neuronal damage by suppressing release of excitatory neurotransmitters. However, histaminergic H2 action facilitates the permeability of the blood-brain barrier and shows deleterious effects on cerebral edema.
Adibhatla, R. M., J. F. Hatcher, et al. (2002). "Citicoline: neuroprotective mechanisms in cerebral ischemia." J Neurochem 80(1): 12-23.
Cytidine-5'-diphosphocholine (citicoline or CDP-choline), an intermediate in the biosynthesis of phosphatidylcholine (PtdCho), has shown beneficial effects in a number of CNS injury models and pathological conditions of the brain. Citicoline improved the outcome in several phase-III clinical trials of stroke, but provided inconclusive results in recent clinical trials. The therapeutic action of citicoline is thought to be caused by stimulation of PtdCho synthesis in the injured brain, although the experimental evidence for this is limited. This review attempts to shed some light on the properties of citicoline that are responsible for its effectiveness. Our studies in transient cerebral ischemia suggest that citicoline might enhance reconstruction (synthesis) of PtdCho and sphingomyelin, but could act by inhibiting the destructive processes (activation of phospholipases). Citicoline neuroprotection may include: (i) preserving cardiolipin (an exclusive inner mitochondrial membrane component) and sphingomyelin; (ii) preserving the arachidonic acid content of PtdCho and phosphatidylethanolamine; (iii) partially restoring PtdCho levels; (iv) stimulating glutathione synthesis and glutathione reductase activity; (v) attenuating lipid peroxidation; and (vi) restoring Na(+)/K(+)-ATPase activity. These observed effects of citicoline could be explained by the attenuation of phospholipase A(2) activation. Based on these findings, a singular unifying mechanism has been hypothesized. Citicoline also provides choline for synthesis of neurotransmitter acetylcholine, stimulation of tyrosine hydroxylase activity and dopamine release.
Akaike, A., H. Katsuki, et al. (2002). "[Role of nitric oxide in survival and death of neurons]." Nippon Yakurigaku Zasshi 119(1): 15-20.
The prominent pathological feature of the brain in Parkinson's disease is selective degeneration of dopaminergic neurons in the substantia nigra of the midbrain. Glutamate and nitric oxide (NO) are the major effectors of the radical stress that may induce selective loss of dopaminergic neurons. It has been postulated that neurotoxicity induced by glutamate and NO in dopaminergic neurons is regulated by certain endogenous factors. We have reported that estradiol protects dopaminergic neurons against NO-mediated glutamate neurotoxicity by reducing intracellular reactive oxygen species (ROS) levels. We further searched for a candidate for neuroprotective substances with unique structure. From the ether extract of fetal calf serum (FCS), we isolated a novel substance possessing protective activity against neurotoxicity induced by glutamate NO. The compound was a sulfur-containing diterpenoid and showed hydroxyl radical scavenging activity. We further analyzed the change of resistance to excitotoxicity in midbrain dopaminergic neurons in co-culture with the striatum by using a slice culture technique. The results suggested that the generation of NO is involved in NMDA cytotoxicity on dopaminergic neurons and that increased activity of SOD in co-culture renders dopaminergic neurons resistant to NMDA cytotoxicity by preventing peroxynitrite formation. Those findings suggest that regulation of intracellular ROS levels plays a critical role in protecting neurons against NO-mediated radical stress in neurodegenerative disorders.
Albert, U., C. Bergesio, et al. (2002). "Management of treatment resistant obsessive-compulsive disorder. Algorithms for pharmacotherapy." Panminerva Med 44(2): 83-91.
Treatment resistant OCD subjects, defined as those patients who undergo an adequate trial of SRI (clomipramine or SSRI) and do not respond or show unsatisfactory results, account for 40-50% of all patients. Once the appropriateness of the trial has been assessed, several options exist for the clinicians. If clomipramine or citalopram have been used, an appropriate strategy consists in giving the same drug intravenously. Double-blind studies exist on the efficacy of clomipramine IV, while data are missing for citalopram. Another option that should be considered first, although data are scarce, is the addition of a cognitive behavioral therapy, when available, in the forms of exposure and response prevention. When such options are not suitable or available, augmentation of the ongoing SRI with another compound represents the preferable strategy. Double-blind, placebo-controlled studies have shown the efficacy of adding pindolol (7.5 mg/d), risperidone (2 mg/d) and olanzapine (5-10 mg/d). Other agents have been proposed, but data emerging from double-blind studies were negative or contradictory. Another option available is switching from CMI to SSRI, or vice versa, or from SSRI to SSRI. Data regarding such treatment strategy, however, are highly preliminary, based on a couple of open label reports and on studies performed in treatment resistant depression. An unresolved question is whether augmentation should be preferred to switching. No data exist in OCD; a practical approach would suggest augmentation first, considering that response should be obtained faster than by switching compound. When all the available and effective strategies prove uneffective, clinicians should consider switching the patient to other compounds in monotherapy, such as venlafaxine, sumatriptan, inositol, although research is strongly needed before conclusions on the efficacy of such compounds can be drawn.
Allam, M. F., M. J. Campbell, et al. (2002). "[Parkinson's disease and smoking: coherence and plausibility]." Rev Neurol 34(7): 686-9.
INTRODUCTION. Many studies have shown that smoking is lower in patients with Parkinson s disease. However, in other investigations this was not observed. The various studies involved showed wide variation with regard to methodology, criteria for diagnosis and periods of observation and hence it is difficult to compare them. DEVELOPMENT. The first studies published were designed to examine the effects of smoking in general and information was obtained regarding the possible disorders related to tobacco smoking according to the records of mortality, which may contain errors due to selective mortality and mistaken diagnosis. Most of the studies of cases and controls included prevalent cases which accepted the study, mainly hospital cases. Also it is probable that the prevalent cases of Parkinson s disease do not smoke because of their disorders of movement. CONCLUSIONS. Many researchers have found important information about the pathophysiology of Parkinson s disease and its association with smoking. However, the hypothesis regarding the association between smoking and low risk of Parkinson s disease are various and independent, apart from the hypothesis of a truly biological mechanisms. Since the subject is still controversial, systematic reviews together with epidemiological and experimental studies are necessary.
Amano, T., H. Matsubayashi, et al. (2002). "[Alteration of neuronal activities following repeated administration of stimulants]." Nihon Arukoru Yakubutsu Igakkai Zasshi 37(1): 31-40.
It has been well-known that abuse of psychostimulants such as amphetamine and methamphetamine (MAP) induces behavioral sensitization (reverse tolerance) to MAP, resulting in psychotic effects such as hallucinatory-delusional state. Animals treated with MAP repeatedly also show the behavioral sensitization to MAP. This paper focuses on the pathogenesis and mechanism underlying sensitization to MAP after repeated treatment with MAP. MAP is known to release dopamine (DA), noradrenalin (NA) and serotonin (5-HT), and bind with the same sites on DA-, NA- and 5-HT-transporters as do these monoamines, thereby inhibiting re-uptake of these substances. As a result, these monoamines accumulate in the synaptic areas unnerved by the monoamine systems. An increase in the monoamines also occurs in the dendritic areas of DA, NA and 5-HT cells probably by a mechanism similar to those in the presynaptic terminals of monoamines. Releases and syntheses of DA, NA and 5-HT are inhibited by the monoamine per se via their autoreceptors such as D2, alpha 2 and 5-HT1A receptors, respectively. It is noteworthy that repeated MAP treatment results in the reduction of DA transporters, and such a decrease in transporters has been also found in MAP abusers by PET studies, suggesting a decrease in DA transporters is related with the appearance of reverse tolerance. Repeated MAP administration induces immediate early gene such as c-fos, c-jun and arc, and the increase in arc is inhibited by D1 and NMDA antagonists, suggesting an important role of such genes in inducing reverse tolerance. In electrophysiological studies using anesthetized rats treated with MAP repeatedly, hyposensitivities and hypersensitivities to DA and MAP have been found in nucleus accumbens receiving dopaminergic input from ventral tegmental area, 24-30 h and 5 days after the final administration of MAP, respectively, although the sensitivities recovered to the normal level 10 days after the treatment. The hypersensitivities were probably mediated via D1/D2 receptors. Thus, the hypersensitivities of nucleus accumbens neurons to DA and MAP are actually completed after repeated treatment of MAP. Therefore, it is of great interest to elucidate the molecular mechanism responsible for the DA receptor hypersensitivity.
Ament, P. W., N. Jamshed, et al. (2002). "Linezolid: its role in the treatment of gram-positive, drug-resistant bacterial infections." Am Fam Physician 65(4): 663-70.
While the choices available for the management of gram-positive, drug-resistant bacterial infections are becoming limited, antimicrobial resistance is becoming increasingly problematic because of the widespread overuse of antibiotics. Linezolid is a synthetic antibiotic belonging to a new class of antimicrobials called the oxazolidinones. Linezolid disrupts bacterial growth by inhibiting the initiation process of protein synthesis--a mechanism of action that is unique to this class of drugs. It is well absorbed with high bioavailability that allows conversion to oral therapy as soon as the patient is clinically stable. It has been approved for certain gram-positive infections including certain drug-resistant enterococcus, staphylococcus, and pneumococcus strains. It is generally well tolerated, with myelosuppression being the most serious adverse effect. As a nonselective inhibitor of monoamine oxidase, caution is recommended when used with adrenergic or serotonergic agents (e.g., tyramine, dopamine, pseudoephedrine, and selective serotonin reuptake inhibitors). Judicious use of this medication should help physicians treat patients with multidrug-resistant infections.
Anastasiadis, A. G., M. A. Ghafar, et al. (2002). "Economic aspects of medical erectile dysfunction therapies." Expert Opin Pharmacother 3(3): 257-63.
The introduction of safe and effective oral therapies has changed the significance of erectile dysfunction (ED) forever. Seldom has a new drug changed the landscape of pharmacotherapy in so many ways as sildenafil (Viagra, Pfizer). This article highlights the various oral, intracavernosal and intraurethral therapies currently available for ED and evaluates the socio-economic impact of each method.
Andersson, K. E. and P. Hedlund (2002). "Pharmacologic perspective on the physiology of the lower urinary tract." Urology 60(5 Suppl 1): 13-20; discussion 20-1.
Myogenic activity, distention of the detrusor, and signals from the urothelium may initiate voiding. In the bladder, afferent nerves have been identified not only in the detrusor, but also suburothelially, where they form a plexus that lies immediately beneath the epithelial lining. Extracellular adenosine triphosphate (ATP) has been found to mediate excitation of small-diameter sensory neurons via P2X3 receptors, and it has been shown that bladder distention causes release of ATP from the urothelium. In turn, ATP can activate P2X3 receptors on suburothelial afferent nerve terminals to evoke a neural discharge. However, most probably, not only ATP but also a cascade of inhibitory and stimulatory transmitters and mediators are involved in the transduction mechanisms underlying the activation of afferent fibers during bladder filling. These mechanisms may be targets for future drugs. The central nervous control of micturition involves many transmitter systems, which may be suitable targets for pharmacologic intervention. gamma-Aminobutyric acid, dopamine, enkephalin, serotonin, and noradrenaline receptors and mechanisms are known to influence micturition, and potentially, drugs that affect these systems could be developed for clinical use. However, a selective action on the lower urinary tract may be difficult to obtain. Most drugs currently used for treatment of detrusor overactivity have a peripheral site of action, mainly the efferent (cholinergic) neurotransmission and/or the detrusor muscle itself. In the normal bladder, muscarinic receptor stimulation produces the main part of detrusor contraction, but evidence is accumulating that in disease states, such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, and interstitial cystitis, as well as in the aging bladder, a noncholinergic activation via purinergic receptors may occur. If this component of activation is responsible not only for part of the bladder contractions, but also for the symptoms of the overactive bladder, it should be considered an important target for therapeutic interventions.
Andersson, K. E. (2002). "Treatment of the overactive bladder: possible central nervous system drug targets." Urology 59(5 Suppl 1): 18-24.
The well-known side effects of antimuscarinic drugs have focused interest on other modalities of treatment of the overactive bladder. To effectively control bladder activity, identification of suitable targets for pharmacologic intervention is necessary. Such targets may be found in the central nervous system (CNS) or peripherally. Several CNS transmitters may modulate voiding, but few drugs with a defined CNS site of action have been developed for treatment of voiding disorders. Drugs affecting gamma-aminobutyric acid, opioid, serotonin, noradrenaline, dopamine, or glutamatergic receptors and mechanisms are known to influence micturition, and potentially such drugs could be developed for clinical use. However, a selective action on the lower urinary tract may be difficult to obtain.
Andersson, K. E. and P. Hedlund (2002). "New directions for erectile dysfunction therapies." Int J Impot Res 14 Suppl 1: S82-92.
Research in the field of erectile function and dysfunction has continued to expand rapidly. Based on the information available, some directions for future erectile dysfunction therapies can be identified. The first direction is improvement of current therapeutic principles. A second generation of orally active phosphodiesterase (PDE) inhibitors is being introduced, and further developments within this field can be expected. The recent introduction of apomorphine has opened the way for new dopamine receptor agonists. The second direction is combinations of existing therapeutic principles. Combinations of apomorphine and sildenafil and apomorphine and alpha(1)-adrenoceptor (AR) antagonists, for example, seem attractive and may have a therapeutic potential in patients not responding satisfactorily to single-drug treatment. Nitrosylated alpha(1)-AR antagonists, combining nitric oxide donation and alpha(1)- or alpha(2)-AR antagonism, are currently being evaluated. The third direction is new targets within the central nervous system. Melanocortin receptor agonists have shown promise not only in animal models, but also in preliminary studies in humans. Other possible targets, such as growth hormone-releasing peptide receptors, are being explored. The fourth direction is new peripheral targets. Rho-kinase antagonism and non-nitric oxide-mediated stimulation of soluble guanylyl cyclase have been suggested as possible new principles for drug development. The fourth direction is gene therapy. Progress has been made in intracavernosal somatic gene therapy and will probably continue. Still, problems remain, and advantages over conventional pharmacological therapies have to be demonstrated. The final direction is prevention strategies. Strategies to prevent cavernosal degeneration and/or to restore cavernosal function will be one of the most exciting challenges for future research.
Andreoli, S. P. (2002). "Acute renal failure." Curr Opin Pediatr 14(2): 183-8.
Acute renal failure is characterized by an increase in the blood concentration of creatinine and nitrogenous waste products and by the inability of the kidney to appropriately regulate fluid and electrolyte homeostasis. There are many different causes of acute renal failure in children, including prerenal disease, intrinsic renal failure, which includes ischemic hypoxic insults, and obstructive uropathy. This review will focus on hypoxic/ischemic acute renal failure, the most common causes of hospital acquired acute renal failure in children. This review will briefly discuss the epidemiology and incidence of acute renal failure in pediatric patients and review new insights into the pathogenesis of acute renal failure. including hemodynamic alterations induced by alterations in nitric oxide and endothelin metabolism, the role of the inflammatory response, and alteration in polarity in the acute renal failure. The therapy of acute renal failure has changed substantially during the past few years. Controlled trials (in adults) to test the efficacy of "renal dose" dopamine have shown that it is ineffective, and hemofiltration has become increasingly popular as a choice of therapy for acute renal failure.
Ankli, A., M. Heinrich, et al. (2002). "Yucatec Mayan medicinal plants: evaluation based on indigenous uses." J Ethnopharmacol 79(1): 43-52.
As part of an ethnopharmacological field study 48 medicinal plants were evaluated using several biological assays with the goal to obtain information on the pharmacological effects of these plants, which may be of direct relevance to the indigenous uses. Three species used to treat gastrointestinal disorders showed remarkable activity against Helicobacter pylori. One of them showed activity against Giardia duodenalis. Cytotoxic effects against KB cells were found for six species. In the group of plants used for dermatological conditions several species were active against gram-positive bacteria and Candida albicans. Two plant species of this group were found to be active in an Nuclear Factor-kappaB (NF-kappaB) assay measuring inhibition of this pro-inflammatory transcription factor. A species of the Solanaceae, applied in cases of pain and fever, showed a weak activity against Plasmodium falciparum. One species traditionally used for diabetes exhibited antihyperglycemic activity. None of the six species from the group of 'women's medicine' showed relevant affinity to the D(2) dopamine receptor. Based on this evaluation, plants with strong activities should be further investigated phytochemically and pharmacologically to identify active fractions and compounds.
Anokhina, I. P. and T. V. Proskuriakova (2002). "[Involvement of the neuropeptide cholecystokinin in the mechanisms of regulation of emotions and craving]." Vestn Ross Akad Med Nauk(6): 36-40.
The paper presents an idea on the organization and functions of the cholecystokinin (CCK) system. Particular emphasis is laid on the modulating influence of CCK on dopamine neuromediation in the mesolymbic structures of the brain, which are linked with the regulation of emotions and craving. Experimental and clinical studies have indicated that CCK and its preparations arrest the major manifestation of the withdrawal syndrome, including pathological craving for alcohol, and anxiety. In the post-withdrawal period, these drugs also effectively suppress alcohol craving. The designed new tetrapeptide, a CCK analogue, selectively inhibits anxiety in animals with this emotional disorder, which is followed by normalization of dopamine exchange and GABA-system functions. It is concluded that by interacting with the dopamine-system, CCK takes a direct part in the regulation of emotions and craving.
Arenas, E. (2002). "Stem cells in the treatment of Parkinson's disease." Brain Res Bull 57(6): 795-808.
Stem cells have been suggested as candidate therapeutic tools for neurodegenerative disorders, given their ability to give rise to the appropriate cell types after grafting in vivo. In this review I summarize some of the evidence currently available concerning two approaches for the treatment of Parkinson's disease: (1) The generation of dopaminergic neurons from embryonic stem cells, multipotent stem cells, and neuronal progenitor cells for cell replacement therapy. (2) The engineering of multipotent stem cells to release glial cell-line derived neurotrophic factor, a potent neurotrophic factor for dopaminergic neurons, in a neuroprotective and neuroregenerative approach to the treatment of Parkinson's disease.
Arsland, D. (2002). "[Dementia with Lewy bodies]." Tidsskr Nor Laegeforen 122(5): 525-9.
BACKGROUND: Some 10%-15% of patients with dementia are diagnosed as dementia with Lewy bodies (DLB), a disorder characterised by the presence of Lewy bodies in the brainstem and cortex. MATERIAL AND METHODS: Review of pathology, clinical symptoms, pharmacological and nonpharmacological treatment, based on the literature and on personal experience. RESULTS: Neurochemical findings are marked cortical reduction of acetylcholine and nigrostriatal dopamine deficiency. Key features of the clinical syndrome are dementia, fluctuating consciousness, visual hallucinations and parkinsonism. There are pathological and clinical overlaps between DLB and Alzheimer's disease on the one hand, and between DLB and Parkinson's disease on the other; the relationship between these diseases awaits further elucidation. Clinical consensus criteria for DLB have been published and shown to have high sensitivity and specificity. Fluctuating consciousness may be difficult to detect, but diagnostic instruments exist that may help in the evaluation. Drug treatment of DLB is difficult. Cholinesterase inhibitors have been shown to improve cognition and psychiatric symptoms. Atypical antipsychotics may improve psychosis, but some patients develop severe sensitivity reactions. The effect of antiparkinson agents is unknown.
Assal, F. and J. L. Cummings (2002). "Neuropsychiatric symptoms in the dementias." Curr Opin Neurol 15(4): 445-50.
PURPOSE OF REVIEW: Neuropsychiatric, or non-cognitive symptoms are increasingly recognized as manifestations of dementias. RECENT FINDINGS: In Alzheimer's disease, recent advances have included the identification of behavioral profiles, differentiation of apathy and depression, characterization of risk factors for psychosis and its links to agitation and aggression, and an analysis of depressive symptoms in the absence of major depression. Functional neuroimaging data mainly supported the role of the anterior cingulate in apathy. The orbitofrontal and anterior cingulate tangle burden were associated with agitation, and increased orbitofrontal and mid-temporal muscarinic M2 receptors with psychosis and hallucinations. Selected genetic polymorphisms of dopamine and serotonin receptors or transporters were linked with aggression, hallucinations or psychosis. When compared with other dementias, individuals with frontotemporal dementia disclosed, as expected, different behaviors and particularly aberrant social behavior. The frequency of delusions and visual hallucinations was increased in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies, suggesting common mechanisms such as Lewy body pathology and cholinergic deficiency. The latter was supported by an improvement of these symptoms by cholinesterase inhibitors. SUMMARY: Future research directions include both clinical and basic neuroscience investigations. The detection of early neuropsychiatric symptoms might be a marker for dementia, and the possible existence of a mild neuropsychiatric impairment syndrome should be explored. More longitudinal studies with pathological confirmation will facilitate correlations with neuropsychiatric symptoms. Functional neuroimaging and behavioral neurogenetics will permit in-vivo correlations and consequently help patient management and care.
Aubin, H. J. (2002). "Tolerability and safety of sustained-release bupropion in the management of smoking cessation." Drugs 62 Suppl 2: 45-52.
Sustained-release bupropion (bupropion SR) was first launched in the US in 1997 as an aid to smoking cessation and has since been launched in many other countries. Adverse events associated with the use of bupropion SR at the recommended dosage of 150mg twice daily in clinical trials most commonly included insomnia, headache, dry mouth, nausea and anxiety; insomnia and anxiety are also recognised as symptoms of nicotine withdrawal. Only insomnia and dry mouth occurred significantly more frequently with bupropion SR than with placebo. Relative to placebo, no significant changes in mean values for heart rate, blood pressure or routine laboratory parameters have been reported in smokers using bupropion SR alone in clinical trials. When bupropion SR was compared with a nicotine transdermal patch in a clinical trial, insomnia predominated in the bupropion SR group, while dream abnormalities were more common in smokers using the nicotine patch. Bupropion SR and the nicotine transdermal patch in combination can be used safely (with appropriate monitoring) as an aid to smoking cessation. Infrequent but clinically important adverse reactions to bupropion SR include seizures and hypersensitivity reactions: in controlled clinical trials of bupropion SR (300 mg/day), where smokers were carefully screened for risk factors for seizure, the incidence of both seizures and severe hypersensitivity reactions was approximately 0.1% for each event. In order to avoid a risk of seizure of greater than 0.1%, smokers should be screened for predisposing risk factors and adhere to the manufacturer's dosage recommendations (maximum daily dose of 300mg). Thus, bupropion SR is generally well tolerated, as seen by the low discontinuation rate due to an adverse event in clinical trials (6 to 12%). The most common adverse events (insomnia and dry mouth) are generally transient and often resolve quickly without therapeutic intervention; they can be managed if necessary by a reduction in bupropion dose.
Baghdadli, A., V. Gonnier, et al. (2002). "[Review of psychopharmacological treatments in adolescents and adults with autistic disorders]." Encephale 28(3 Pt 1): 248-54.
Autism is an early developmental disorder. It leads to severe and durable disturbances. Given this problem, no treatment can be excluded a priori. Thus, many approaches are used to deal with autistic disorders. In France, pharmacological treatments are, for instance, largely and mostly used in adults. In the USA, these treatments concern 50% of persons with autism of any age. Nevertheless, they are rarely based on controlled studies. At the present, however, prescriptions and expected effects appear to be hard to localize. Furthermore, only few controlled studies validate their use. Aim - We offer a review of studies about medical treatments used in adolescents and adults with autism. They are classified in 3 categories: the first (category I) includes drugs used for their neurochemical effects focusing on autistic signs. The second (category II) covers drugs used for treatment of behavioural disorders frequently associated with autism. The third (category III) corresponds to a wide range of drugs or vitamins for wich only few case studies exist reporting irregular positive effects. The main hypothesis of this review is that autism involves a dysfunction of the neuromediation systems. This hypothesis opens new perspectives in the research of medical treatments in autism by focusing on molecules, which are supposed to have an effect on neuromediation systems. Method - Our review is based on studies, which have been published during the past twenty years. For many studies, data are limited to adolescents and adults. So we expanded our review to data available in children. The data bases that we have used are medline and psyclit. Keywords have been chosen according to: pharmacological considerations (psychotropic, psychoactive drugs, psychopharmacology) and clinical symptoms (autism, automutilations, aggressive behavior, and hyperactivity). Hypothesis of a dysfunction in the neuromediation systems in autism - Many studies exist about biochemical abnormalities in autism. As in schizophrenia and mental retardation, dysfunctions of the neuromediation systems are considered to be etiological factors. In 30% of people with autism the most regular dysfunction is the increase of serotonine. This led to the serotoninergic hypothesis in autism and to the use of active drugs in the serotonine system. However, the presence of other neurometabolic abnormalities also motivates the use of drugs, supposed to be active in other neuromediation systems. Pharmacological treatments in autism - Category I section sign 1 Active drugs in the dopamine system. Haloperidol (Dopamine antagonist): The effects of this molecule have been broadly studied in autism. Results indicate high efficiency in some symptoms of autism (lack in social behaviour, stereotypical behaviour) and in behavioural impairments that may be associated with autism (aggressive behaviour, hyperactivity). Its side effects, particulary the risk of late dyskinesy, make atypical antipsychotics preferable because of their lower risks. Risperidone (Dopamine and serotonine antagonist): Among several studies only few have been controlled. They indicate that Risperidone has positive effects on the behaviour and is quite well tolerated. section sign 2 Active drugs in the serotonine system. Clomipramine: after promising results, the medium-term efficiency has decreased and severe side effects have limited its use. Fluvoxamine, Fluoxetine, Sertraline (Specific serotonine drugs): Their efficiency has been mainly tested through open studies and their results are contrasted. In some cases, social behaviours have improved and aggressiveness and stereotyped behaviours have decreased. Fenfluramine: At present, this drug is removed from the market. Yet, some studies have suggested that it improves behavioural disturbances as well as performances in autism. section sign 3 Active drugs in the opiate system. Naltrexone: Several controlled studies have indicated an improvement in social and aggressive behaviours. Nevertheless, these studies have used small size sample and have not been replicated. Category II. This category correspond to drugs supposed to be active on neurochemical disturbances found in autism but their target symptoms are not autism specific signs as defined by the ICD 10. Buspirone: This serotonine agonist may have a good impact on emotional disorders and sleeping confusions. Methylphenidate: Most of the current studies about this noradrenergic drug concern children. The results are variable. Paradoxical effects may exist in children with severe mental retardation. Propanolol: Some isolated studies habe reported its efficiency on behavioural disturbances. Clonidine: This adrenergic drug treats efficiently some cases of aggressive behaviour and hyperactivity. Category III. This category contains a wide range of drugs, vitamins or method used in autism after sporadic observations of their positive effects. Secretine: An important improvement has been reported in isolated cases. However, controlled studies in children do not confirm these results. Vitamines B6, B12 and Magnesium: An improvement in socialization and in behavioural disorders have been reported in some cases, but these results are not yet confirmed. Lithium, Carbamazepine, Valproate: Results of some case studies have found it to be efficient in cyclic disorders. Gluten and casein free diet: An improvement of social behaviour have been reported by some parents after these diets. No controlled study has validated this observation. Conclusion - There is no consensus on the use of psychopharmacological treatments in autism. Although there exist many clinical observations, only few controlled studies have validated the efficiency and safety of these treatments. At the present time and until having sufficient studies, drugs are generally limited to severe disorders, for which usual psycho-educational approaches are insufficient.
Balachandran, K. P., D. Stewart, et al. (2002). "Chronic pericardial constriction linked to the antiparkinsonian dopamine agonist pergolide." Postgrad Med J 78(915): 49-50.
Constrictive pericarditis is present when a fibrotic, thickened, and adherent pericardium restricts diastolic filling of the heart. Several drugs can cause pericarditis, which can lead to chronic pericardial constriction. A case of constrictive pericarditis in a patient receiving the antiparkinsonian drug pergolide is reported.
Balfour, D. J. (2002). "The neurobiology of tobacco dependence: a commentary." Respiration 69(1): 7-11.
This commentary summarises the evidence that nicotine has the pharmacological properties of a psychostimulant drug of dependence. Behaviourally it serves as a reinforcer in self-administration experiments. Within the brain, acute nicotine stimulates the release of dopamine (DA) in the shell of the nucleus accumbens whereas repeated nicotine results in selective sensitization of its effects on DA overflow in the accumbal core. These effects are thought to play a central role in the acquisition of responding for nicotine and the development of associations between delivery of the drug and cues that predict its delivery. These responses, therefore, are thought to be pivotal to its ability to cause dependence. The commentary also emphasises the evidence that cigarette smoke provides a vehicle for nicotine that maximises its addictive potential since it delivers nicotine directly into the lungs and, within 10-15 s, to the brain. For habitual cigarette smokers, this process is repeated frequently and regularly and in the context of many other sensory cues within the smoke that potentially provide additional conditioned reinforcers. This, it is argued, explains the strong addiction that many smokers develop to tobacco smoke. Smoking cessation is also associated with the expression of an abstinence syndrome that can, largely, be attributed to nicotine withdrawal and is also likely to contribute to the maintenance of the habit. The commentary closes with a brief review of the pharmacological mechanisms that may contribute to the efficacy of nicotine replacement therapy and Zyban (bupropion) as aids to smoking cessation.
Balthazart, J., M. Baillien, et al. (2002). "Interactions between aromatase (estrogen synthase) and dopamine in the control of male sexual behavior in quail." Comp Biochem Physiol B Biochem Mol Biol 132(1): 37-55.
In male quail, like in other vertebrates including rodents, testosterone acting especially through its estrogenic metabolites is necessary for the activation of male sexual behavior. Also, the administration of dopamine agonists and antagonists profoundly influences male sexual behavior. How the steroid-sensitive neural network and dopamine interact physiologically, remains largely unknown. It is often implicitly assumed that testosterone or its metabolite estradiol, stimulates male sexual behavior via the modification of dopaminergic transmission. We have now identified in quail two possible ways in which dopamine could potentially affect sexual behavior by modulating the aromatization of testosterone into an estrogen. One is a long-acting mechanism that presumably involves the modification of dopaminergic transmission followed by the alteration of the genomic expression of aromatase. The other is a more rapid mechanism that does not appear to be dopamine receptor-mediated and may involve a direct interaction of dopamine with aromatase (possibly via substrate competition). We review here the experimental data supporting the existence of these controls of aromatase activity by dopamine and discuss the possible contribution of these controls to the activation of male sexual behavior.
Bandmann, O. and N. W. Wood (2002). "Dopa-responsive dystonia -- the story so far." Neuropediatrics 33(1): 1-5.
Dopa-responsive dystonia (DRD) is an eminently treatable condition and its recognition is therefore of crucial importance. In classical cases, the disease manifests in early childhood with walking problems due to dystonia of the lower limbs. The dystonia is frequently accompanied by "parkinsonian" features such as reduced facial expression or slowing of fine finger movements. Biochemically, the disorder is typically characterized by low levels of the neurotransmitter metabolite homovanillic acid and reduced levels of neopterin and tetrahydrobiopterin (BH4) in the cerebrospinal fluid. This is due to heterozygote mutations of the GTP cyclohydrolase I gene, which is the rate-limiting enzyme in the synthesis of BH4. BH4 is an essential co-factor for tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine. Reduced levels of BH4 lead to the dopamine-deficit syndrome DRD because of reduced TH activity. Other genes implicated in the pathogenesis of this disorder are the TH gene itself and the parkin gene. This article summarizes all relevant aspects of DRD including recent advances in the genetics of this disorder and the widening phenotype. Particular emphasis is given to clinically relevant aspects such as diagnostic difficulties and atypical presentations in infancy and early childhood.
Barrington, K. and L. P. Brion (2002). "Dopamine versus no treatment to prevent renal dysfunction in indomethacin-treated preterm newborn infants." Cochrane Database Syst Rev(3): CD003213.
BACKGROUND: Indomethacin therapy for closure of patent ductus arteriosus frequently causes oliguria, and occasionally more serious renal dysfunction. Low dose dopamine has been suggested as a means for preventing this side effect. OBJECTIVES: Primary objective: To determine whether dopamine therapy may prevent indomethacin-mediated deterioration in renal function in the preterm newborn infant without serious adverse effects. Secondary objective: To assess the effects of dopamine on the above variables in two subgroups: (1) patients given indomethacin as prophylaxis of intraventricular hemorrhage, and (2) patients given indomethacin as treatment of patent ductus arteriosus SEARCH STRATEGY: Standard methods of the Cochrane Neonatal Review Group (CNRG) were used. We searched MEDLINE (1966-2001) using PubMed as the search engine, EMBASE (1974-2001) and the Cochrane Controlled Trials Register (CCTR) from the Cochrane Library (Issue 3, 2001). In addition we contacted the principal investigators if necessary to ascertain the required information. SELECTION CRITERIA: Randomized or quasi-randomized studies of the effects of dopamine on urine output, glomerular filtration rate, fluid balance or incidence of renal failure, in preterm newborn infants receiving indomethacin. The comparison group should have received no dopamine. DATA COLLECTION AND ANALYSIS: We used the standard methods of the Cochrane Collaboration and those of the CNRG. The primary outcomes of interest were: mortality before discharge; intraventricular hemorrhage, grade three or four; cystic periventricular leukomalacia; renal failure (either oliguria, defined as a urine output less than 1 ml/kg/hour or an elevation in creatinine by more than 40 micromoles/L); failure to close the ductus arteriosus; need for surgical PDA ligation. For categorical outcomes, we calculated typical estimates for relative risk and risk difference. For continuous outcomes the weighted mean difference (WMD) was calculated. Fixed effect models were assumed for meta-analysis. MAIN RESULTS: Three studies were found (total number randomized patients, 75) which fulfilled the entry criteria for this review. All were single center trials which enrolled NICU patients receiving indomethacin for symptomatic patent ductus arteriosus. There are no (or only partial) results for effects of dopamine on several of the primary outcomes, including death before discharge, serious intraventricular hemorrhage, cystic periventricular leukomalacia, or renal failure. There has been inadequate investigation of the effects of dopamine on cerebral perfusion or cardiac output, or GI complications, or endocrine toxicity. Dopamine improved urine output [WMD 0.68 ml/kg/hour (95% CI 0.22, 1.44)], but there was no evidence of effect on serum creatinine (WMD 2.04 micromoles/liter, CI -17.90, 21.97) or the incidence of oliguria (urine output < 1 ml/kg/hour) (RR 0.73, CI 0.35, 1.54). There was no evidence of effect of dopamine on the frequency of failure to close the ductus arteriosus (RR 1.11, CI 0.56, 2.19). REVIEWER'S CONCLUSIONS: There is no evidence from randomized trials to support the use of dopamine to prevent renal dysfunction in indomethacin-treated preterm infants.
Becker, G., M. Kocher, et al. (2002). "Radiation therapy in the multimodal treatment approach of pituitary adenoma." Strahlenther Onkol 178(4): 173-86.
BACKGROUND: Pituitary tumors are relatively uncommon, comprising 10-12% of all intracranial tumors. The treatment consisting of surgery, radiotherapy and drug therapy or a combination of these modalities is aimed at the control of tumor cell proliferation and--in endocrine active tumors--the reduction of hormone secretion. However, the slow proliferation characteristics of pituitary tumors necessitate long-term studies for the evaluation of the treatment results. In the last decade there has been continuous improvement in surgical procedures, radiotherapy techniques and drug generation. In this paper, literature will be reviewed to assess the role of modern radiotherapy and radiosurgery in the management of pituitary adenomas. MATERIAL AND METHODS: Nowadays, magnetic resonance imaging for the definition of the target volume and a real three-dimensional (3-D) treatment planning with field conformation and the possibility for non-coplanar irradiation has to be recommended. Most groups irradiate these benign tumors with single doses of 1.8-2.0 Gy up to a total dose of 45 Gy or 50.4 Gy in extensive parasellar adenomas. Adenomas are mostly small, well circumscribed lesions, and have, therefore, attracted the use of stereotactically guided high-precision irradiation techniques which allow extreme focussing and provide steep dose gradients with selective treatment of the target and optimal protection of the surrounding brain tissue. RESULTS: Radiation therapy controls tumor growth in 80-98% of patients with non-secreting adenomas and 67-89% for endocrine active tumors. Reviewing the recent literature including endocrine active and non-secreting adenomas, irradiated postoperatively or in case of recurrence the 5-, 10- and 15-year local control rates amount 92%, 89% and 79%. In cases of microprolactinoma primary therapy consists of dopamine agonists. Irradiation should be preferred in patients with macroprolactinomas, when drug therapy and/or surgery failed or for patients medically unsuitable for surgery. Reduction and control of prolactin secretion can be achieved in 44-70% of patients. After radiotherapy in acromegaly patients somatomedin-C and growth hormone concentrations decrease to normal levels in 70-90%, with a decrease rate of 10-30% per year. Hypercortisolism is controlled in 50-83% of adults and 80% of children with Cushing's disease, generally in less than 9 months. Hypopituitarism is the most common side effect of pituitary irradiation with an incidence of 13-56%. Long-term overall risk for brain necrosis in a total of 1,388 analyzed patients was estimated to be 0.2%. Other side effects are rare too, and do also depend on the damage produced by tumor itself or preceding surgery. They include deterioration of vision in 1.7% of all cases, vascular changes in 6.3%, neuropsychological disorders such as dementia in 0.7% and secondary malignancies in 0.8%, if single doses of 2.0 Gy and total doses of 50 Gy are not exceeded. CONCLUSION: Conventional radiation therapy of pituitary adenoma is highly effective. It is recommended after subtotal resection of primary tumors such as macroadenomas, after gross total resection from endocrine active adenomas with postsurgical hormone secretion and for recurrent tumors. Radiosurgery seems to be a possible treatment alternative in experienced centers, and only in patients with adenomas smaller than 25-30 mm with a minimum distance of 2-3 mm to the chiasm.
Beckers, A., H. Valdes-Socin, et al. (2002). "[Differential diagnosis and medical treatment in Cushing's disease]." Neurochirurgie 48(2-3 Pt 2): 163-72.
Cushing's disease remains a difficult diagnosis in spite of new technical procedures such as pituitary MRI, selective bilateral petrosal or cavernous sampling, (111)In pentreotide scan and 18 Flurodeoxyglucose pituitary PET scan. In this article, we review biological diagnostic procedures of Cushing's disease and corticotroph adenomas. According to our experience and the literature, we summarize the approach in medical treatment of Cushing's disease.
Ben-Shachar, D. (2002). "Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine." J Neurochem 83(6): 1241-51.
Mitochondria are not only the principal source of high energy intermediates, but play an important role in intracellular calcium buffering, are main producers of reactive oxygen species, and are the source of pro- and antiapoptotic key factors. Moreover, the mitochondria are of a ubiquitous nature and the respiratory chain has a dual genetic basis, i.e. the mitochondrial and the nuclear DNAs. Thus mitochondrial impairment could provide an explanation for the tremendous heterogeneity of clinical and pathological manifestations in schizophrenia. This article reviews several independent lines of evidence that suggest an involvement of mitochondrial dysfunction in schizophrenia. Among them are altered cerebral energy metabolism, mitochondrial hypoplasia, dysfunction of the oxidative phosphorylation system and altered mitochondrial related gene expression. In addition, the interaction between dopamine, a predominant etiological factor in schizophrenia, and mitochondrial respiration is considered as a possible mechanism underlying the hyper- and hypo-activity cycling in schizophrenia. Understanding the role of mitochondria in schizophrenia may encourage novel treatment approaches, the identification of candidate genes and new insights into the pathophysiology and etiology of the disorder.
Bergman, H. and G. Deuschl (2002). "Pathophysiology of Parkinson's disease: from clinical neurology to basic neuroscience and back." Mov Disord 17 Suppl 3: S28-40.
Parkinson's disease (PD) is characterized by motor and nonmotor (cognitive and limbic) deficits. The motor signs of PD include hypokinetic signs such as akinesia/bradykinesia, rigidity and loss of normal postural reflexes, and hyperkinetic signs such as tremor. Dopamine depletion in the striatum is the hallmark of PD and of its animal models, still the pathophysiology of the parkinsonian symptoms and especially of parkinsonian tremor are under debate. The most extreme hypotheses argue about peripheral versus central nervous system origin, intrinsic cellular oscillator versus network oscillators, and basal ganglia-based pathophysiology versus cerebellar-thalamic based pathophysiology. Recent studies support the view that parkinsonian symptoms are most likely due to abnormal synchronous oscillating neuronal activity within the basal ganglia. Peripheral factors do only play a minor role for the generation, maintenance, and modulation of PD tremor and other signs. The most likely candidates producing these neuronal oscillations are the weakly coupled neural networks of the basal ganglia-thalamo-cortical loops. However, the present evidence supports the view that the basal ganglia loops are influenced by other neuronal structures and systems and that the tuning of these loops by cerebello-thalamic mechanisms and by other modulator neurotransmitter systems entrain the abnormal synchronized oscillations. Neurosurgical procedures, such as lesions or high-frequency stimulation of different parts of the loop, might resume the normal unsynchronized activity of the basal ganglia circuitry, and, therefore, ameliorate the clinical symptoms of Parkinson's disease.
Betarbet, R., T. B. Sherer, et al. (2002). "Animal models of Parkinson's disease." Bioessays 24(4): 308-18.
Animal models are important tools in experimental medical science to better understand pathogenesis of human diseases. Once developed, these models can be exploited to test therapeutic approaches for treating functional disturbances observed in the disease of interest. On the basis of experimental and clinical findings, Parkinson's disease (PD) was the first neurological disease to be modeled and, subsequently, to be treated by neurotransmitter replacement therapy. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine have been used to develop PD models. Recently, it has been found that agricultural chemicals, such as rotenone and paraquat, when administered systemically, can reproduce specific features of PD in rodents, apparently via oxidative damage. Transgenic animals that over-express alpha-synuclein are used to study the role of this protein in dopaminergic degeneration. This review critically discusses animal models of PD and compares them with characteristics of the human disease.
Beyer, C., T. Ivanova, et al. (2002). "Cell type-specificity of nonclassical estrogen signaling in the developing midbrain." J Steroid Biochem Mol Biol 81(4-5): 319-25.
Estrogens have widespread biological functions in the CNS involving the coordination of developmental processes, the regulation of cell physiology, and the control of neuroendocrine systems. In the midbrain, estrogens promote the survival, maturation, and function of neurons and, in particular, of dopamine cells. Aside from classical signaling through nuclear estrogen receptors, we have provided evidence that cellular transmission of estrogen effects in the midbrain comprises a complex intracellular signaling scenario. The major conclusion drawn from our studies is that estrogens interact with yet unidentified membrane receptor complexes which stimulate the phospholipase C and induce the formation of inosite-tri-phosphate (IP(3)). This causes a rapid and transitory rise in intracellular free calcium. The modulation of calcium homeostasis is the primary nonclassical physiological response to estrogens in all cell types. Surprisingly, a different secondary downstream signaling cascade seems to be activated in each estrogen-responsive cell population, i.e. phosphatidylinositol-3 kinase (PI3-kinase) in GABAergic and cAMP/ protein kinase A (PKA) in dopaminergic neurons, mitogen-activated protein kinase (MAP-kinase) in astrocytes. The precise biological role of estrogens for the different cell types is still fragmentary. We assume that estrogens positively influence intracellular signaling mechanisms which are important for cell differentiation and survival. It remains to be elucidated what determines the cell type-specificity of these estrogen responses.
Biglan, K. M. and R. G. Holloway (2002). "A review of pramipexole and its clinical utility in Parkinson's disease." Expert Opin Pharmacother 3(2): 197-210.
Parkinson's disease (PD) is a common neurodegenerative disorder characterised by selective loss of dopaminergic neurones in the substantia nigra and resulting in progressive disability. Therapy has focused on replacing depleted dopamine (DA) via supplementation with levodopa or DA agonists. Pramipexole (Mirapex), Pharmacia Corp.) has recently been approved for the treatment of PD. Evidence from preclinical studies and clinical trials have proven the effectiveness of this agent in ameliorating the symptoms of PD. There is also non-human evidence that pramipexole may be neuroprotective and could therefore possibly slow disease progression; however, this has yet to be proven in humans. The use of pramipexole may be limited by its side effect profile compared to standard therapies and its relatively higher cost compared to levodopa. Despite these concerns, pramipexole does have a role in the treatment of PD in all stages of the illness and may arguably be the treatment of choice in early disease. In addition to its use in PD, pramipexole has shown some utility in the treatment of restless legs syndrome (RLS), depression and schizophrenia.
Bjorklund, L. M. and O. Isacson (2002). "Regulation of dopamine cell type and transmitter function in fetal and stem cell transplantation for Parkinson's disease." Prog Brain Res 138: 411-20.
Blain, I., P. Slama, et al. (2002). "Copper-containing monooxygenases: enzymatic and biomimetic studies of the O-atom transfer catalysis." J Biotechnol 90(2): 95-112.
This review reports our recent studies or the mechanism of O-atom transfer to a benzylic C-H bond promoted by Dopamine beta-Hydroxylase (DBH) and its biomimetic models. We demonstrate that it is possible to carry out parallel and comparative studies on this enzyme (DBH) and its biomimetic models with the same substrate: 2-aminoindane (3). It was chosen because its two stereogenic centers, both in benzylic positions, make it very powerful for studying the stereochemistry of an O-atom transfer reaction. DBH-catalyzed hydroxylation of 3 produced exclusively 14% of trans-(1S,2S)-2-amino-1-indanol (4) (93% ee). Studies with stereospecifically deuterium-labeled 2-aminoindanes (1R,2S)-3b and (1S,2S)-3a showed that the formation of 4 was the rcsult of an overall process with retention of configuration where an O-atom is stereospecifically inserted in the trans pro-S position of the substrate. With copper(I) and (II) complexes of IndPY2 ligands we studied the reaction with dioxygen and observed an O-atom transfer to a benzylic C-H bond which was performed in the same manner as that of DBH. With the deuterium-labeled cis-2-d-IndPY2 ligand, we demonstrated that the reaction occurs by a stereospecific process with retention of configuration. In both cases (enzymatic vs. biomimetic) the O-atom transfers occur in a two-step process involving radical intermediates.
Blankenberg, F. G. and H. W. Strauss (2002). "Nuclear medicine applications in molecular imaging." J Magn Reson Imaging 16(4): 352-61.
With the emergence of the new field of molecular imaging, there is an increasing demand for development of sensitive and safe novel imaging agents that can be rapidly translated from small animal models into patients. Nuclear medicine and positron emission tomography (PET) techniques have the ability to detect and serially monitor a variety of biologic and pathophysiologic processes, usually with tracer quantities of radiolabeled peptides, drugs, and other molecules at doses free of pharmacologic side effects, unlike the current generation of intravenous agents required for magnetic resonance (MR) and computed tomography (CT) scanning. In this article, we will review a representative sampling of the wide array of radiopharmaceuticals developed specifically for nuclear medicine radionuclide imaging that have been approved for clinical use, and those in pre-clinical trials. We will also review the existing strategies used to select the appropriate biologic markers and targets for radionuclide labeling that have been employed in the development of novel radiotracers and the imaging of small animals with new microSPECT (single photon emission computed tomography) technologies.
Blount, P. J., C. D. Nguyen, et al. (2002). "Clinical use of cholinomimetic agents: a review." J Head Trauma Rehabil 17(4): 314-21.
BACKGROUND: There are many agents in clinical use that manipulate central nervous system levels of epinephrine, dopamine, and serotonin. However, development of pharmacological options to manipulate central acetylcholine systems has lagged behind because of poor penetration of the blood-brain barrier and significant peripheral nervous system side effects. Newer agents have demonstrated some efficacy in the management of behavioral and cognitive side effects in Alzheimer's disease, and preliminary data in traumatic brain injury suggest acetylcholine esterase inhibitors may play a significant role in the treatment of this patient population as well. CONCLUSIONS: In this article, the basic neuroanatomy and pharmacology of the central acetylcholine system are reviewed, along with agents currently available for clinical use.
Bonuccelli, U., A. Colzi, et al. (2002). "Pergolide in the treatment of patients with early and advanced Parkinson's disease." Clin Neuropharmacol 25(1): 1-10.
Introduced on the market in 1989, pergolide, a D1/D2 dopamine receptor agonist, is still widely prescribed for the treatment of patients with early and advanced Parkinson's disease (PD). Initially, pergolide was introduced as an adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor responses and dyskinesias. Results of recent randomized controlled clinical trials in de novo patients with PD show that pergolide is able to improve parkinsonian symptoms when used as monotherapy. Moreover, preliminary results of a long-term monotherapy study in early PD suggest that pergolide is as effective as levodopa, and that a significant delay in the time of the onset of levodopa-induced motor complications can be obtained. A number of randomized studies have shown that pergolide is more effective than bromocriptine as adjunct therapy to levodopa in patients with advanced PD; the greater benefit found with pergolide could be ascribed to its action on both D1 and D2 dopamine receptors. However, controlled comparative studies with new dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not been performed yet. Interestingly, few open studies in patients with complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to improve motor fluctuations and dyskinesias through a dramatic reduction of levodopa dosage. The side-effect profile of pergolide is similar to that of other dopamine agonists, and complications such as sleep attack and serosal fibrosis have been rarely reported.
Boraud, T., E. Bezard, et al. (2002). "From single extracellular unit recording in experimental and human Parkinsonism to the development of a functional concept of the role played by the basal ganglia in motor control." Prog Neurobiol 66(4): 265-83.
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects the whole basal ganglia (BG). Various techniques have been used to study BG physiology and pathophysiology. Among these, extracellular single unit recording remains of particular importance. An impressive number of studies of BG electrophysiological activity have been carried out, both in non-human and in human primates, but the data collected show many omissions and disparities. BG activity has been well defined in the physiological situation, but remains far from clear in the Parkinsonian and virtually unexplored in the dopamine (DA)-replacement situation. This paper provides a brief synopsis of (i) recording techniques and (ii) BG electrophysiological activity in normal, Parkinsonian, and dopamine-replacement situations. We have restricted the data used to those obtained in BG structures of human and non-human primates. Only single unit recordings have been reported and four electrophysiological characteristics retained: mean firing frequency, firing pattern, periodic oscillation, and response to both passive and active movement. We have attempted to summarize (i) the commonly accepted characteristics of each BG structure in the three situations, (ii) discrepancies that exist, and (iii) missing elements. Then, the main successive theories aimed to explain the role played by BG in motor control are presented and discussed in the light of the most recently obtained results using the latest technological advances.
Borsini, F., K. Evans, et al. (2002). "Pharmacology of flibanserin." CNS Drug Rev 8(2): 117-42.
Flibanserin has preferential affinity for serotonin 5-HT(1A), dopamine D(4k), and serotonin 5-HT(2A) receptors. In vitro and in microiontophoresis, flibanserin behaves as a 5-HT(1A) agonist, a very weak partial agonist on dopamine D(4) receptors, and a 5-HT(2A) antagonist. In vivo flibanserin binds equally to 5-HT(1A) and 5-HT(2A) receptors. However, under higher levels of brain 5-HT (i.e., under stress), flibanserin may occupy 5-HT(2A) receptors in higher proportion than 5-HT(1A) receptors. The effects of flibanserin on adenylyl cyclase are different from those of buspirone and 8-OH-DPAT, two other purported 5-HT(1A) receptor agonists. Flibanserin reduces neuronal firing rate in cells of the dorsal raphe, hippocampus, and cortex with the CA1 region being the most sensitive in the brain. Flibanserin-induced reduction in firing rate in the cortex seems to be mediated through stimulation of postsynaptic 5-HT(1A) receptors, whereas the reduction of the number of active cells seems to be mediated through dopamine D(4) receptor stimulation. Flibanserin quickly desensitizes somatic 5-HT autoreceptors in the dorsal raphe and enhances tonic activation of postsynaptic 5-HT(1A) receptors in the CA3 region. Flibanserin preferentially reduces synthesis and extracellular levels of 5-HT in the cortex, where it enhances extracellular levels of NE and DA. Flibanserin displays antidepressant-like activity in most animal models sensitive to antidepressants. Such activity, however, seems qualitatively different from that exerted by other antidepressants. Flibanserin seems to act via direct or indirect stimulation of 5-HT(1A), DA, and opioid receptors in those animal models. Flibanserin does not display consistent effects in animal models of anxiety and seems to exert potential antipsychotic effects. Flibanserin may induce some sedation but does not induce observable toxic effects at pharmacologically relevant doses.
Bourin, M., D. J. David, et al. (2002). "[Mechanism of action of antidepressants and therapeutic perspectives]." Therapie 57(4): 385-96.
Depression is an incapacitating disease which needs appropriate treatment. This article reviews the pharmacology of antidepressant drugs and the future perspectives of treating mood disorders such as depression. The foremost theory for explaining the biological basis of depression has been the monoamine hypothesis. Depression is due to a deficiency in one or other biogenic monoamines (serotonin, 5-HT; noradrenaline, NA; dopamine, DA). Antidepressant drugs are therefore classified according to their ability to improve monoaminergic transmission. Since this first theory, other explanations based on abnormal function of monoamine receptors or associated with impaired signalling pathways have been suggested. Notable progress has been accomplished in the treatment of major depressive disorders with new compounds recently discovered (selective serotonin reuptake inhibitors: SSRI; serotonin noradrenaline reuptake inhibitors: SNRI). Behavioural, electrophysiological and microdialysis studies have shown that serotonin (5-HT) receptors, mainly 5-HT1A, 5-HT1B and 5-HT2C sub-types, exert a key role in modulating antidepressant activity. Indirect activation of neurotransmitter receptors by antidepressants may also lead, via increases in endogenous levels of serotonin in synapses in specific brain regions, to activation of various G proteins coupled to a receptor, signal of transduction, transcription factors and neurotrophic factors such as brain-derived neurotrophic factor (BDNF). Thus, depression may be considered as a transduction mechanism anomaly. This hypothesis needs to be clarified by molecular biology. Although antidepressants have improved the therapeutic potential compared to tricyclics (TCA) in terms of reduced side effects, a number of problems still occur with these drugs. Clinical effects are not always observed until after this time has elapsed (4-6 weeks) and a substantial proportion of depressed patients show only partial or no response to antidepressants. Knowledge of the existence of links between neurotransmitter systems and the discovery of the most specific target, 5-HT receptors, should lead to improvements in antidepressant therapy. Developing drugs using innovative mechanisms such as directly acting on 5-HT receptors (5-HT1A agonists or 5-HT2 antagonists), would appear to be useful in the treatment of depression. The use of antidepressants in anxiety disorders such as obsessional compulsive disorders and even generalised anxiety, highlights the distinction between antidepressants and classic anxiolytics such as benzodiazepines, or even buspirone.
Bradberry, C. W. (2002). "Dynamics of extracellular dopamine in the acute and chronic actions of cocaine." Neuroscientist 8(4): 315-22.
Cocaine amplifies dopaminergic neurotransmission via blockade of presynaptic neuronal uptake. This action is believed to be a crucial component of cocaine's ability to exert its reinforcing effects. This review will provide a brief overview of extracellular dopamine dynamics associated with cocaine. The acute effects of cocaine reviewed include comparison of intravenous and intraperitoneal routes of administration to better understand how fast and slow routes (e.g., crack and intranasal) differ in their pharmacokinetics and neurochemical effects and how those differences relate to differences in abuse potential. Changes in the acute effects of cocaine within a session have been examined in neurochemical studies of acute tolerance to self-administered cocaine in rhesus monkeys, and the potential impact of that tolerance to patterns of use is discussed. Between-session sensitization of the dopaminergic response to cocaine is reviewed, and data indicating this also occurs in primates have been obtained in self-administering rhesus monkeys, demonstrating neurochemical sensitization in a primate species. The important question of whether cocaine-associated environmental cues elicit conditioned increases in dopamine release has also been examined in the rhesus monkey, with results indicating that, unlike rats, nonhuman primates do not show conditioned increases in dopamine release.
Braus, D. F. (2002). "[Temporal perception and organisation, neuronal synchronisation and schizophrenia]." Fortschr Neurol Psychiatr 70(11): 591-600.
Basic perceptual or motor skills involving the central nervous system as well as the subjective present require the orderly temporal organization of internal and external information. Current research in schizophrenia increasingly centers on the accompanying neurocognitive deficits with frequent reports of altered temporal processes. There has been, however, less explicit research on the basic phenomenon of temporal order. Using concrete operationalized neuropsychological procedures the present study addressed the question whether chronic schizophrenic patients (28 medicated as well as 7 unmedicated) differ in their ability to correctly judge the temporal order of visual or acoustic stimuli when compared with a healthy control group (n = 26). Within this context we found a significant impairment in basal temporal perception among patients. Moderating variables such as medication, attention deficits or the effects of motivation as an essential explanatory factor for this finding could be excluded by statistical analysis. Instead, our findings point to a fundamental disturbance in the temporal coordination of neuronal network functions in association with schizophrenic psychoses. Within this context neurophysiological, neurochemical, neuroanatomical and neuropsychological overlapping of schizophrenia and temporal perception are being presented along with a discussion of the hypothesis that disturbances in neuronal synchronization and in timing processes at different levels are of essence and a possible underlying substrate in the schizophrenic spectrum.
Braver, T. S. and D. M. Barch (2002). "A theory of cognitive control, aging cognition, and neuromodulation." Neurosci Biobehav Rev 26(7): 809-17.
A theory is described which links cognitive changes observed in normal aging to an underlying decline in the function of the dopamine (DA) system projection to prefrontal cortex (PFC). The theory postulates that this neural mechanism is integral to the representation, maintenance and updating of context information, and as such impacts cognitive control across a wide range of cognitive domains, including working memory, attention, and inhibition. Behavioral and brain imaging data in support of the theory are discussed, which demonstrate selective impairments in context processing among healthy older adults associated with abnormal PFC activation. These findings highlight the utility of a computational approach to cognitive aging. Current directions for further refinement and validation of the model are outlined.
Breese, G. R., D. J. Knapp, et al. (2002). "Integrative role for serotonergic and glutamatergic receptor mechanisms in the action of NMDA antagonists: potential relationships to antipsychotic drug actions on NMDA antagonist responsiveness." Neurosci Biobehav Rev 26(4): 441-55.
NMDA receptor antagonists worsen symptoms in schizophrenia and induce schizophrenic-like symptoms in normal individuals. In animals, NMDA antagonist-induced behavioral responses include increased activity, head weaving, deficits in paired pulse inhibition and social interaction, and increased forced swim immobility. Repeated exposure to NMDA antagonists in animals results in behavioral sensitization-a phenomenon accentuated in rats with dopaminergic neurons lesioned during development. In keeping with an involvement of serotonin and glutamate release in NMDA antagonist action, selected behaviors induced by NMDA antagonists are minimized by 5-HT(2A) receptor antagonists and mGLU2 receptor agonists. These observations provide promising new approaches for treating acute NMDA antagonist-induced psychosis. Further, acute atypical antipsychotic drugs also minimize NMDA antagonist actions to a greater degree than typical antipsychotics. However, because knowledge concerning acute versus chronic effectiveness of various antipsychotic drugs against NMDA antagonist neuropathology is limited, future studies to define more fully the basis of their differences in efficacy after chronic treatment could provide an understanding of their actions on neural mechanisms responsible for the core pathogenesis of schizophrenia.
Bullock, R. and S. Libretto (2002). "Risperidone in the treatment of psychoses in the elderly: a case report series." Eur Psychiatry 17(2): 96-103.
Risperidone is one of the newer atypical antipsychotic agents, which combines potent serotonin and dopamine receptor antagonism. It shows efficacy against the positive and negative symptoms of schizophrenic psychoses and other psychotic conditions, and has a low propensity to cause extrapyramidal side effects. The aim of these case reports in elderly patients is to provide the benefit of personal experience with risperidone to the body of published literature and to demonstrate the types of patients that may benefit from treatment. These cases were compiled retrospectively from data collected on referral and during routine hospital appointments. This series covers four main areas of concern when treating the elderly: low-maintenance dosing minimising the likelihood of adverse events; successful treatment of patients previously uncontrolled and experiencing side effects with other antipsychotics; the possibility of intermittent rather than continuous treatment; and the benefits to patients, carers and the health services. At low doses, risperidone is an effective and well-tolerated treatment for psychoses in elderly patients that improves the quality of life for both patients and their caregivers.
Burckhardt, G., F. Di Sole, et al. (2002). "The Na+/H+ exchanger gene family." J Nephrol 15 Suppl 5: S3-21.
Na+/H+ exchangers (NHEs) extrude protons from, and take up sodium ions into cells. Six isoforms, NHE-1 - NHE-6, have been cloned. NHE proteins are composed of an N-terminal domain, which most likely crosses the cell membrane 12 times and constitutes the cation exchange machinery, and a C-terminal tail, which modulates the exchanger by interacting with protein kinases and regulatory factors. The "house-keeping" NHE-1 is located at the basolateral membrane of most renal tubule cells; NHE-2 is located apically in selected nephron segments. As suggested from data with NHE-1 and NHE-2 deficient mice, both isoforms play a minor role in renal salt and water handling. NHE-3 is located at the apical membrane of proximal tubule and thick ascending limb cells, is involved in Na+ absorption, and is responsible for the majority of bicarbonate absorption. NHE-3 is modulated by the NHE regulating factor, which interacts with further proteins, protein kinases, and the cytoskeleton. Downregulation of NHE-3 by parathyroid hormone, dopamine, and by an increase in blood pressure leads to saluresis/diuresis. The failure of dopamine to downregulate NHE-3 may cause hypertension through renal salt and water retention. NHE-3 knockouts are hypotonic and can not survive on low salt diet. In chronic acidosis, NHE-3 is upregulated possibly through increased local endothelin production. NHE4 has been found mostly in renal medulla. The precise function of this isoform, which is activated by hypertonicity and can perform K+/H+ exchange, is not clear. The segmental location and function of NHE-5 and NHE-6 in the kidney are unknown at present.
Bymaster, F. P. and C. C. Felder (2002). "Role of the cholinergic muscarinic system in bipolar disorder and related mechanism of action of antipsychotic agents." Mol Psychiatry 7 Suppl 1: S57-63.
The evidence for the involvement of cholinergic muscarinic receptors in mania and depression is reviewed. Small pilot trials with cholinesterase inhibitors and muscarinic agonists suggest that stimulation of muscarinic receptors may produce an antimanic effect, possibly by activation of muscarinic M(4) receptors. It is concluded that it is not likely that currently used mood stabilizers, such as lithium, valproic acid and carbamazepine, work directly through muscarinic receptor mechanisms. Furthermore, the evidence indicates that antipsychotic agents used for mania are working through the common mechanism of antagonism of dopamine D(2) receptors, and interactions with muscarinic receptors do not play a key role. Finally, it is hypothesized that olanzapine has robust antimanic activity, due to blockade of dopamine D(2) receptors and antagonism of other monoaminergic receptors. Olanzapine may normalize mood due to antidepressant-like activities, such as 5-HT(2A) receptor antagonism and increasing cortical norepinephrine and dopamine.
Cabib, S., S. Puglisi-Allegra, et al. (2002). "The contribution of comparative studies in inbred strains of mice to the understanding of the hyperactive phenotype." Behav Brain Res 130(1-2): 103-9.
Attention-deficit hyperactivity disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity and impulsivity. Converging evidence, suggests a primary role of disturbances in brain dopamine (DA) transmission and a role of genetic factors in its pathology. Inbred provide a well-defined and stable genotype for analysis. C57BL/6 (C57) and DBA/2 (DBA) mice are amongst the most studied inbred strains in the behavioral pharmacology of DA, and they differ in several parameters of the DA system that relate directly to behavioral differences. These strains also exhibit several qualitatively different behavior patterns that rely on separate DA networks (e.g. mesoaccumbens vs. nigrostriatal) and on different modes of inheritance. C57 mice are good learners in most tasks also involving associative learning but are totally unable to learn active avoidance although being very active. Moreover, C57 mice show greater novelty-induced locomotor activity than DBA, which is modulated strongly by DA neurons in the ventral tegmental area (VTA) region. Pharmacological studies also indicate a facilitated mesoaccumbens DA transmission in C57 mice when compared to DBAs. Increased density of D2 autoreceptors located on VTA neurons, and lower D2 postsynaptic receptors in the NAS were observed in DBA relative to C57. Activation of D2 autoreceptors inhibits impluse flow, synthesis, and release rates of DA neurons. As would be predicted from their higher D2 autoreceptor: DBA compared to C57 mice show reduced DA synthesis and release within the mesoaccumbens DA system when challenged with DA direct agonists. However, DBA mice are by fare more susceptible than C57s to stress-induced enhanced mesoaccumbens DA release and in stressful situation, they show sustained active behavioral responses whilst C57 adopt extremely passive responses (behavioral despair). Finally, chronic or repeated stress promote opposite adaptation of VTA DA autoreceptors in the two strains and render the hypoactive DBAs as active as the C57 mice. These results indicate that a complex interaction between genetic and environmental factors controls, mesoaccumbens DA functioning and hyperactive phenotype.
Caley, C. F. and C. K. Cooper (2002). "Ziprasidone: the fifth atypical antipsychotic." Ann Pharmacother 36(5): 839-51.
OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of ziprasidone as a treatment for schizophrenia. DATA SOURCES: Information was selected from a MEDLINE search (July 2000-October 2001) of English-language medical literature using ziprasidone as the search term. Manual searches of pertinent journal article references, request for medical information from Pfizer, and access of the Web site of the Food and Drug Administration were also performed. STUDY SELECTION: All available published information regarding the pertinent characteristics of ziprasidone were considered for selection. DATA EXTRACTION: Pharmacology and pharmacokinetic studies were selected to provide a comprehensive description of these characteristics. Clinical investigations were evaluated for design, sample size, diagnosis, duration, and outcome. Data from all investigations were selected by 1 author and reviewed by both authors. DATA SYNTHESIS: Ziprasidone is a benzisothiazolyl piperazine-type atypical antipsychotic that shares the serotonin(2A)/dopamine(2) (5-HT(2A)/D(2)) profile of the available atypical antipsychotics. Ziprasidone has demonstrated in vitro activity as a 5-HT(1A) receptor agonist and as a very weak inhibitor of serotonin and norepinephrine reuptake. These data do not support ziprasidone as being a clinically meaningful inhibitor of serotonin/norepinephrine reuptake. Oral bioavailability of ziprasidone taken with food is approximately 60%, half-life is approximately 6-7 hours, and protein binding is extensive at >99%. Twelve metabolites have been identified, yet only 4 of these are considered to be primary metabolites. Metabolism of ziprasidone by aldehyde oxidase produces its only metabolite with potential pharmacologic activity; CYP3A4 also contributes to the metabolism of ziprasidone. Clinical studies support ziprasidone as efficacious for the treatment of patients with acute exacerbations of schizophrenia or schizoaffective disorder. Daily doses permitted in these clinical trials ranged from 40 to 160 mg, but only doses between 120 and 160 mg/d have been superior to placebo. Future research efforts should be directed toward refractory schizophrenia, cognitive impairment in schizophrenia, affective and anxiety symptoms associated with schizoaffective disorder, and bipolar disorder. Adverse effect characteristics of ziprasidone commonly include headache, nausea, and somnolence; infrequent effects include extrapyramidal symptoms and weight gain. Ziprasidone has been reported to cause an average QTc prolongation of approximately 20 msec; there have only been 2 patients (0.06%) reported by the manufacturer to have a measured QTc interval >500 msec. CONCLUSIONS: Ziprasidone is a safe and efficacious atypical antipsychotic for the acute management of schizophrenia. Efficacy data and most safety data for ziprasidone support its use as a first-line treatment for schizophrenia; however, its potential effects on ventricular repolarization relegate it to second-line status in patients with comorbid cardiovascular risks.
Candito, M., E. Billaud, et al. (2002). "[Biochemical diagnosis of pheochromocytoma and neuroblastomas]." Ann Biol Clin (Paris) 60(1): 15-36.
Pheochromocytoma and neuroblastoma are distinct tumours, but their biological diagnosis is based on secretion increase of one or several catecholamines. Assays have to be very sensible and specific for an early diagnosis. 24 hours urinary catecholamines and metabolites are currently measured, but technical improvements permit plasma metanephrine assay, an excellent indicator of pheochromocytoma. HPLC coupled to electrochemical detection represents the most efficient methodology. After a review of urinary and plasma assay methods, the authors show usual values of catecholamines, metanephrines, HVA and VMA, according to ages, and give examples of results encountered in classical or not tumours and in falsely positive cases. Urinary metanephrine assay is the most sensible and specific in biological diagnosis of pheochromocytoma, while catecholamines and VMA assays lack of sensibility. Results have to be given by 24 hours and by creatinine ratio. Metanephrine assay can be performed also in plasma and exhibits the same interest. However, in urine as in plasma, in case of renal failure, results cannot be interpreted. Neuroblastoma biological diagnosis is based classically on HVA, VMA, and dopamine assays, nowadays only in 24 hours urine (or in urinary micturition for screening), and results are also expressed as creatinine ratio. But even if several assays are advisable, 5% of the neuroblastoma cases do not produce increased catecholamine values. In some cases, metanephrine assay could be of interest. After the age of 12 months, clinical expression of neuroblastoma is dramatic in 70% of cases. So, a biological screening has been experimented in several countries including France. A French translation of the consensus conference report (1998) is appended, which shows the complexity of neuroblastoma screening. Now, there is no evidence that early tumour detection by screening lessens the mortality rate, but a weak benefit is not excluded.
Cantello, R., R. Tarletti, et al. (2002). "Transcranial magnetic stimulation and Parkinson's disease." Brain Res Brain Res Rev 38(3): 309-27.
While motor cortical areas are the main targets of the integrative activity of basal ganglia, their main output consists of the corticospinal system. Transcranial magnetic stimulation (TMS), a relatively new method to investigate corticospinal physiology, has been widely used to assess possible changes secondary to Parkinson's disease (PD). The use of single- and paired-pulse TMS, two varieties of the original technique, disclosed multiple functional alterations of the corticospinal pathway. For instance, when the latter was tested at 'rest', or in response to somesthetic afferents, it showed excess excitability or reduced inhibition. In turn, during production of a voluntary output, its activation was defective, or inadequately modulated. One major mechanism may be a dysfunction of the interneurons mediating the level of excitation within cortical area 4. For instance, there is a shortening of the so-termed 'central silent period', which is a complex, TMS-induced, inhibitory phenomenon possibly mediated by activation of GABA(B) receptors. The so-called 'short-interval intracortical inhibition', which is possibly mediated by GABA(A) receptors, is also diminished. Levodopa restores these and other TMS alterations, thus demonstrating that cortical area 4 is sensitive to dopamine modulation. Overall, TMS has provided substantial new pathophysiological insights, which point to a central role of the primary motor cortex in the movement disorder typical of PD. Repetitive (r-)TMS, another form of TMS, has been studied as a treatment for PD motor signs. Although some reports are favorable, others are not, and have raised the problem of appropriate control experiments. Although extremely interesting, the potential therapeutic role of r-TMS in PD needs further evaluation.
Capuano, B., I. T. Crosby, et al. (2002). "Schizophrenia: genesis, receptorology and current therapeutics." Curr Med Chem 9(5): 521-48.
Schizophrenia is a debilitating mental disease affecting approximately 1% of the population worldwide. Since the discovery of the first modern treatment for schizophrenia, chlorpromazine, in 1952 there have been many new structures investigated, only a small fraction of which have resulted in clinically useful drugs. Of these, haloperidol may be regarded as the drug for first line treatment. Since then, clozapine has emerged as the benchmark therapeutic ameliorating positive and negative symptoms and devoid of movement disorders, with its greatest feature being improvement of treatment-resistant patients. However, a major, potential lethal side-effect of clozapine is the induction of agranulocytosis, a blood disorder with unknown mechanism that results in lowered white-blood cell counts and consequent susceptibility to infections. In the 50 years of antipsychotic drug development, several novel theories have evolved that focus on receptor sub-types (serotonin 5-HTsub>2A, dopamine D(2) and D(4)) and the degree to which they need to be selectively attenuated by the drugs. Also of significance is the location of these receptors in the brain in relation to the disease state, the myriad of side-effects associated with antipsychotics and physicochemical properties of antipsychotic molecules relative to models of the drugs and the GPCR receptors involved. The techniques for investigation have shown increasing sophistication and refinement over this period, involving cloned receptors and PET scanning for determination of receptor location, density and binding, and rate constants at receptors. Knowledge of receptor structure, although in its infancy since no membrane bound CNS-receptor has yet been crystallized, is likely to benefit substantially with advances in computer-aided modelling. Overall, these new techniques have resulted in a number of novel antipsychotics such as risperidone, sertindole, olanzapine, seroquel, zotepine and ziprasidone, whose design, synthesis and testing has benefited enormously from the accumulated knowledge base of the past 50 years. In this review, we will provide a comprehensive update of the theories of action and clinical profiles of the latest drugs listed. The following appraisal of the literature will provide the practising medicinal chemist interested in this critical area of research with sufficient insight and understanding, to embark on productive investigations into the design and development of new therapeutic agents devoid of clinically limiting side-effects.
Carlsson, A. (2002). "Treatment of Parkinson's with L-DOPA. The early discovery phase, and a comment on current problems." J Neural Transm 109(5-6): 777-87.
Carr, K. D. (2002). "Augmentation of drug reward by chronic food restriction: behavioral evidence and underlying mechanisms." Physiol Behav 76(3): 353-64.
Chronic food restriction and maintenance of low body weight have long been known to increase the self-administration and motor-activating effects of abused drugs. Using a lateral hypothalamic self-stimulation (LHSS) rate-frequency method, it is shown that chronic food restriction augments the rewarding (i.e., threshold lowering) effect of diverse drugs of abuse. Further, the effect is attributed to increased sensitivity of a neural substrate, rather than a change in drug bioavailability or pharmacokinetics, because it is preserved when drugs are injected directly into the lateral cerebral ventricle (intracerebroventricularly). The food restriction regimen that augments drug reward also increases the induction of c-fos, by intracerebroventricular amphetamine, in limbic forebrain dopamine (DA) terminal areas. The possibility of increased DA receptor function is suggested by findings that rewarding and motor-activating effects of direct DA receptor agonists are augmented by food restriction, and the augmented behavioral effects of amphetamine are reversed by an otherwise subthreshold dose of D-1 antagonist. Initial studies of DA receptor-mediated signal transduction, that are focused on the D-2 receptor, suggest increased functional coupling between receptor and G-protein (i.e., quinpirole-stimulated [(35)S]GTPgammaS binding) in dorsal striatum. Unlike behavioral sensitization induced by intermittent stress or psychostimulant treatment, which persist indefinitely following induction, the augmenting effect of food restriction abates within 1 week of restored ad libitum feeding and weight gain. The possible involvement of endocrine hormones and/or 'feeding-related' neuropeptides, whose levels change dynamically with depletion and repletion of adipose stores, is therefore under investigation. Initial tests have been limited to acute treatments aimed at attenuating the effects of hypoinsulinemia, hypoleptinemia and elevated corticosterone levels in food-restricted rats. None of these treatments has attenuated the behavioral effect of food restriction. While a melanocortin receptor agonist has been found to enhance drug reward, melanocortin receptors do not seem to mediate the augmenting effect of food restriction. Continuing investigations of endocrine adiposity signals, 'feeding-related' neuropeptides and dopaminergic signal transduction may further elucidate the way in which drugs of abuse exploit mechanisms that mediate survival-related behavior, and help explain the high comorbidity of drug abuse and eating disorders.
Castellanos, F. X. and R. Tannock (2002). "Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes." Nat Rev Neurosci 3(8): 617-28.
Cavalieri, E. L., E. G. Rogan, et al. (2002). "Initiation of cancer and other diseases by catechol ortho-quinones: a unifying mechanism." Cell Mol Life Sci 59(4): 665-81.
Exposure to estrogens is a risk factor for breast and other human cancers. Initiation of breast, prostate and other cancers has been hypothesized to result from reaction of specific estrogen metabolites, catechol estrogen-3,4-quinones, with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine by 1,4-Michael addition. The catechol of the carcinogenic synthetic estrogen hexestrol, a hydrogenated derivative of diethylstilbestrol, is metabolized to its quinone, which reacts with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine. The catecholamine dopamine and the metabolite catechol (1,2-dihydroxybenzene) of the leukemogen benzene can also be oxidized to their quinones, which react with DNA to form predominantly analogous depurinating adducts. Apurinic sites formed by depurinating adducts are converted into tumor-initiating mutations by error-prone repair. These mutations could initiate cancer by estrogens and benzene, and Parkinson's disease by the neurotransmitter dopamine. These data suggest a unifying molecular mechanism of initiation for many cancers and neurodegenerative diseases and lay the groundwork for designing strategies to assess risk and prevent these diseases.
Chaudhuri, K. R., S. Pal, et al. (2002). "'Sleep attacks' or 'unintended sleep episodes' occur with dopamine agonists: is this a class effect?" Drug Saf 25(7): 473-83.
Controversial reports of sudden onset 'sleep attacks' resulting in road traffic accidents have recently been reported in patients with Parkinson's disease (PD) taking the non-ergot dopamine D(2 )/D(3) receptor agonists pramipexole and ropinirole. These reports have generated considerable debate as the concept of 'sleep attacks' is disputed amongst sleep specialists and most believe that isolated 'sleep attacks' not preceded by warning on the background of chronic sleepiness or 'unintended sleepiness' do not exist. A series of case reports suggested that this phenomenon may not be exclusive to the non-ergot dopamine agonists such as pramipexole or ropinirole and indeed may occur with most dopaminergic agents. Recent evidence suggest that a 'sleepiness' or 'hypoactivity' reaction to dopaminergic therapy may be related to underlying dopamine deficiency of PD rather than a drug effect. In this report we provide the evidence for the phenomenon being a class effect attributable to all dopamine agonists currently employed in the management of PD. Controversy surrounding excessive daytime sleepiness (EDS) in PD and the use of the Epworth Sleepiness Scale (ESS) in relation to PD is also discussed. In spite of variable reports, EDS is recognised to be common in PD and is likely to be related to both the disease process and drug therapy. Studies using multiple sleep latency tests have also reported differing results in PD although a recent study indicated that a subset of 'sleepy' patients with PD may experience pathological somnolence with resultant detrimental consequence on daytime and cognitive functions. We recommend that the issue of 'sleepiness' or 'sleep attacks' in PD should be routinely checked in all patients with PD and indirectly assessed by using either the ESS or the recently introduced Parkinson's Disease Sleep Scale. Those with reported 'sleep attacks' or 'unintended sleep episodes' and excessive daytime sleepiness while taking dopamine agonists or dopaminergic agents such as levodopa should have a review of their medication, should not be driving a car on their own and some may merit formal sleep architecture studies. The latter may identify sleep disorders such as secondary narcolepsy which may benefit from the use of a wakefulness promoting agent.
Citver, A. S., A. M. Shields, et al. (2002). "Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for schizophrenia: III. Retinoids." J Clin Pharm Ther 27(3): 161-8.
Present antipsychotic drugs, whose clinical activity correlates with direct binding to dopamine D2 or other receptors, alleviate some of the symptoms of schizophrenia, but not all and not completely in many patients. In continuation of our overview of potential novel antipsychotic pharmacotherapy that would be based upon indirect modulation of dopamine or other neurotransmitter functioning, we focus in this article on the postulated use of retinoid analogs as novel antipsychotic agents. Several lines of evidence can be viewed as implicating retinoid dysregulation in schizophrenia, either as a causative or contributory factor. It has been proposed that using retinoid analogs to alter the downstream expression of dopamine D2 receptors might represent a novel approach to the treatment of the disease or amelioration of symptoms when used either as monotherapy or as adjunct pharmacotherapy to dopamine D2 receptor antagonists.
Clarke, C. E. and M. Guttman (2002). "Dopamine agonist monotherapy in Parkinson's disease." Lancet 360(9347): 1767-9.
CONTEXT: Levodopa is the gold-standard therapy for Parkinson's disease. However, long-term treatment leads to involuntary movements and response fluctuations which add to the complexities of later disease-management. In addition, preclinical evidence suggests that levodopa is toxic to dopaminergic neurons. These problems have led to a move away from levodopa towards initial monotherapy with a dopamine agonist. STARTING POINT: Positron-emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers have been developed which may be considered surrogate markers for remaining dopaminergic neurons. In a randomised controlled trial in patients with early Parkinson's disease, the Parkinson Study Group used 123I-beta-CIT SPECT (JAMA 2002; 287: 1653-61). Those patients given pramipexole had significantly reduced loss of striatal uptake at 46 months compared with those given levodopa (16.0% vs 25.5%). In a similar trial, Alan Whone and colleagues used 18F-DOPA PET (Neurology 2002; 58 [suppl 3]: A82-83). Patients given ropinirole had significantly reduced loss of striatal uptake at 24 months compared with those given levodopa (13% vs 20%). These studies suggest that agonist monotherapy may be neuroprotective and/or that levodopa is toxic. This work has been criticised as the SPECT results may have resulted from a differential effect of the agonist and levodopa on the regulation of the dopamine transporter, thereby influencing the imaging outcome measure. Other criticisms include insufficient data on the use of the potential neuroprotectant selegiline and patients on pramipexole in the SPECT study appear to have been clinically slow progressors. Single clinical trials with each of the four modern agonists compared with levodopa show that as monotherapy the agonists delay the onset of involuntary movements, although at the expense of poorer treatment of motor impairments and disability and more dopaminergic adverse events. The only health-related quality of life data show no difference between pramipexole and levodopa after 4 years. No information on health-economics measures is available but agonists cost two to three times as much as levodopa. WHERE NEXT? Young patients should be treated with agonist monotherapy since the trials included predominantly younger patients who have a higher incidence of motor complications. Those with significant co-morbidity, dementia, or a short life-expectancy should be treated with the lowest dose of levodopa required to maintain motor function. For the vast majority though, no clear guidance can be given. Further large-scale pragmatic trials in large numbers of patients over prolonged periods are urgently required.
Clemmesen, O. (2002). "Splanchnic circulation and metabolism in patients with acute liver failure." Dan Med Bull 49(3): 177-93.
Acute liver failure is associated with mortality of around 50%. The aim of the present studies was to examine the circulatory and metabolic state of the splanchnic region in acute liver failure. This had not been studied previously and it could be expected that improved understanding of the pathophysiology of acute liver failure could lead to improved therapy. Hepatic plasma flow was estimated in patients with acute liver failure after development of hepatic encephalopathy grade III, by the use of liver vein catheterization and continuous infusion of sorbitol. The method was evaluated against the prerequisites of Fick's principle. Hepatic plasma flow could be estimated with sorbitol but not in all patients and the standard error of the estimated hepatic blood flow was higher than in other patient groups. In 20 patients with acute liver failure, mean hepatic blood flow was increased. At the same time, the systemic and the peripheral hemodynamics were examined. The ratio hepatic blood flow/cardiac output was increased in many patients. Lower extremity blood flow was within normal limits. Thus, low systemic vascular resistance index in acute liver failure was likely to be a consequence of vasodilatation in the muscular resistance vessels and, in particular, in the splanchnic resistance vessels. Intervention with high-volume plasmapheresis changed systemic and splanchnic hemodynamics differently, suggesting that the splanchnic vasodilatation in liver failure may by caused by a specific mechanism different from the one that leads to peripheral vasodilatation. Infusion of dopamine increased mean arterial pressure, cardiac output, and hepatic blood flow in acute liver failure. The splanchnic exchange of substrates for oxidative metabolism was examined. Splanchnic oxygen consumption was increased. The ratio splanchnic oxygen consumption/systemic oxygen consumption indicated that 1/3 of the oxygen used in the whole body in acute liver failure was used in the splanchnic region. The splanchnic metabolism of fuel substrates was abnormal. Lactate and pyruvate was released and there were no detectable gradients of free fatty acids or of the sum of amino acids. There was a small release of ketone bodies. The data suggested that the energy needs of the failing liver was covered by intracellular fat. The hypothesis of splanchnic tissue hypoxia was examined from different approaches. The normal hepatic venous oxygen saturation, the splanchnic release of both lactate and pyruvate, and a normal hepatic venous pyruvate/lactate ratio in the presence of low acetoacetate/hydroxybutyrate ratio rather indicated high substrate turnover than splanchnic tissue hypoxia. Amino acid and ammonia metabolism was examined. It was observed that arterial ammonia concentration measured after institution of mechanical ventilation was associated with cerebral herniation 1-5 days later. The background for hyperammonemia was that ammonia was released from the splanchnic circulation. The data implied that glutamine was deamidated in the gut and alanine and ammonia was released into the portal vein as during normal circumstances. Then due to severely decreased hepatic function the liver was unable to remove ammonia and alanine as it normally would. Further, the data implied that urea synthesis was impaired. Exchange of ammonia in muscle tissue was studied in 7 patients with acute liver failure and muscle tissue seems to play a major role in ammonia detoxification in acute liver failure. Treatment with high-volume plasmapheresis decreased arterial ammonia, which was likely due to increased urea production or stimulation of glutamine synthesis in muscle tissue. These findings add to our understanding of the pathophysiology and have implications for the management of acute liver failure.
Cohen, J. D. and K. I. Blum (2002). "Reward and decision." Neuron 36(2): 193-8.
Cohen, J. D., T. S. Braver, et al. (2002). "Computational perspectives on dopamine function in prefrontal cortex." Curr Opin Neurobiol 12(2): 223-9.
Dopamine and the prefrontal cortex are critical for thought and behaviour. Recently, computational models have tried to elucidate the specific and intricate roles of dopamine in the prefrontal cortex, at the neurophysiological, system and behavioral levels, with varying degrees of success.
Colao, A., A. di Sarno, et al. (2002). "Dopamine receptor agonists for treating prolactinomas." Expert Opin Investig Drugs 11(6): 787-800.
Prolactinomas are the most common hormone-secreting pituitary tumours and cause infertility and gonadal and sexual dysfunction in both sexes. The approach to prolactinomas has changed in the last 25 years thanks to the availability of dopaminergic drugs characterised by a potent prolactin-inhibitory effect, a tumour shrinking effect associated with a satisfactory tolerability. In more recent years, cabergoline 1-[(6-allelylergolin-8beta-yl)carbonyl]-1-[3-(dimethylamino) propyl]-3-ethyl-urea an ergoline derivative with potent, selective and long-lasting inhibitory activity on prolactin release, has been used to suppress prolactin secretion in women with hyperprolactinaemia. Cabergoline was shown to be significantly more effective than bromocriptine in inducing a complete biochemical response and clinical efficacy and was better tolerated than bromocriptine in the majority of patients. Notable tumour shrinkage until tumour disappearance was observed during cabergoline treatment in most patients with macroprolactinoma and it was also proven effective in patients resistant to or with a poor response to bromocriptine. In view of the limited data on cabergoline-associated pregnancies and the long half-life of the drug, it is currently recommended that women hoping to become pregnant, once ovulatory cycles have been established, should discontinue cabergoline therapy 1 month before they intend to conceive. However, no data concerning negative effects on pregnancy or offspring have been reported. The great efficacy of this compound together with its excellent tolerability makes this drug the current treatment of choice for the majority of patients with hyperprolactinaemic disorders.
Collins, M. A. and E. J. Neafsey (2002). "Potential neurotoxic "agents provocateurs" in Parkinson's disease." Neurotoxicol Teratol 24(5): 571-7.
Idiopathic Parkinson's disease (PD), one of the most common neurodegenerative disorders associated with aging, is characterized neurochemically by abnormal and profound loss of nigrostriatal dopamine (DA) neurons. A prominent current view is that the excessive degeneration of the dopaminergic system is the outcome of extended insults by environmental neurotoxins or endogenous neurotoxic factors in genetically vulnerable or susceptible individuals. Recent insights into the identities and mechanisms of potential neurotoxic species, which span pesticides, environmental contaminants including heterocyclic amines with beta-carboline (betaC) and isoquinoline (IQ) structures, endogenous DA metabolites or intermediates, neuromelanin, metals, and infectious agents, are presented.
Colosimo, C. and F. R. Pezzella (2002). "The symptomatic treatment of multiple system atrophy." Eur J Neurol 9(3): 195-9.
Multiple system atrophy (MSA) is a neurodegenerative disease of undetermined aetiology that occurs sporadically and manifests itself as a combination of parkinsonian, autonomic, cerebellar and pyramidal signs. Despite the lack of any effective therapy to reverse this condition, some of the symptoms may be, at least temporarily, improved with adequate symptomatic therapies. Medical treatment is largely aimed at mitigating the parkinsonian and autonomic features. The therapeutic results of levodopa therapy in cases of MSA are difficult to interpret because of their variability. Nevertheless, the statement that patients with MSA are non or poorly levodopa-responsive is misleading. Clinical and pathologically proven series document about 40-60% levodopa efficacy in patients with MSA presenting with predominant parkinsonian features. Unfortunately, other antiparkinsonian compounds (dopamine agonists, amantadine) are not more effective than levodopa. Orthostatic hypotension (OH) can be suspected from the patient's history and subsequently documented in the clinic by measuring lying and standing blood pressure. The diagnosis ideally should be confirmed in the laboratory with additional tests to determine the cause and evaluate the functional deficit, so as to aid treatment. A variety of pharmacological agents with different mechanisms of action have been used in MSA to reduce OH when this is symptomatic. OH can also be alleviated by avoiding aggravating factors, such as the effects of food, micturition, exposure to a warm environment and physiological diurnal changes and by using other non-pharmacological strategies. The treatment of the very common genito-urinary symptoms (incontinence, retention, impotence) should also be considered in order to improve the quality of life of these patients.
Compton, M. T. and A. H. Miller (2002). "Antipsychotic-induced hyperprolactinemia and sexual dysfunction." Psychopharmacol Bull 36(1): 143-64.
This overview of antipsychotic-induced hyperprolactinemia provides a summary of the current literature in relation to conventional antipsychotic agents and the five atypical antipsychotics currently available in the United States--clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. Dopaminergic antagonism within the tuberoinfundibular system causes elevation in plasma prolactin levels. Conventional antipsychotic medications and the atypical agent risperidone cause significant elevations in prolactin. Clozapine, olanzapine, quetiapine, and ziprasidone cause minimal effects on prolactin levels in adults, which may be due to a higher 5-HT2A:D2 binding ratio and differential effects on dopamine neurotransmission, with less interference in the tuberoinfundibular pathway. Antipsychotic-induced hyperprolactinemia presumably causes clinical side effects similar to those caused by other forms of hyperprolactinemia. Clinical and endocrinologic changes of hypogonadism also likely occur during chronic antipsychotic-induced hyperprolactinemia. Because hyperprolactinemia may cause clinically significant side effects in patients treated with antipsychotic medications, clinicians should be familiar with the evaluation and treatment of antipsychotic-induced hyperprolactinemia.
Connor, D. F. (2002). "Preschool attention deficit hyperactivity disorder: a review of prevalence, diagnosis, neurobiology, and stimulant treatment." J Dev Behav Pediatr 23(1 Suppl): S1-9.
The clinical use of stimulant medications for 3- to 6-year-old preschool children who meet diagnostic criteria for attention deficit hyperactivity disorder (ADHD) is becoming more common. A systematic computerized literature search extending back to 1970 identified nine controlled studies of stimulant treatment and two controlled trials of stimulant side effects in preschool ADHD children. Treatment benefits are reported for eight of nine (89%) controlled stimulant trials involving a total of 206 preschool subjects. In comparison with school-aged ADHD youth, there may be a greater variability of stimulant response in ADHD preschoolers. Domains assessing cognition, interpersonal interactions, and hyperactive-impulsive behavior are noted to improve on drugs relative to placebos. Side effects in this age range are generally reported as mild. ADHD preschool children may experience slightly more and different types of stimulant-induced side effects compared with older children. High rates of behavior reported as stimulant side effects are found for children receiving a placebo, necessitating a baseline evaluation for medication side effects before stimulants are initiated. Despite the lack of research assessing stimulant effects on the very young and developing brain and the need for more controlled medication trials in this age range, this review of the extant literature finds stimulants to meet evidence based criteria as beneficial and safe for carefully diagnosed ADHD preschool children aged 3 years and older.
Contreras, F., C. Fouillioux, et al. (2002). "Dopamine, hypertension and obesity." J Hum Hypertens 16 Suppl 1: S13-7.
Dopamine, a neurotransmitter, precursor of noradrenaline, is responsible for cardiovascular and renal actions, such as increase in myocardial contractility and cardiac output, without changes in heart rate, producing passive and active vasodilatation, diuresis and natriuresis. These cardiovascular and renal actions take place through the interaction with dopamine receptors, D(1), D(2), D(3), D(4), and D(5). Recent findings point to the possibility of D(6) and D(7)receptors. Dopamine is known to influence the control of arterial pressure by influencing the central and peripheral nervous system and target organs such as kidneys and adrenal glands, in some types of hypertension. Although dopamine and its derivatives have been shown to have antihypertensive effects, these are still being studied; therefore it is important to explain some physiological and pharmacological aspects of dopamine, its receptors, and the clinical uses it could have in the treatment of arterial hypertension and more recently in obesity, based on evidence proving a clear association between obesity and the decrease in the expression of D(2) receptors in the brain of obese persons.
Cooper, D. C. (2002). "The significance of action potential bursting in the brain reward circuit." Neurochem Int 41(5): 333-40.
The brain reward circuit consists of specialized cortical and subcortical structural components that code for various cognitive aspects of goal-directed behavior. These components include the prefrontal cortex (PFC), amygdala (AMY), nucleus accumbens (Nac), subiculum (SUB) of the hippocampal formation, and the dopamine (DA) neurons in the ventral tegmental area (VTA). Both serial and parallel processing in the different components of the circuit code the various aspects of reward-related behavior. Individual neurons within each component have developed specialized intrinsic membrane properties that have led them to be typically defined as either single spiking or high frequency burst-firing neurons. However, a strict definition based on the output mode may not be appropriate. Under the right conditions, neurons can switch between bursting and single-spiking modes, therefore providing a conditional output state. The preferred mode of each individual neuron depends on a combination of different plastic neuronal properties such as, dendritic architecture, neuromodulation, intracellular calcium (Ca(++)) buffering, excitatory and inhibitory synaptic strength, and the spatial distribution and density of voltage and ligand-gated channels. It is likely that, in vivo, most neurons in the circuit, despite variations in intrinsic membrane properties, are conditional output neurons equipped with the versatility of switching between output modes under appropriate conditions. Bursting mode may be used to boost the gain of neural signaling of important or novel events by enhancing transmitter release and enhancing dendritic depolarization, thereby increasing synaptic potentiation. Conversely, single spiking mode may be used to dampen neuronal signaling and may be associated with habituation to unimportant events. Mode switching may provide flexibility to the circuit allowing different sets of neurons to conditionally code for the various aspects of reward-related memory and behavior.
Corelli, R. L. and K. S. Hudmon (2002). "Medications for smoking cessation." West J Med 176(2): 131-5.
Cousins, M. S., D. C. Roberts, et al. (2002). "GABA(B) receptor agonists for the treatment of drug addiction: a review of recent findings." Drug Alcohol Depend 65(3): 209-20.
A growing preclinical and clinical literature suggests that GABA(B) receptor agonists promote abstinence and reduce the use of cocaine, heroin, alcohol and nicotine. The purpose of this paper is to critically review these data. GABA(B) receptor agonists, such as baclofen, appear to reduce the reinforcing effects of abused drugs in animal models under multiple experimental procedures. This occurs at doses that have little effect on responding for other positive reinforcers such as food or water. We review evidence that these potential therapeutic effects may be mediated by modulation of mesolimbic dopamine neurons. This review also examines the preliminary clinical data from studies of the efficacy of baclofen for treatment of cocaine, alcohol, and nicotine dependence. We suggest that these preliminary data provide a rationale for conducting more systematic studies of the effects of GABA(B) receptor agonists as treatment for drug abuse. This line of research may also improve our understanding of the neurochemical mechanisms underlying the drug dependence process.
Culler, M. D., J. E. Taylor, et al. (2002). "Somatostatin receptor subtypes: targeting functional and therapeutic specificity." Ann Endocrinol (Paris) 63(2 Pt 3): 2S5-12.
Somatostatin is a regulatory peptide involved in a wide variety of biological functions throughout the body. A key physiological question, as well as the challenge to developing somatostatin-based therapeutics, is how functional specificity can be conferred in such a widespread, multifunctional hormonal system. With the discovery of distinct subtypes of the somatostatin receptor, we have attempted to elucidate the manner in which somatostatin selectively regulates specific biological functions using panels of somatostatin analogs that have been fully characterized for their unique selectivity and specificity for the various receptor subtypes. By testing these selective analogs in well-established biological assay systems, we and our collaborators have revealed functional interactions between the somatostatin receptor subtypes that can either potentiate or antagonize the cellular response to somatostatin. These observations have resulted in several novel concepts for treating acromegaly that should offer greater efficacy to a larger percentage of patients than current therapeutic options. Further, these studies are providing evidence of interaction between the somatostatin receptor subtypes and receptors of other G-protein-coupled receptor families. These various levels of interaction provide a means by which the cellular response to somatostatin can be exquisitely controlled and modified by both physiological status and disease. Greater understanding of these interactions will provide the conceptual basis for future therapeutics with enhanced efficacy and with greater cellular and functional specificity.
Curran, M. P. and C. M. Perry (2002). "Spotlight on amisulpride in schizophrenia." CNS Drugs 16(3): 207-11.
Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D(2)/D(3) autoreceptors. At higher doses, amisulpride antagonises postsynaptic D(2) and D(3) receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission. In patients with acute exacerbations of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day, although dosages < or = 1200 mg/day may be administered. In comparative trials, amisulpride administered within this range (400 to 1200 mg/day) was as effective as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in patients with acute exacerbations of schizophrenia with predominantly positive symptoms. Amisulpride was more effective than haloperidol but equally effective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixol in controlling affective symptoms in these patients. In randomised, double-blind trials involving patients with predominantly negative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more effective than placebo. Amisulpride is effective as maintenance therapy in patients with chronic schizophrenia. Long-term treatment with amisulpride was associated with improvements in quality of life and social functioning. Amisulpride is generally well tolerated. In well-controlled trials, the neurological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. At low dosages of amisulpride (< or = 300 mg/day), the incidence of adverse events (including extrapyramidal symptoms) reported with amisulpride was similar to that with placebo. Conclusion: In comparative trials, amisulpride 400 to 1200 mg/day showed efficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in patients with acute exacerbations of schizophrenia. Moreover, its effective alleviation of negative and affective symptoms, its lower association with extrapyramidal symptoms and loss of cognitive function than conventional antipsychotics and its long-term efficacy justifies consideration of the use of higher dosages of amisulpride in this group of patients. Consequently, the dosage of amisulpride that is recommended in patients with acute exacerbations of schizophrenia is 400 to 800 mg/day, although dosages < or = 1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with negative symptoms of schizophrenia. Amisulpride is a first-line treatment option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.
Cyr, M., F. Calon, et al. (2002). "Estrogenic modulation of brain activity: implications for schizophrenia and Parkinson's disease." J Psychiatry Neurosci 27(1): 12-27.
Evidence suggests the estrogens may play a role in various mental and neurodegenerative diseases. We review the evidence implicating estradiol in schizophrenia and Parkinson's disease. Epidemiologic and clinical studies on the effects of estrogens in schizophrenia are surveyed, and animal studies and in vitro models of the modulatory effects of estrogens on neurotransmitters associated with schizophrenia (i.e., dopamine, serotonin, glutamate) are reviewed. Epidemiologic and clinical data suggesting a role for estrogens in Parkinson's disease and in vivo and in vitro models demonstrating neuroprotective effects of estrogens are then examined. Despite the numerous animal studies on the effects of estrogens in the brain, clinical data are sparse and often contradictory. Compounds with more specific and potent estrogenic activity in the brain are required to further research efforts in this area. Possible candidates are the selective estrogen receptor modulators (SERMs), whose agonist or antagonist properties depend on the target tissue. The effects of various SERMs in the brain are reviewed, and our novel findings on the effects of SERMs on 5-HT2A receptors in the rat cortex and nucleus accumbens are presented. We suggest that drugs with estrogenic activity in the brain may have therapeutic potential, either by modulating brain neurotransmission or through neuroprotective activity.
Da Cunha, C., M. E. Angelucci, et al. (2002). "The lesion of the rat substantia nigra pars compacta dopaminergic neurons as a model for Parkinson's disease memory disabilities." Cell Mol Neurobiol 22(3): 227-37.
1. In this article we review the studies of memory disabilities in a rat model of Parkinson's disease (PD). 2. Intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to rats causes a partial lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. 3. These animals present learning and memory deficits but no sensorimotor impairments, thus modeling the early phase of PD when cognitive impairments are observed but the motor symptoms of the disease are barely present. 4. The cognitive deficits observed in these animals affect memory tasks proposed to model habit learning (the cued version of the water maze task and the two-way active avoidance task) and working memory (a working memory version of the water maze), but spare long-term spatial memory (the spatial reference version of the Morris water maze). 5. The treatment of these animals with levodopa in a dose that restores the striatal level of dopamine does not reverse these memory impairments, probably because this treatment promotes a high level of dopamine in extrastriatal brain regions, such as the prefrontal cortex and the hippocampus. 6. On the other hand, the adenosine receptor antagonist, caffeine, partly reverse the memory impairment effect of SNc lesion in these rats. This effect may be due to caffeine action on nigrostriatal neurons, since it induces dopamine release and modulates the interaction between adenosine and dopamine receptor activity. 7. These results suggest that the MPTP SNc-lesioned rats are a good model to study memory disabilities related to PD and that caffeine and other selective A(2A) adenosine receptor antagonists are promising drugs to treat this symptoms in PD patients.
Danisi, F. (2002). "Parkinson's disease. Therapeutic strategies to improve patient function and quality of life." Geriatrics 57(3): 46-50; quiz 52.
Idiopathic Parkinson's disease (PD) is an age-related neuro-degenerative disorder characterized by slowness, stiffness, resting tremor, gait impairment, and postural instability. Levodopa is the most potent pharmacologic agent for symptom management and is associated with an increase in quality of life and longevity for patients with PD, but chronic use causes motor complications. The availability of several newer types of agents--dopamine agonists, monoamine oxidase inhibitors, and catechol-O-methyltransferase inhibitors--gives physicians increased flexibility with regard to first-line therapy, adjunct therapy, and managing or reducing the frequency of motor complications and other side effects associated with chronic levodopa therapy.
Dawson, T., A. Mandir, et al. (2002). "Animal models of PD: pieces of the same puzzle?" Neuron 35(2): 219-22.
Parkinson's disease (PD) is a common neurodegenerative disorder with no known cure. The etiology of PD is likely due, in part, to combinations of genetic susceptibilities and environmental factors. In rare familial cases, PD is due to genetic mutations. A number of new genetic and toxin models of PD and advances in older models are yielding important new information about the pathogenesis of PD. This has prompted us to critically review the current animal models for PD and discuss how these models may yield fresh insights into the pathogenesis of PD, as well as new therapeutic opportunities.
Dayan, P. and B. W. Balleine (2002). "Reward, motivation, and reinforcement learning." Neuron 36(2): 285-98.
There is substantial evidence that dopamine is involved in reward learning and appetitive conditioning. However, the major reinforcement learning-based theoretical models of classical conditioning (crudely, prediction learning) are actually based on rules designed to explain instrumental conditioning (action learning). Extensive anatomical, pharmacological, and psychological data, particularly concerning the impact of motivational manipulations, show that these models are unreasonable. We review the data and consider the involvement of a rich collection of different neural systems in various aspects of these forms of conditioning. Dopamine plays a pivotal, but complicated, role.
de Angelis, L. (2002). "5-HT2A antagonists in psychiatric disorders." Curr Opin Investig Drugs 3(1): 106-12.
Several lines of evidence support a role for serotoninergic (5-HT) system abnormalities in the pathogenesis and treatment of several psychiatric disorders. This review summarizes information about the association between the 5-HT2A receptor gene and its relevance to schizophrenia, tardive dyskinesia, major depression, suicidality, anorexia nervosa and obsessive-compulsive disorder. Evidence is presented that implies that selective 5-HT2A antagonists may be considered useful in investigating the role of 5-HT2A receptor function and in the treatment of psychosis, and possibly alcohol and cocaine dependence. Additionally, findings are reviewed on the importance of 5-HT2A receptor antagonism in contributing to the therapeutic effect of several clinically effective and potential atypical antipsychotics as well as several antidepressants. In conclusion, the ability of selective 5-HT2A receptor antagonists to interfere with the heightened state of dopamine activity without altering basal tone, suggests that these drugs possess antipsychotic activity and may provide the basis for new therapies for psychosis and drug dependence, in addition to contributing towards a more complete understanding of 5-HT2A receptor function.
De Erausquin, G. A. (2002). "[Neurodevelopment and schizophrenia]." Vertex 13(49): 189-97.
The evidence of neuroleptics' antipsychotic action due to their antagonism of dopamine receptors led to the hyperdopaminergic theory of schizophrenia. But the functional disturbance of the dopamine neurons should explain the increase and the reduction of some symptoms at the same time through the D2 receptors blockade. The prodromical manifestations of schizophrenia include abnormal movements which precede and predict the beginning of the disease. They also suggest a dopamine deficit. An injury in the mesocortical dopamine projection during the neural development could result in a functional impairment of the prefrontal cortex which causes the cognitive deficit symptoms. It would result also in an excessive compensatory subcortical dopamine activity which would cause the psychotic symptoms. The evidence in behalf of this physiopathology is complex. The mechanism of the subcortical compensation of the prefrontal dopamine deficit remains unknown. It is necessary to find out which is the exact mechanism of the injury that causes the mesocortical projection loss in the schizophrenia. We have suggested that the injury would depend on the excitotoxicity induced by the perinatal hypoxia which would provoke the selective death of a dopamine neurons subset which are very sensitive during the critical period of the mesencephalic development.
de la Fuente-Fernandez, R. and A. J. Stoessl (2002). "Parkinson's disease: imaging update." Curr Opin Neurol 15(4): 477-82.
PURPOSE OF REVIEW: We aim to review recent neuroimaging contributions to our understanding of the cause and pathogenesis of Parkinson's disease, as well as treatment-related complications of disease, with a focus on functional anatomy and neurochemistry. RECENT FINDINGS: Recent reports describe altered dopaminergic activity in extrastriatal regions, as well as changes in other monoaminergic systems, such as serotonin. Attempts to correlate altered dopaminergic function with personality traits have also been described in the last year. The role of different markers of presynaptic dopaminergic integrity in the assessment of disease progression is discussed, as is the role of biomarkers in detection of preclinical disease. Cerebral activation studies not only confirm altered function of cortico-striatal-thalamo-cortical loops in Parkinson's, but also emphasize the importance of networks involving the cerebellum. The ability to detect changes in synaptic availability of dopamine using positron emission tomography with [(11)C]raclopride is reviewed, including the application to detect altered levels of dopamine in response to pharmacological, mechanical and behavioral stimuli. Such studies have been used to identify altered patterns associated with the development of motor fluctuations, as well as a biochemical substrate underlying the placebo effect in Parkinson's. SUMMARY: Functional imaging studies can provide novel insights into the etiopathogenesis of Parkinson's disease, as well as the mechanisms that contribute to complications of long-term therapy. They also shed light on the mechanisms that may underly behavioral changes and benefit derived from surgical interventions.
de la Fuente-Fernandez, R. and A. J. Stoessl (2002). "The placebo effect in Parkinson's disease." Trends Neurosci 25(6): 302-6.
The biochemical bases of the placebo effect are still incompletely known. We show here that the placebo effect in Parkinson's disease is due, at least in part, to the release of dopamine in the striatum. We propose that the placebo effect might be related to reward mechanisms. The expectation of reward (i.e. clinical benefit) seems to be particularly relevant. According to this theory, brain dopamine release could be a common biochemical substrate for the placebo effect encountered in other medical conditions, such as pain and depression. Other neurotransmitters or neuropeptides, however, are also likely to be involved in mediating the placebo effect (e.g. opioids in pain disorders, serotonin in depression).
de Lima, M. S., B. G. de Oliveira Soares, et al. (2002). "Pharmacological treatment of cocaine dependence: a systematic review." Addiction 97(8): 931-49.
AIMS: Cocaine dependence is a common and serious condition, associated with severe medical, psychological and social problems, including the spread of infectious diseases. This systematic review assesses critically the efficacy of pharmacotherapy for treating cocaine dependence. METHODS: The literature search strategy included: electronic searches of Cochrane Library holdings, EMBASE, MEDLINE, PsycLIT, Biological Abstracts and LILACS; scans of reference lists of relevant articles, personal communications, conference abstracts, unpublished trials from the pharmaceutical industry and book chapters on the treatment of cocaine dependence. Randomized controlled trials (RCTs) focusing on the use of antidepressants (ADs), carbamazepine (CBZ), dopamine agonists (DAs) and other drugs used in the treatment of cocaine dependence were included. The reviewers extracted data independently, and relative risks (RR) with 95% confidence interval (CI) were estimated. Qualitative assessments were carried out using a Cochrane validated checklist. Where possible, analysis was carried out according to 'intention-to-treat' principles. FINDINGS: The search strategy generated 45 different trials. Most studied drugs were ADs (20 studies), DAs and CBZ. Data were very heterogeneous, with dropout rates within the studies between 0 and 84%. A non-significant trend favoring CBZ was found in terms of dropouts (RR 0.88; 95% CI 0.75-1.03) and results from one trial suggest that fluoxetine patients are less likely to drop out. The main efficacy outcome reported in the studies was the presence of cocaine metabolites in the urine. No significant results were found, regardless the type of drug or dose used for all relevant outcomes assessed. CONCLUSIONS: There is no current evidence supporting the clinical use of CBZ, antidepressants, dopamine agonists, disulfiram, mazindol, phenytoin, nimodipine, lithium and NeuRecover-SA in the treatment of cocaine dependence. Larger randomized investigation must be considered, while taking into account that these time-consuming efforts should be reserved for medications showing more relevant and promising evidence. Given the high dropout rate among the test population, clinicians may wish to consider adding psychotherapeutic supportive measures aimed at keeping patients in treatment programs.
de Paulis, T. (2002). "Perospirone (Sumitomo Pharmaceuticals)." Curr Opin Investig Drugs 3(1): 121-9.
Perospirone is a serotonin 5-HT2 antagonist and dopamine D2 antagonist developed by Sumitomo Pharmaceuticals for the potential treatment of schizophrenia and other psychoses [381769]. Its receptor binding profile and animal pharmacology resemble those of other atypical antipsychotic agents, in particular risperidone. In November 2000, CPAC's First Committee on Drugs recommended the approval of this product in Japan, [394007]; approval was granted in December 2000 [396121]. In January 2001, the NHI price was agreed by the Chuikyo [398222] and the drug was added to the NHI price list in February 2001 13982261. It was finally launched in Japan on February 8 2001 [399401]. In November 2000, Sumitomo and Welfide signed an agreement whereby Welfide's subsidiary Yoshitomi Yakuhin will copromote perospirone [394007]. Based on data from the Chuikyo, peak sales of perospirone are forecast to be yen9 billion in the sixth year following launch [398222], [398226]. In February 2001, Sumitomo predicted that perospirone would reach sales of yen10 billion within five to six years [399401].
Deleu, D., M. G. Northway, et al. (2002). "Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease." Clin Pharmacokinet 41(4): 261-309.
Current research in Parkinson's disease (PD) focuses on symptomatic therapy and neuroprotective interventions. Drugs that have been used for symptomatic therapy are levodopa, usually combined with a peripheral decarboxylase inhibitor, synthetic dopamine receptor agonists, centrally-acting antimuscarinic drugs, amantadine, monoamine oxidase-B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors. Drugs for which there is at least some evidence for neuroprotective effect are certain dopamine agonists, amantadine and MAO-B inhibitors (selegiline). Levodopa remains the most effective drug for the treatment of PD. Several factors contribute to the complex clinical pharmacokinetics of levodopa: erratic absorption, short half-life, peripheral O-methylation and facilitated transport across the blood-brain barrier. In patients with response fluctuations to levodopa, the concentration-effect curve becomes steeper and shifts to the right compared with patients with stable response. Pharmacokinetic-pharmacodynamic modelling can affect decisions regarding therapeutic strategies. The dopamine agonists include ergot derivatives (bromocriptine, pergolide, lisuride and cabergoline), non-ergoline derivatives (pramipexole, ropinirole and piribedil) and apomorphine. Most dopamine agonists have their specific pharmacological profile. They are used in monotherapy and as an adjunct to levodopa in early and advanced PD. Few pharmacokinetic and pharmacodynamic data are available regarding centrally acting antimuscarinic drugs. They are characterised by rapid absorption after oral intake, large volume of distribution and low clearance relative to hepatic blood flow, with extensive metabolism. The mechanism of action of amantadine remains elusive. It is well absorbed and widely distributed. Since elimination is primarily by renal clearance, accumulation of the drug can occur in patients with renal dysfunction and dosage reduction must be envisaged. The COMT inhibitors entacapone and tolcapone dose-dependently inhibit the formation of the major metabolite of levodopa, 3-O-methyldopa, and improve the bioavailability and reduce the clearance of levodopa without significantly affecting its absorption. They are useful adjuncts to levodopa in patients with end-of-dose fluctuations. The MAO-B inhibitor selegiline may have a dual effect: reducing the catabolism of dopamine and limiting the formation of neurotoxic free radicals. The pharmacokinetics of selegiline are highly variable; it has low bioavailability and large volume of distribution. The oral clearance is many-fold higher than the hepatic blood flow and the drug is extensively metabolised into several metabolites, some of them being active. Despite the introduction of several new drugs to the antiparkinsonian armamentarium, no single best treatment exists for an individual patient with PD. Particularly in the advanced stage of the disease, treatment should be individually tailored.
Deslandes, P. N., D. M. Pache, et al. (2002). "Drug dependence: neuropharmacology and management." J Pharm Pharmacol 54(7): 885-95.
This overview has attempted to highlight the brain regions associated with reward, and the pathways and neurotransmitters responsible for communication between these regions. Work conducted in this field has shown that stimulants and opioids, despite interactions with different receptor types and different neurotransmitter reuptake transporters, appear to share a common action on brain reward pathways. Their effects on these pathways (the distinct brain regions making up the mesocorticolimbic dopaminergic system) are predominantly mediated through changes in dopamine neurotransmission, and compounds aimed at selectively modulating these effects may form the basis of drugs to treat addiction. Other transmitters such as GABA, acetylcholine and serotonin inevitably have a role to play in reward, although at present the exact nature of their effects remains unclear. Diverging from manipulating the CNS directly as a management strategy for dependence, it might be possible to exploit the immune system to prevent administered psychostimulants penetrating the brain, but antibody saturation and specificity are problematic.
Deumens, R., A. Blokland, et al. (2002). "Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway." Exp Neurol 175(2): 303-17.
Human idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by degeneration of the dopaminergic neurons of the nigrostriatal pathway. Different 6-OHDA rat models of PD have been developed in which this toxin has been injected into different parts of the nigrostriatal pathway: (a) the medial forebrain bundle which leads to extensive dopamine (DA) depletion; (b) the substantia nigra pars compacta, which leads to more specific and moderate DA depletions; and (c) subregions of the caudate-putamen complex (CPu), which also leads to specific DA depletions. In this article we review the dopaminergic depletion and behavioral consequences of 6-OHDA lesions in the rat. It was examined whether the relation between DA depletion and behavioral deficits mimic idiopathic PD. In addition, it was evaluated which model most closely approximates the human situation, especially in relation to the stage of this progressive disease. It was concluded that with respect to the site of the lesion, rats with partial lesions of the ventrolateral CPu are the most appropriate models to study early and late stages of PD. The choice of the behavioral parameters determines the use of unilateral or bilateral lesions, although it is obvious that the bilateral model mimics the human situation more closely.
Di Matteo, V., M. Cacchio, et al. (2002). "Role of serotonin(2C) receptors in the control of brain dopaminergic function." Pharmacol Biochem Behav 71(4): 727-34.
There is substantial evidence that the functional status of mesocorticolimbic dopaminergic (DA) system originating in the ventral tegmental area (VTA) is under a phasic and tonic inhibitory control by the serotonergic system, which acts by stimulating serotonin(2C) (5-HT(2C)) receptor subtypes. This assertion is based upon a number of electrophysiological and biochemical data showing that 5-HT(2C) receptor agonists decrease, while 5-HT(2C) receptor antagonists enhance mesocorticolimbic DA function. On the other hand, it does not seem that 5-HT(2C) receptors play a relevant role in the control of nigrostriatal DA system originating in the substantia nigra pars compacta (SNc). The authors of this article review the most relevant data regarding the role of 5-HT(2C) receptors in the control of brain DA function and underline the importance of this subject in the search of new therapies for neuropsychiatric disorders such as depression, schizophrenia, drug addiction, and Parkinson's disease.
Di Monte, D. A., M. Lavasani, et al. (2002). "Environmental factors in Parkinson's disease." Neurotoxicology 23(4-5): 487-502.
Evidence discussed in this review article lends strong support in favor of an etiologic role of environmentalfactors in Parkinson's disease. First, thanks to the discovery of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), it is now clear that, by targeting the nigrostriatal system, neurotoxicants can reproduce the neurochemical and pathological features of idiopathic parkinsonism. The sequence of toxic events triggered by MPTP has also provided us with intriguing clues concerning mechanisms of toxicant selectivity and nigrostriatal vulnerability. Relevant examples are (i) the role of the plasma membrane dopamine transporter in facilitating the access of potentially toxic species into dopaminergic neurons; (ii) the vulnerability of the nigrostriatal system to failure of mitochondrial energy metabolism; and (iii) the contribution of inflammatory processes to tissue lesioning. Epidemiological and experimental data suggest the potential involvement of specific agents as neurotoxicants (e.g. pesticides) or neuroprotective compounds (e.g. tobacco products) in the pathogenesis of nigrostriatal degeneration, further supporting a relationship between the environment and Parkinson's disease. A likely scenario that emerges from our current knowledge is that neurodegeneration results from multiple events and interactive mechanisms. These may include (i) the synergistic action of endogenous and exogenous toxins (e.g. the ability of the pesticide diethyldithiocarbamate to promote the toxicity of other compounds); (ii) the interactions of toxic agents with endogenous elements (e.g. the protein alpha-synuclein); (iii) the tissue response to an initial toxic insult; and, last but not least, (iv) the effects of environmental factors on the background of genetic predisposition and aging.
Diekmann, S., J. Weston, et al. (2002). "Metal-mediated reactions modeled after nature." J Biotechnol 90(2): 73-94.
The Collaborative Research Center (CRC) 436 'Metal-Mediated Reactions Modeled after Nature' was founded for the express purpose of analyzing the catalytic principles of metallo-enzymes in order to construct efficient catalysts on a chemical basis. The structure of the active center and neighboring chemical environment in enzymes serves as a focal point for developing reactivity models for the chemical redesign of catalysts. Instead of simply copying enzyme construction, we strive to achieve new chemical intuition based on the results of long-lasting natural evolution. We hope for success, since nature uses a limited set of building blocks, whereas we can apply the full repertoire of chemistry. Key substrates in this approach are small molecules, such as CO2, O2 NO3- and N2. Nature complexes these substrates, activates them and performs chemical transformations--all within the active center of a metalloenzyme. In this article, we report on some aspects and first results of the Collaborative Research Center (CRC) 436, such as nitrate reductase, sphingolipid desaturase, carbonic anhydrase, leucine aminopeptidase and dopamine beta-monooxygenase.
Djaldetti, R. and E. Melamed (2002). "New drugs in the future treatment of Parkinson's disease." J Neurol 249 Suppl 2: II30-5.
During the last few decades, there has been a remarkable progress in our understanding of the biology of Parkinson's disease (PD), which has been translated into the development of numerous antiparkinsonian drugs. There are different therapeutic strategies for patients in an early stage versus patients in a late stage of the disease. The current therapeutic arsenal includes levodopa preparations, MAO-B inhibitors, dopamine agonists, COMT inhibitors and several other compounds that target non-dopaminergic systems. Much interest is focused on the potential neuroprotective effect of the already available drugs, as well as on new research approaches for the development of disease-modifying agents. These include mainly anti-glutamategic compounds, anti-apoptotic and antioxidative agents. Future therapy might include targeted delivery of trophic factors or genes involved in the pathogenesis of the disease. Apart from the classic levodopa-associated motor complications, such as dyskinesias and response fluctuations and psychosis, many other problems of advanced disease should be focused upon and solved including fatigue, freezing of gait, postural instability, depression, anxiety and panic attacks, sleep disturbances, autonomic dysfunction and sensory complaints.
Dluzen, D. E. and J. L. McDermott (2002). "Estrogen, anti-estrogen, and gender: differences in methamphetamine neurotoxicity." Ann N Y Acad Sci 965: 136-56.
In Part 1 of this report, we review data on the effects of estrogen (E), the anti-E tamoxifen (TMX), and testosterone (T) on methamphetamine (METH)-induced neurotoxicity in female and male CD-1 mice. Treatment of gonadectomized females with a physiological regimen of E significantly diminished the amount of striatal dopamine (DA) depletion to METH compared with non-E-treated mice. If these E-treated mice received coadministered TMX, the neuroprotective effects of E were abolished. However, TMX administration to either intact female or male mice appeared to exhibit a neuroprotective effect. Whereas E administration one week before METH treatment serves as a neuroprotectant, reversing the treatment order (METH-->one week-->E) failed to indicate any neurorestorative effects for E. This striatal DA-preserving effect of E was gender specific, because males receiving an identical treatment of E followed by METH failed to show any evidence of neuroprotection, nor did the predominantly male gonadal steroid hormone T afford any neuroprotection in gonadectomized male or female mice. In the second part of the report, we direct our attention toward examining some of the means by which E can exert this neuroprotective effect. The findings that gonadectomized female, but not intact male, mice treated with E show a significant reduction in body temperature can contribute to the gender-specific METH neuroprotection. E also diminishes the initial amounts of DA evoked by METH, as observed when E is co-infused with METH into superfused striatal tissue fragments of gonadectomized female and male mice. By contrast, T tends to increase METH-evoked DA responses. Finally, differences in mRNA levels were obtained between male and female mice treated with METH. Intact female mice tend to show greater levels of striatal glial fibrillary acidic protein and decreased levels of plasminogen activator inhibitor-1 compared with males. Each of these factors, combined with our previous findings that E can inhibit DA transporter function, represent significant events contributing to E/gender-dependent effects on METH neurotoxicity.
Doggrell, S. A. (2002). "The therapeutic potential of dopamine modulators on the cardiovascular and renal systems." Expert Opin Investig Drugs 11(5): 631-44.
In the periphery, physiological dopamine increases renal blood flow, decreases renal resistance and acts on the kidney tubule to enhance natriuresis and diuresis. The loss of dopamine function may be involoved in the deterioration in kidney function associated with ageing and may have a role in the pathogenesis of hypertension and diabetes. Intravenous dopamine is used as a positive inotrope in the treatment of acute heart failure and cardiogenic shock and as a diuretic in renal failure. The clinical uses of dopamine are limited, as it must be given intravenously, and also has widespread effects. The levels of peripheral dopamine can be increased by the administration of L-dopa to increase synthesis, prodrugs to release dopamine (docarpamine, glu-dopa) or by inhibiting the breakdown of dopamine (nitecapone). Preliminary clinical trials suggest that docarpamine may be useful in patients with low cardiac output syndrome after cardiac surgery and in refractory cirrhotic ascites. Ibopamine is an agonist at dopamine D1 and D2 receptors, which may retard the progression of chronic renal failure. Glu-dopa is selective for the kidney, thus avoiding widespread side effects. The early clinical studies with ibopamine as a diuretic in heart failure were favourable but the subsequent large mortality study showed that ibopamine increased mortality. Fenoldopam is a selective dopamine D1 receptor agonist. Intravenous fenoldopam may be useful in the treatment of hypertension associated with coronary artery bypass surgery or in hypertensive emergencies. Although our understanding of physiological and pathological roles of peripheral dopamine has been increasing rapidly in recent times, we still need more information to allow the design of clinically useful drugs that modify these roles. One priority is an orally-active selective dopamine D1 receptor agonist.
Dostrovsky, J. O., W. D. Hutchison, et al. (2002). "The globus pallidus, deep brain stimulation, and Parkinson's disease." Neuroscientist 8(3): 284-90.
Parkinson's disease (PD) is caused by the degeneration of the dopaminergic neurons in the substantia nigra. Loss of dopaminergic innervation leads to hyperactivity in the internal segment of the globus pallidus (GPi), the main output nucleus of the basal ganglia and to a profound disturbance in the function of motor circuits. Lesions of the GPi (or in its upstream modulator, the subthalamic nucleus) can greatly improve the motor symptoms of PD presumably by reducing this pathological activity. Paradoxically, high-frequency electrical stimulation of the GPi (deep brain stimulation, DBS) mimics the effects of pallidotomy and has become an accepted therapeutic technique. The mechanisms underlying the beneficial effects of pallidal DBS are not known. Various mechanisms that might account for inhibiting or disrupting the pathological pallidal outflow by high-frequency DBS have been proposed ranging from depolarization block to stimulation-evoked release of GABA, and these are discussed.
Double, K. L., D. Ben-Shachar, et al. (2002). "Influence of neuromelanin on oxidative pathways within the human substantia nigra." Neurotoxicol Teratol 24(5): 621-8.
Neuromelanin (NM) is a dark-coloured pigment produced in the dopaminergic neurons of the human substantia nigra (SN). The function of NM within the pigmented neurons is unknown but other melanins are believed to play a protective role via attenuation of free radical damage. Experimental evidence suggests that NM may also exhibit this characteristic, possibly by directly inactivating free radical species or via its ability to chelate transition metals, such as iron. Increased tissue iron, however, may saturate iron-chelating sites on NM and a looser association between iron and NM may result in an increased, rather than decreased, production of free radical species. The death of NM-pigmented neurons in Parkinson's disease (PD) is associated with both a measurable increase in tissue iron concentrations and indices of free radical mediated damage, suggesting that NM is involved in the aetiology of this disorder. As yet, it is unknown whether NM in the parkinsonian brain differs to that found in healthy tissue and thus may fulfil a different role within this tissue.
Dwoskin, L. P. and P. A. Crooks (2002). "A novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse." Biochem Pharmacol 63(2): 89-98.
Lobeline, an alkaloidal constituent of Lobelia inflata LINN., has a long history of therapeutic usage ranging from emetic and respiratory stimulant to tobacco smoking cessation agent. Although classified as both an agonist and an antagonist at nicotinic receptors, lobeline has no structural resemblance to nicotine, and structure--function relationships do not suggest a common pharmacophore. Lobeline inhibits nicotine-evoked dopamine release and [3H]nicotine binding, thus acting as a potent antagonist at both alpha3beta2(*) and alpha4beta2(*) neuronal nicotinic receptor subtypes. However, lobeline does not release dopamine from its presynaptic terminal, but appears to induce the metabolism of dopamine intraneuronally. Reevaluation of the mechanism by which lobeline alters dopamine function reveals that its primary mechanism is inhibition of dopamine uptake and promotion of dopamine release from the storage vesicles within the presynaptic terminal, via an interaction with the tetrabenazine-binding site on the vesicular monoamine transporter (VMAT2). Thus, lobeline appears to perturb the fundamental mechanisms of dopamine storage and release. Based on its neurochemical mechanism, the ability of lobeline to functionally antagonize the neurochemical and behavioral effects of the psychostimulants amphetamine and methamphetamine was examined. Lobeline was found to inhibit the amphetamine-induced release of dopamine in vitro, and amphetamine-induced hyperactivity, drug discrimination, and self-administration. However, lobeline does not support self-administration in rats, suggesting a lack of addiction liability. Thus, lobeline may reduce the abuse liability of these psychostimulants. The development of lobeline and lobeline analogs with targeted selectivity at VMAT2 represents a novel class of therapeutic agents having good potential as efficacious treatments for methamphetamine abuse.
Dybing, E. and T. Sanner (2002). "[Nicotine dependence--medico-biological aspects]." Tidsskr Nor Laegeforen 122(3): 302-5.
The nicotine in tobacco products is strongly addictive. This was generally recognised no earlier than in the late 1970s, though it was well known within the international tobacco industry in the early 1960s. Nicotine acts as an addictive substance by binding to acetylcholine receptors and causing the release of dopamine in the brain, though other signalling substances are also important for the action of nicotine in the central nervous system. Withdrawal syndrome is the typical evidence of physical addiction to nicotine. Nicotine addiction can develop rapidly. There are, however, individual differences; genetic predisposition may have a bearing on these differences.
Ebadi, M., S. Sharma, et al. (2002). "Neuroprotective actions of selegiline." J Neurosci Res 67(3): 285-9.
Selegiline, a selective inhibitor of monoamine oxidase-B (MAO-B), was one of the first adjunct therapies in clinical neurology. A retrospective analysis of data from patients with Parkinson's disease found a significant increase in survival in those treated with selegiline plus L-dopa compared with L-dopa alone. The mechanism of action of selegiline is complex and cannot be explained solely by its MAO-B inhibitory action. Pretreatment with selegiline can protect neurons against a variety of neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), 6-hydroxydopamine, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), methyl-beta-acetoxyethyl-2-chloroethylamine (AF64A), and 5,6-dihydroxyserotonin, which damage dopaminergic, adrenergic, cholinergic, and sertoninergic neurons, respectively. Selegiline produces an amphetamine-like effect, enhances the release of dopamine, and blocks the reuptake of dopamine. It stimulates gene expression of L-aromatic amino acid decarboxylase, increases striatal phenylethylamine levels, and activates dopamine receptors. Selegiline reduces the production of oxidative radicals, up-regulates superoxide dismutase and catalase, and suppresses nonenzymatic and iron-catalyzed autooxidation of dopamine. Selegiline compensates for loss of target-derived trophic support, delays apoptosis in serum-deprived cells, and blocks apoptosis-related fall in the mitochondrial membrane potential. Most of the aforementioned properties occur independently of selegiline's efficacy to inhibit MAO-B.
Eder, D. N. (2002). "CEE-03-310 CeNeS pharmaceuticals." Curr Opin Investig Drugs 3(2): 284-8.
CEE-03-310 is a selective dopamine D1-like receptor antagonist with no appreciable binding affinity for other receptors. Although originally developed by Novo Nordisk A/S as NNC-687 for the treatment of schizophrenia, the company changed its therapeutic focus in the mid-1990s and the full rights to CEE-03-310 and several related compounds were subsequently granted to CeNeS Pharmaceuticals in 1999. CeNeS is currently investigating the drug's potential in the treatment of insomnia and alcohol dependency [340965], [382293], [401496],[416026]. A phase II, double-blind, placebo-controlled trial of CEE-03-310 demonstrated a dose-dependent enhancement of NREM sleep at the beginning of the night without any effects on the quantity of REM sleep [410739].
Endlich, N. and K. Endlich (2002). "cAMP pathway in podocytes." Microsc Res Tech 57(4): 228-31.
Podocytes possess receptors for a variety of hormones. The following receptors whose stimulation results in increased cAMP levels have been detected in podocytes: adrenergic beta(2) receptor, dopamine D(1) receptor, prostaglandin IP and EP(4) receptors, and parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor. Besides activating protein kinase A, increased levels of cAMP depolarize podocytes via opening of chloride channels. Relatively little is known about the impact of the cAMP pathway on podocyte function. Results obtained in a limited number of studies indicate that cAMP in podocytes may regulate cell morphology, actin assembly, and matrix production. In addition, cAMP seems to attenuate the action of hormones, which activate the Ca(2+)/protein kinase C pathway. Effects of the cAMP pathway on further aspects of podocyte biology, such as contractility, phosphorylation state of slit membrane-associated proteins, glomerular permeability, cell cycle control, and synthesis of reactive oxygen species can be anticipated from studies on other cell types and from studies on isolated glomeruli. In summary, the data available indicate that the cAMP pathway affects several aspects of podocyte biology in an overall glomerulo-protective manner.
Erfurth, A., N. Michael, et al. (2002). "Bupropion as add-on strategy in difficult-to-treat bipolar depressive patients." Neuropsychobiology 45 Suppl 1: 33-6.
Bupropion, a selective norepinephrine and dopamine reuptake inhibitor, has been suggested for the treatment of bipolar depression, not only because of its efficacy, but also because of a probably lower risk of inducing switches to hypomania or mania. Most studies on bupropion treatment in bipolar patients have been performed in moderately ill out-patients. In contrast, we report on a sample of difficult-to-treat, predominantly severely ill, co-morbid, psychotic or therapy-refractory bipolar depressive in-patients. In this open and prospective study, 13 patients were treated with bupropion as an add-on strategy mainly to other antidepressants and to various mood stabilizers. Our data support the idea that bupropion is a first-line antidepressant in the treatment of severe bipolar depression. Eight of 13 patients showed a >50% reduction of Montgomery-Asberg Depression Scale ratings within 4 weeks. Co-medication with drugs commonly used in treatment-resistant bipolar disorder including venlafaxine, clozapine, lithium, topiramate and sodium valproate was safe in our small sample. While adhering to the suggestion of Goren and Levin not to exceed a daily dose of 450 mg of bupropion when treating bipolar depressed patients, we did not observe any switch from depression to hypomania or mania.
Erkinjuntti, T. (2002). "Treatment options: the latest evidence with galantamine (Reminyl)." J Neurol Sci 203-204: 125-30.
Vascular dementia (VaD) has a great deal of overlap (in terms of features and symptoms) with Alzheimer's disease (AD). Mixed dementia, or AD with concomitant cerebrovascular disease (AD with CVD), is increasingly being recognized as a distinct clinical condition that occurs with substantial frequency. The robust evidence for the effectiveness of cholinergic treatments such as galantamine (Reminyl) in AD suggests its potential use in the treatment of dementias related to CVD, and preclinical evidence supports this rationale. Galantamine, which has a unique dual cholinergic mode of action, may be of particular benefit in VaD and AD with CVD. For example, behavioral symptoms, which can be more severe in VaD than in AD and are important determinants of the impact of dementia, may be especially benefited by galantamine. This results from its potential to modulate systems involving other neurotransmitters such as 5-HT (serotonin) and dopamine, which affect mood and emotional balance. The results of a recent landmark clinical trial with galantamine in patients with VaD, or AD with CVD, indicate that galantamine produces benefits across a broad range of symptoms of dementia in both patient populations. Significant cognitive improvements over 6 months, long-term maintenance of cognition for at least 12 months, and global benefits, as well as efficacy in both behavioral and functional symptoms, indicate efficacy with galantamine that is so far unsurpassed by any other drug treatment for dementia. Galantamine therefore has potential to benefit a wide range of patients with dementia in the clinic.
Fava, M. and M. Rankin (2002). "Sexual functioning and SSRIs." J Clin Psychiatry 63 Suppl 5: 13-6; discussion 23-5.
This article reviews the literature concerning the relationship between sexual functioning and selective serotonin reuptake inhibitors (SSRIs). Reduced sexual functioning is a common depressive symptom that typically improves after successful antidepressant treatment. On the other hand, sexual dysfunction has been observed in a substantial proportion of patients treated with all classes of antidepressants. In particular, SSRI use has been shown to be associated with sexual dysfunction. A number of pharmacologic interventions have been found to be helpful in anecdotal case reports. Unfortunately, the lack of placebo-controlled studies in this area limits our ability to draw firm conclusions on the efficacy of such interventions. Three classes of drugs have primarily been used to counteract sexual side effects of SSRIs: serotonin receptor antagonists, a2-adrenergic receptor antagonists, and dopaminergic agents. An open trial from our group suggests the potential usefulness of oral sildenafil in the treatment of antidepressant-associated sexual side effects, but further studies are needed.
Feger, J., M. Pessigliore, et al. (2002). "[Experimental models of Parkinson's disease]." Ann Pharm Fr 60(1): 3-21.
Parkinson's disease is a neurodegenerative condition who is related to a large loss of nigral dopaminergic neurons leading to a depletion of dopamine in the striatum. Experimental research is required in order to increase our knowledge on the cellular mechanism and functional consequences of this degenerative process. These models allow investigations of new therapeutics in order to improve the treatment of patients or to test new drugs able to protect any remaining dopaminergic neurons. It is relatively easy to obtain animal models of this disease since the target structure and the neuronal population are clearly defined. Two neurotoxic compounds are available for inducing animal models of Parkinson's disease, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A new one, rotenone, requires further investigations. Each of the neurotoxic compounds requires a specific protocol which can be used either with rodents or non-human primates. Progressive lesioning, using MPTP on green african monkeys (Cercopithecus aethiops sabaeus) provides the most reliable model of the idiopathic disease.
Fernandez-Espejo, E. (2002). "[Neurobiological basis of drug addiction]." Rev Neurol 34(7): 659-64.
INTRODUCTION. Drugs of abuse cause addiction, characterized by compulsive and out of control drug use. Several neurochemical and molecular changes take place in the brain during the first phase of drug use which lead to dependence, addiction and drug abuse. DEVELOPMENT. Every drug of abuse acts through similar neurophysiological mechanisms, mostly based on the abnormal activation of the mesolimbic dopamine system. Although the addicted brain tries to adapted to the drug action, there are permanent neural changes at the cellular and molecular levels which seem to underlie the addictive process and the emergence of abstinence symptoms after drug taking stops. Furthermore, these neural changes appear to subserve the emergence of cravings once the abstinent syndrome has been overcome. Cravings are the main factor leading to relapse, and they are often initiated by exposure to drug related cues.
Ficzere, A. and L. Csiba (2002). "[Treatment of migraine in patients with hypertension and ischemic heart disease]." Ideggyogy Sz 55(1-2): 25-9.
Migraine is a common disorder with a prevalence of 9-10% in Hungary. Migraine can be accompanied by hypertension and/or ischemic heart disease sometimes in younger patients, but more frequently in the elderly, which is important for therapeutical considerations. The article reviews the literature with special focus on hypertension and coronary heart disease. In the second part, the authors summarize their experiences on headache patients.
Firoz, A. H., A. H. Rahman, et al. (2002). "Brief report on Ziprasidone." Mymensingh Med J 11(2): 129-32.
Ziprasidone is a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. The initial evidence suggests an effective dosage range of 80-160 mg/day. Clinical trials suggest that the drug is an effective antipsychotic in schizophrenia and schizo-affective disorder with a beneficial effect on negative symptoms and symptoms of depression. The main adverse effects appear to be somnolence (14%) and nausea (10%). Ziprasidone has relatively fewer side effects and yet has at least equivalent efficacy for florid 'positive' symptoms compared to conventional anti psychotics. The additional serotonergic actions deliver further efficacy against 'negative' and affective symptoms of schizophrenia. Reduced effects on cognitive abilities compared to conventional anti psychotics make Ziprasidone more attractive.
Freeman, M. P., S. A. Freeman, et al. (2002). "The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues." J Affect Disord 68(1): 1-23.
BACKGROUND: Although symptoms of anxiety as well as anxiety disorders commonly occur in patients with bipolar disorder, the pathophysiologic, theoretical, and clinical significance of their co-occurrence has not been well studied. METHODS: The epidemiological and clinical studies that have assessed the overlap of bipolar and anxiety disorders are reviewed, with focus on panic disorder and obsessive-compulsive disorder (OCD), and to a lesser extent, social phobia and post-traumatic stress disorder. Potential neural mechanism and treatment response data are also reviewed. RESULTS: A growing number of epidemiological studies have found that bipolar disorder significantly co-occurs with anxiety disorders at rates that are higher than those in the general population. Clinical studies have also demonstrated high comorbidity between bipolar disorder and panic disorder, OCD, social phobia, and post-traumatic stress disorder. Psychobiological mechanisms that may account for these high comorbidity rates likely involve a complicated interplay among various neurotransmitter systems, particularly norepinephrine, dopamine, gamma-aminobutyric acid (GABA), and serotonin. The second-messenger system constituent, inositol, may also be involved. Little controlled data are available regarding the treatment of bipolar disorder complicated by an anxiety disorder. However, adequate mood stabilization should be achieved before antidepressants are used to treat residual anxiety symptoms so as to minimize antidepressant-induced mania or cycling. Moreover, preliminary data suggesting that certain antimanic agents may have anxiolytic properties (e.g. valproate and possibly antipsychotics), and that some anxiolytics may not induce mania (e.g. gabapentin and benzodiazepines other than alprazolam) indicate that these agents may be particularly useful for anxious bipolar patients. CONCLUSIONS: Comorbid anxiety symptoms and disorders must be considered when diagnosing and treating patients with bipolar disorder. Conversely, patients presenting with anxiety disorders must be assessed for comorbid mood disorders, including bipolar disorder. Pathophysiological, theoretical, and clinical implications of the overlap of bipolar and anxiety disorders are discussed.
Freudenmann, R. W. (2002). "[Delusions of parasitosis: An up-to-date review]." Fortschr Neurol Psychiatr 70(10): 531-41.
This paper gives an up-to-date review on delusional parasitosis (DP) and particularly meets clinical interests. Facing the lack of clear guidelines for clinical practice an efficient diagnostic staircase procedure is presented. The different approaches in the therapy of DP are reviewed and summed up in a checklist. The available information on the therapeutic gold standard, the neuroleptic agent pimozide, is discussed. Symptoms and clinical characteristics of DP are presented partly based on material from an internet website run by patients. Moreover, this paper delivers a comprehensive literature review on the pathogenesis of DP and its classification. To conclude, possible future therapies in DP, e. g. serotonin-dopamine-antagonists, as well as current methods in research on hallucinations are discussed.
Friend, K. E. (2002). "Acromegaly: a new therapy." Cancer Control 9(3): 232-5.
BACKGROUND: The treatment of acromegaly can be challenging. Despite a multimodality approach (surgery,radiation, dopamine agonists, somatostatin analogs), many patients do not achieve normalization of serum insulin-like growth factor I (IGF-I) concentrations. METHODS: The author discusses the characteristics and indications of pegvisomant therapy for patients with acromegaly and compares the use of this newly developed GH receptor antagonist with other pharmacological agents such as somatostatin and dopamine agonists. RESULTS: Therapy with pegvisomant allows serum IGF-I concentrations to be normalized in up to 97% of patients with acromegaly, including those who have failed other treatment modalities. With this agent,circulating GH levels increase as a result of the drop in IGF-I levels. The rise is rapid (within 2 weeks) and does not appear to be progressive over time. CONCLUSIONS: Published studies have shown pegvisomant to have efficacy in the treatment of acromegaly. As it appears to be well tolerated and safe, this novel compound may be an important therapeutic option for patients with acromegaly. Additional study of this novel agent and its mode of action is warranted.
Fukui, K. (2002). "[Basic and clinical studies on solvent abuse]." Seishin Shinkeigaku Zasshi 104(1): 66-70.
Gabay, M. P. (2002). "Galactogogues: medications that induce lactation." J Hum Lact 18(3): 274-9.
Galactogogues are medications that aid in initiating and maintaining adequate milk production. Most exert their pharmacologic effects through interactions with dopamine receptors, resulting in increased prolactin levels and thereby augmenting milk supply. Metoclopramide remains the galactogogue of choice due to its documented record of efficacy and safety in women and infants. Domperidone crosses the blood brain barrier and into the breast milk to a lesser extent than metoclopramide, decreasing the risk of toxicity to both mother and infant possibly making it an attractive alternative. Traditional antipsychotics, sulpiride and chlorpromazine, have been evaluated, but adverse events limit their use. Human growth hormone, thyrotrophin-releasing hormone, and oxytocin have also been studied. Finally, a natural product, fenugreek, has been purported to be effective in anecdotal reports. Use of this agent may be warranted after considering risks versus benefits.
Gagnon, J. F., J. Montplaisir, et al. (2002). "[Rapid-eye-movement sleep disorders in Parkinson's disease]." Rev Neurol (Paris) 158(2): 135-52.
During the past 10 years, there has been an increasing interest in the study of rapid-eye-movement (REM) sleep in neurodegenerative diseases and more particulary in Parkinson's disease (PD). This interest is justified by the strong association observed between these diseases and REM sleep behavior disorder (RBD). In the first section of this paper, a critical review of the literature on the presence of REM sleep disorders in PD is presented. Studies that show an association between PD and RBD are reviewed. Studies that report the presence of other REM sleep disorders in PD (short latency, abnormal length and/or proportion of REM sleep, increasing occurrence of hallucinations) are then discussed. Limitations of the criteria proposed by Rechtschaffen et Kales (1968) for the quantification of REM sleep are also presented. Some authors believe that dopaminergic (DA) agents used in the treatment of PD (levodopa, bromocriptine, pergolide, pramipexole and selegiline) could be a responsable factor for the occurence of REM sleep disorders observed in this disease. The literature concerning the impact of these DA agents on human REM sleep is therefore critically reviewed. It is concluded that DA agents cannot explain on their own the presence of REM sleep disorders in PD. Other causes, among which the disturbance of some neurochemical systems linked to the neuropathological process of the disease, must be considered in order to explain these REM sleep disorders. In the second section of this paper, we present the different pathophysiological hypotheses proposed to explain REM sleep disorders in PD, such as a dysfunction of the cholinergic, noradrenergic, serotonergic, dopaminergic or GABAergic neurons. Emphasis is placed on the role of cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei, structures shown to be particularly impaired in PD. Neurophysiological, neuroanatomical and neuropharmacological studies demonstrate that these neurons are strongly implicated in the different REM sleep parameters (muscular atonia, electroencephalographic desynchronisation, ponto-geniculo-occipital spikes). Finally, future research directions are proposed.
Gainetdinov, R. R., T. D. Sotnikova, et al. (2002). "Monoamine transporter pharmacology and mutant mice." Trends Pharmacol Sci 23(8): 367-73.
Monoamine transporters, such as the dopamine transporter, 5-HT transporter and noradrenaline transporter, in the plasma membrane provide effective control over the intensity of monoamine-mediated signaling by recapturing neurotransmitters released by presynaptic neurons. These proteins represent established targets for several psychotropic drugs, including psychostimulants and antidepressants; however, important issues regarding the selectivity and mechanisms of action of these drugs remain unresolved. Although monoamine transporter knockout mice have profound changes in neurotransmission, they provide useful in vivo models to analyze the effects of psychotropic drugs. In this review, we summarize recent insights into the pharmacology of psychotropic drugs using mice in which the genes encoding these transporters have been deleted.
Gambaro, G., G. Bertaglia, et al. (2002). "Diuretics and dopamine for the prevention and treatment of acute renal failure: a critical reappraisal." J Nephrol 15(3): 213-9.
The efficacy of diuretics and dopamine in preventing and treating acute renal failure (ARF) is still debated, although these drugs are widely used in clinical practice. The present review addresses this debate providing an update on available data. There are very few well controlled and sufficiently large trials testing these agents in different ARF clinical settings, with either a preventive or a curative goal. Unfortunately, most findings rule out any favourable effects of diuretics, mannitol, atrial natriuretic peptides, and dopamine. In fact, at least in some clinical conditions, they can even worsen the risk of ARF or aggravate its course.
Gao, X. F., X. Q. Wang, et al. (2002). "[Progress of monoaminergic receptor investigation on depression]." Sheng Li Ke Xue Jin Zhan 33(1): 17-20.
It is widely accepted that monoamine transmitters are playing an important role in the progress of depression. The functions of monoamine transmitters and their receptors change profoundly during depression and its treatment. This paper is attempted to review the new progress of investigation into serotonin receptors, adrenoceptors and dopamine receptors related with depression mechanism respectively.
Gareri, P., P. De Fazio, et al. (2002). "Neuropharmacology of depression in aging and age-related diseases." Ageing Res Rev 1(1): 113-34.
Depression in the elderly is nowadays a predominant health care problem, mainly due to the progressive aging of the population. It results from psychosocial stress, polypathology, as well as some biochemical changes which occur in the aged brain and can lead to cognitive impairments, increased symptoms from medical illness, higher utilization of health care services and increased rates of suicide and non-suicide mortality. Depression may be also caused by a various number of drugs currently administered; this is remarkable especially in elderly people, where polypathology is often associated with polypharmacotherapy. However, the pathogenesis of geriatric depression is not well understood; major depression may arise from dysfunction of the limbic-hypothalamic-pituitary-adrenal axis. Some clinical observations also suggest that striato-frontal dysfunction is associated with late life depression. A number of hypotheses have been made, focusing that mood disturbances are probably linked to a disturbed central metabolism of monoamines 5-hydroxytryptamine, noradrenaline and dopamine; however most of this knowledge is derived from animal models. Parkinson's and Alzheimer's diseases are age-related diseases associated to decreased activity or brain lesions in the orbital frontal cortex and basal ganglia. These observations lead to the hypothesis that the dysfunction of one or more of the cortical basal ganglia-thalamic neuronal loops are involved in the pathophysiology of primary and secondary depression. This dysfunction may be mediated by decreased serotonin release and probably, also by reduction in serotonin receptors. Development of novel approaches such as dynamic brain imaging methods, together with indirect knowledge coming from the effects of new antidepressants, will increase the understanding of neurochemistry of depression in old age.
Garland, E. M., M. K. Hahn, et al. (2002). "Genetic basis of clinical catecholamine disorders." Ann N Y Acad Sci 971: 506-14.
Norepinephrine and epinephrine are critical determinants of minute-to-minute regulation of blood pressure. Here we review the characterization of two syndromes associated with a genetic abnormality in the noradrenergic pathway. In 1986, we reported a congenital syndrome of undetectable tissue and circulating levels of norepinephrine and epinephrine, elevated levels of dopamine, and absence of dopamine-beta-hydroxylase (DBH). These patients appeared with ptosis and severe orthostatic hypotension and lacked sympathetic noradrenergic function. In two persons with DBH deficiency, we identified seven novel polymorphisms. Both patients are compound heterozygotes for a variant that affects expression of DBH protein via impairment of splicing. Patient 1 also has a missense mutation in DBH exon 2, and patient 2 carries missense mutations in exons 1 and 6. Orthostatic intolerance is a common syndrome affecting young women, presenting with orthostatic tachycardia and symptoms of cerebral hypoperfusion on standing. We tested the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to its etiology. In our proband, we found an elevated plasma norepinephrine with standing that was disproportionate to the increase in levels of dihydroxphenylglycol, as well as impaired norepinephrine clearance and tyramine resistance. Studies of NET gene structure revealed a coding mutation converting a conserved alanine residue in transmembrane domain 9 to proline. Analysis of the protein produced by the mutant cDNA demonstrated greater than 98% reduction in activity relative to normal. The finding of genetic mutations responsible for DBH deficiency and orthostatic intolerance leads us to believe that genetic causes of other autonomic disorders will be found, enabling us to design more effective therapeutic interventions.
Gauda, E. B. (2002). "Gene expression in peripheral arterial chemoreceptors." Microsc Res Tech 59(3): 153-67.
The peripheral arterial chemoreceptors of the carotid body participate in the ventilatory responses to hypoxia and hypercapnia, the arousal responses to asphyxial apnea, and the acclimatization to high altitude. In response to an excitatory stimuli, glomus cells in the carotid body depolarize, their intracellular calcium levels rise, and neurotransmitters are released from them. Neurotransmitters then bind to autoreceptors on glomus cells and postsynaptic receptors on chemoafferents of the carotid sinus nerve. Binding to inhibitory or excitatory receptors on chemoafferents control the electrical activity of the carotid sinus nerve, which provides the input to respiratory-related brainstem nuclei. We and others have used gene expression in the carotid body as a tool to determine what neurotransmitters mediate the response of peripheral arterial chemoreceptors to excitatory stimuli, specifically hypoxia. Data from physiological studies support the involvement of numerous putative neurotransmitters in hypoxic chemosensitivity. This article reviews how in situ hybridization histochemistry and other cellular localization techniques confirm, refute, or expand what is known about the role of dopamine, norepinephrine, substance P, acetylcholine, adenosine, and ATP in chemotransmission. In spite of some species differences, review of the available data support that 1). dopamine and norepinephrine are synthesized and released from glomus cells in all species and play an inhibitory role in hypoxic chemosensitivity; 2). substance P and acetylcholine are not synthesized in glomus cells of most species but may be made and released from nerve fibers innervating the carotid body in essentially all species; 3). adenosine and ATP are ubiquitous molecules that most likely play an excitatory role in hypoxic chemosensitivity.
Gekht, A. B. (2002). "[Use of dopamine agonists in the treatment of Parkinson's disease]." Zh Nevrol Psikhiatr Im S S Korsakova 102(9): 54-8.
Gill, J. R., J. A. Hayes, et al. (2002). "Ecstasy (MDMA) deaths in New York City: a case series and review of the literature." J Forensic Sci 47(1): 121-6.
MDMA ("ecstasy") has gained renewed popularity as a drug of abuse. To access the epidemiology and causes of death of MDMA-positive fatalities, all deaths investigated by the OCME that tested positive for MDMA (22 deaths) between January 1997 and June 2000 were reviewed. There were three deaths in each 1997 and 1998, eleven in 1999, and five in the first part of 2000. Of these 22 deaths, 13 were due to acute drug intoxications, 7 due to mechanical injury (blunt trauma, gunshot wounds), and 2 due to a combination of natural disease and acute drug intoxication. Evidence of recent opiate and/or cocaine use was found in 7 of the acute intoxication deaths and in none of the traumatic or combination natural/intoxication deaths. The race of all decedents was White between the ages of 17-41 years, and 18 of 22 were men.
Giuliano, F., O. Rampin, et al. (2002). "Neurophysiology and pharmacology of female genital sexual response." J Sex Marital Ther 28 Suppl 1: 101-21.
Vaginal sexual arousal is a vasocongestive and neuromuscular event controlled by facilitatory parasympathetic and inhibitory sympathetic inputs. Autonomic preganglionic parasympathetic and inhibitory sympathetic fibers to the vagina and clitoris originate in the spinal cord in the sacral parasympathetic nucleus at the sacral level and in the dorsal gray commissure and the intermediolateral cell column at the thoracolumbar level, respectively. Parasympathetic fibers are conveyed by the pelvic nerve, and sympathetic fibers are conveyed by the hypogastric nerve and the paravertebral sympathetic chain. The activity of these spinal nuclei is controlled by descending projections from the brain and sensory afferens (conveyed in the pudendal, hypogastric, pelvic, and vagus nerves) from the genitalia. A key but unresolved issue concerns the neurotransmitters involved in the control of genital sexual arousal. At the peripheral level, acetylcholine plays a minor role in the regulation of vaginal blood flow, however, recent data suggests that it may be involved in the control of vaginal smooth muscle contractions. Vasoactive intestinal peptide and nitric oxide may be responsible for the increase in vaginal blood flow during sexual arousal, whereas noradrenaline is likely inhibitory. Within the central nervous system, serotoninergic projections from the brain to the spinal cord likely inhibit the induction of genital arousal by peripheral informations (spinal reflex). Although some neurotransmitters regulating the display of sexual behavior have been identified (for example, dopamine), their involvement in the control of genital sexual arousal has not been invested. Anatomical and electrophysiological data point to a contribution of the paraventricular nucleus of he hypothalamus and the median preoptic area, respectively, as key elements in the control of genital arousal. The recent development of models allowing the assessment of vaginal sexual arousal in anesthetized female rats should assist in deciphering the neurochemical pathways controlling vaginal sexual arousal and the development of suitable pharmacological treatment for female sexual dysfunctions.
Giuliano, F. and J. Allard (2002). "Apomorphine SL (Uprima): preclinical and clinical experiences learned from the first central nervous system-acting ED drug." Int J Impot Res 14 Suppl 1: S53-6.
An exclusive central site of action for the proerectile effect of apomorphine, including not only the brain but also the spinal cord, is supported by extensive experimental data. Assuming that the mechanisms of action of apomorphine are similar in humans and animal models, its use for the treatment of erectile dysfunction (ED) validates the emerging idea that erectile response could be enhanced by acting directly within the central nervous system (CNS). It also emphasized the key role of the dopaminergic system in the control of erection. As exemplified with the clinical development of apomorphine, targeting the CNS does not rule out the occurrence of undesirable side effects. Because the rare event of syncope induced by apomorphine is not well understood, further research should be conducted to explore its possible mechanisms. In clinical practice, however, approved doses of apomorphine SL are well tolerated. It is noteworthy that no modification of sexual desire was observed with apomorphine. Indeed, drugs acting within the CNS may more likely interact with sexual desire than peripherally acting drugs, and care should be taken to assess this point in the future. Although our knowledge of the control of penile erection by the CNS is restricted, there are many potential sites for CNS-acting ED drugs. New centrally acting therapy for ED should concentrate on receptor targets more specific to erectile command. Clinical efficacy of new centrally-acting compounds will assess the well-founded purpose of this rationalization.
Glennon, R. A., K. Metwally, et al. (2002). "Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists." Curr Top Med Chem 2(6): 539-58.
The structures of ketanserin (1) and spiperone (2) were examined in detail to determine the role of various substituent groups on 5-HT(2A) receptor affinity and selectivity. It was found that the presence of the quinazoline ring of ketanserin detracts from selectivity and that various ring-opened analogs displayed ketanserin-like affinity and up to 30-fold enhanced selectivity. The triazaspirodecanone portion of spiperone is a major determinant of its 5-HT affinity and selectivity. The conformational rigidity imposed by the ring, as well as the nature of the N(1)-substituent, are important factors in controlling binding at 5-HT(2A), 5-HT(2C), 5-HT(1A), and dopamine D2 receptors. Replacement of the N(1)-phenyl ring of spiperone with a methyl group (KML-010; 48) resulted in a compound that binds at 5-HT(2A) receptors with slightly lower affinity than spiperone, but that lacked affinity (Ki >10,000 nM) for 5-HT(2C) and 5-HT(1A) receptors and binds with 400-fold reduced affinity at D2 receptors.
Goeders, N. E. (2002). "Stress and cocaine addiction." J Pharmacol Exp Ther 301(3): 785-9.
The hypothalamo-pituitary-adrenal (HPA) axis is involved in all aspects of cocaine self-administration. Corticosterone seems to be crucial for the acquisition of drug use since self-administration does not occur unless this stress hormone is increased above a critical reward threshold. Increasing circulating levels of corticosterone also augments sensitivity to low doses of cocaine, possibly from a sensitization-associated phenomenon involving dopamine, suggesting that exposure to stress can increase individual vulnerability to cocaine. Drugs affecting the synthesis and/or secretion of corticosterone decrease ongoing, low-dose cocaine self-administration. When higher doses falling on the descending limb of the cocaine dose-response curve are self-administered, plasma corticosterone can still reach this reward threshold even when synthesis is inhibited and drug intake is not affected. Corticotropin-releasing hormone (CRH) seems to play a more prominent role in the maintenance of cocaine self-administration and may even be involved in the incentive motivation for the drug. Corticosterone and CRH are also critical for the stress- and cue-induced reinstatement of extinguished cocaine-seeking behavior. Therefore, cocaine self-administration may represent an attempt to seek out specific sensations, with the internal state produced being very similar to that perceived by individuals who engage in risky, thrill-seeking behavior. During abstinence, exposure to stressors or cocaine-associated cues can stimulate the HPA axis to remind the individual about the effects of cocaine, thus producing craving and promoting relapse. Stress reduction, either alone or in combination with pharmacotherapies targeting the HPA axis may prove beneficial in reducing cravings and promoting abstinence in individuals seeking treatment for cocaine addiction.
Goeders, N. E. (2002). "The HPA axis and cocaine reinforcement." Psychoneuroendocrinology 27(1-2): 13-33.
Scientists have been aware of the existence of a complex relationship between stress and the subsequent activation of the hypothalamic-pituitary-adrenal (HPA) axis and the endocrine and neurobehavioral effects of cocaine for many years now. Our research program has focused on the involvement of HPA axis activation in cocaine reinforcement using the intravenous self-administration model. Behaviorally, there are at least three general phases in the etiology of drug self-administration to consider: acquisition, maintenance and reinstatement. We have investigated the role for the HPA axis during each of these three phases. Corticosterone is necessary during acquisition; self-administration does not occur unless this stress-related hormone is increased above a threshold critical for reward. Sensitivity to low doses of cocaine falling on the ascending limb of the acquisition dose-response curve can be augmented by increasing circulating levels of corticosterone, but similar treatments do not affect responding maintained by higher doses. In a similar vein, ongoing, low-dose cocaine self-administration is decreased by drugs affecting the synthesis and/or secretion of corticosterone. When higher doses falling on the descending limb of the cocaine dose-response curve are self-administered, plasma corticosterone can still reach this hypothetical reward threshold even when synthesis is inhibited, and drug intake is not affected. On the other hand, the self-administration of doses falling on both the ascending and descending limbs of the cocaine dose-response curve can each be attenuated by drugs that block central corticotropin-releasing hormone (CRH) receptors. Finally, corticosterone and CRH are also critical for the stress- and cue-induced reinstatement of extinguished cocaine-seeking behavior, demonstrating an involvement of the HPA axis in the relapse to cocaine use as well. Continued investigations into how stress and the subsequent activation of the HPA axis affect cocaine self-administration will likely result in the identification of more effective and efficient treatment for cocaine addiction.
Goldstein, R. Z. and N. D. Volkow (2002). "Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex." Am J Psychiatry 159(10): 1642-52.
OBJECTIVE: Studies of the neurobiological processes underlying drug addiction primarily have focused on limbic subcortical structures. Here the authors evaluated the role of frontal cortical structures in drug addiction. METHOD: An integrated model of drug addiction that encompasses intoxication, bingeing, withdrawal, and craving is proposed. This model and findings from neuroimaging studies on the behavioral, cognitive, and emotional processes that are at the core of drug addiction were used to analyze the involvement of frontal structures in drug addiction. RESULTS: The orbitofrontal cortex and the anterior cingulate gyrus, which are regions neuroanatomically connected with limbic structures, are the frontal cortical areas most frequently implicated in drug addiction. They are activated in addicted subjects during intoxication, craving, and bingeing, and they are deactivated during withdrawal. These regions are also involved in higher-order cognitive and motivational functions, such as the ability to track, update, and modulate the salience of a reinforcer as a function of context and expectation and the ability to control and inhibit prepotent responses. CONCLUSIONS: These results imply that addiction connotes cortically regulated cognitive and emotional processes, which result in the overvaluing of drug reinforcers, the undervaluing of alternative reinforcers, and deficits in inhibitory control for drug responses. These changes in addiction, which the authors call I-RISA (impaired response inhibition and salience attribution), expand the traditional concepts of drug dependence that emphasize limbic-regulated responses to pleasure and reward.
Gordon, N. (2002). "Stuttering: incidence and causes." Dev Med Child Neurol 44(4): 278-81.
Goth, M., E. Hubina, et al. (2002). "[Novel pharmacologic therapies in acromegaly]." Orv Hetil 143(19 Suppl): 1057-62.
The primary aim of therapy should be to remove symptoms, reduce tumor bulk, prevent relapse, and improve long-term outcome. Surgery, radiotherapy and medical therapies are used to achieve these aims. Post-treatment mean "safe" serum growth hormone values of < 2.5 ng/ml should be the therapeutic goal. Transsphenoidal surgery remains the first line treatment for acromegaly. Patients with microadenoma can expect 85%, while those with macroadenoma 50% chance to achieve safe serum growth hormone levels. Less than 20% of acromegalics respond to treatment with bromocriptine, while quinagolide and cabergoline may show better clinical response; the success rate is higher for tumors secreting both growth hormone and prolactin. Dopamine agonists may be considered either in combination with somatostatin-analogues or as monotherapy in selected patients, and in those with co-secretion of prolactin. Octreotide (Sandostatin, Novartis) is a synthetic somatostatin-analogue, which is administered subcutaneously in doses between 100 and 250 micrograms 3 times daily. Long-acting octreotide (Sandostatin LAR, Novartis) contains octreotide incorporated into microspheres of biodegradable polymer. To effectively lower serum growth hormone levels, monthly injections of 10-30 mg of long-acting octreotide are needed, serum growth hormone falls to 2.5 ng/ml in 70% of cases, and serum insulin-like growth factor I normalizes in 67%. Slow release lanreotide (Somatuline SR, Ipsen) is an alternative depot long-acting somatostatin-analogue, which is administered in a dose of 30 mg intramuscularly every 14, 10 or 7 days. Both compounds are equally, if not more, effective than subcutaneous octreotide, and significantly improve patient compliance. Pegvisomant (Sensus Drug Development Corporation) is a genetically engineered growth hormone receptor antagonist, which inhibits growth hormone action. When given subcutaneously in a dose of 20 mg/day, serum insulin-like growth factor I levels return to normal in 90% of patients. Theoretical concerns of tumor expansion have not been a problem to date, but long term studies are needed. Primary medical--somatostatin-analogue--therapy is recommended if surgery fails, if the patient refuses or unsuited for surgery and it may be also considered in patients with macroadenoma with extra--but not suprasellar extension, since the surgical "cure" rates of these tumors are low.
Gottesmann, C. (2002). "The neurochemistry of waking and sleeping mental activity: the disinhibition-dopamine hypothesis." Psychiatry Clin Neurosci 56(4): 345-54.
This paper describes a hypothesis related to the neurochemical background of sleep-waking mental activity which, although associated with subcortical structures, is principally generated in the cerebral cortex. Acetylcholine, which mainly activates cortical neurons, is released at the maximal rate during waking and rapid eye movement (REM) sleep dreaming stage. Its importance in mental functioning is well-known. However, brainstem-generated monoamines, which mainly inhibit cortical neurons, are released during waking. Both kinds of influences contribute to the organized mentation of waking. During slow wave sleep, these two types of influence decrease in intensity but maintain a sufficiently high level to allow mental activity involving fairly abstract pseudo-thoughts, a mode of activity modelled on the diurnal pattern of which it is a poor reply. During REM sleep, the monoaminergic neurons become silent except for the dopaminergic ones. This results in a large disinhibition and the maintained dopamine influence may be involved in the familiar psychotic-like mental activity of dreaming. Indeed, in this original activation-disinhibition state, the increase of dopamine influence at the prefrontal cortex level could explain the almost total absence of negative symptoms of schizophrenia during dreaming, while an increase in the nucleus accumbens is possibly responsible for hallucinations and delusions, which are regular features of mentation during this sleep stage.
Grasby, P. M. (2002). "Imaging the neurochemical brain in health and disease." Clin Med 2(1): 67-73.
Neurochemical transmission is a fundamental element of brain organisation that has been relatively unexplored in the living human brain. Continuing advances in radionuclide imaging, particularly positron emission tomography (PET) and single photon emission tomography (SPET), mean that elements of neurochemical transmission can now be directly measured in vivo. With these techniques convincing abnormalities of monoaminergic neurotransmitter systems have been revealed in illnesses such as Parkinson's disease and schizophrenia. Furthermore, mechanisms of drug action and treatment responses can be monitored in vivo. This brief review describes some of our recent attempts to image the neurochemical brain in health and disease at the MRC Cyclotron Unit, Hammersmith Hospital, London.
Grieb, P. and R. Rejdak (2002). "Pharmacodynamics of citicoline relevant to the treatment of glaucoma." J Neurosci Res 67(2): 143-8.
Citicoline (exogenous CDP-choline) is a nontoxic and well-tolerated drug used in pharmacotherapy of brain insufficiency and some other neurological disorders, such as stroke, brain trauma, and Parkinson's disease. A few reports indicate that citicoline treatment may also be beneficial in glaucoma. Currently glaucoma is considered a neurodegenerative disease in which retinal ganglion cells (RGC) slowly die, likely in the apoptotic mechanism. Endogenous CDP-choline is a natural precursor of cellular synthesis of phospholipids, mainly phosphatydylcholine (PtdCho). Enhancement of PtdCho synthesis may counteract neuronal apoptosis and provide neuroprotection. Citicoline, when administered, undergoes a quick transformation to cytidine and choline, which are believed to enter brain cells separately and provide neuroprotection by enhancing PtdCho synthesis; similar effect may be expected to occur in glaucomatous RGC. Furthermore, citicoline stimulates some brain neurotransmitter systems, including the dopaminergic system, and dopamine is known as a major neurotransmitter in retina and postretinal visual pathways. In a double-blind, placebo-controlled study, treatment of glaucoma resulted in functional improvement in the visual system noted with electrophysiological methods. Development of citicoline as a treatment for glaucoma is indicated.
Gu, Q. (2002). "Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity." Neuroscience 111(4): 815-35.
Cortical neuromodulatory transmitter systems refer to those classical neurotransmitters such as acetylcholine and monoamines, which share a number of common features. For instance, their centers are located in subcortical regions and send long projection axons to innervate the cortex. The same transmitter can either excite or inhibit cortical neurons depending on the composition of postsynaptic transmitter receptor subtypes. The overall functions of these transmitters are believed to serve as chemical bases of arousal, attention and motivation. The anatomy and physiology of neuromodulatory transmitter systems and their innervations in the cerebral cortex have been well characterized. In addition, ample evidence is available indicating that neuromodulatory transmitters also play roles in development and plasticity of the cortex. In this article, the anatomical organization and physiological function of each of the following neuromodulatory transmitters, acetylcholine, noradrenaline, serotonin, dopamine, and histamine, in the cortex will be described. The involvement of these transmitters in cortical plasticity will then be discussed. Available data suggest that neuromodulatory transmitters can modulate the excitability of cortical neurons, enhance the signal-to-noise ratio of cortical responses, and modify the threshold for activity-dependent synaptic modifications. Synaptic transmissions of these neuromodulatory transmitters are mediated via numerous subtype receptors, which are linked to multiple signal transduction mechanisms. Among the neuromodulatory transmitter receptor subtypes, cholinergic M(1), noradrenergic beta(1) and serotonergic 5-HT(2C) receptors appear to be more important than other receptor subtypes for cortical plasticity. In general, the contribution of neuromodulatory transmitter systems to cortical plasticity may be made through a facilitation of NMDA receptor-gated processes.
Guerot, E., O. Sanchez, et al. (2002). "[Acute complications in cocaine users]." Ann Med Interne (Paris) 153(3 Suppl): 1S27-31.
Cocaine use has increased considerably during the last twenty years and several related complications can be identified. Clinical features of cocaine intoxication are variable, but predominantly involve cardiovascular events. Chest pain is the most main complaint; myocardial ischemia must be ruled out. Other cardiovascular manifestations are left ventricular dysfunction, arrhythmia, endocarditis and aortic dissection. Non-cardiac complications include neurological (seizures, stroke, cerebral hemorrhage), respiratory (asthma, interstitial pneumonitis, pulmonary edema), renal (acute renal failure, rhabdomyolysis) and obstetrical disorders. Detection of cocaine in the urine provides the diagnosis. Symptomatic treatment is generally given, combining conventional treatment of the complication and broad use of benzodiazepines.
Guignard, J. P. (2002). "[Aggression to the immature kidney]." Pediatr Med Chir 24(2): 105-10.
The main causes for acute renal failure (ARF) in the newborn include endogenous factors (such as hypotension, hypovolemia, hypoxemia, perinatal asphyxia, and neonatal septicemia) and exogenous factors such as mechanical ventilation, nephrotoxic agents (antibiotics, indomethacin, ibuprofen, angiotensin converting enzyme inhibitors, and tolazoline). These conditions determinate vasoactive disturbances interfering with the delicate balance of intrarenal vasoconstrictor and vasodilator forces, which regulates the glomerular filtration rate (GFR) in the healthy term, and particularly in the premature infant. Factors influencing renal prognosis are the severity of the underlying disorder, the rapidity of an accurate diagnosis, prompt treatment, and avoidance of severe iatrogenic complications. Plasma creatinine concentrations should be used with some caution for ARF diagnosis in the first days of life. General measures of kidney protection include correcting abnormalities in fluid homeostasis, adequate ventilation and rational choice of drugs. Moreover, in order to protect the kidney, different compounds have been proposed such as diuretics (furosemide and torasemide), and dopaminergic agents (dopamine, dopexamine). With the increasing knowledge of the mechanisms governing the development of ARF, progress has been made in the development of new treatment modalities. For example theophylline, calcium antagonists, ATP-MgCl2, thyroxine, and antibodies against endothelin may in the near future be used to prevent or ameliorate the prognosis of the neonatal stressed kidney. The main renal replacement therapies are possible in the newborn. However preventive measures are easily available in the neonatal period and they often represent the most efficacious procedures.
Guymer, E. K. and D. J. Clauw (2002). "Treatment of fatigue in fibromyalgia." Rheum Dis Clin North Am 28(2): 367-78.
Clearly, fatigue is a large and challenging problem for those suffering from fibromyalgia. It adds greatly to the morbidity and disability associated with the disease. In the management of this specific symptom in fibromyalgia, attention should first be focused on identifying comorbidities that may be present and contribute to fatigue. As with other symptoms of fibromyalgia, education is a critical component of management. This can be done by the practitioner, with available free resources, or with specialized cognitive behavioral programs. This education process can be augmented with a variety of other nonpharmacologic therapies, especially very gradually increasing, low-impact, aerobic exercise programs. Numerous pharmacologic therapies may also be helpful as an adjunct to treatment. Classes of compounds that raise central levels of norepinephrine or dopamine appear to be the most specific for management of fatigue. There are also many medications used to combat fatigue in other disorders that have not yet been adequately explored as to the possible benefits in alleviating the fatigue of fibromyalgia. Advances in the management of fatigue in fibromyalgia are likely to come from a variety of directions. Easier access to well designed nonpharmacologic therapies is essential, because these treatments are underutilized in clinical practice at present. Improvements in pharmacologic therapies will come from new insights into mechanisms, especially those that might only be present in subsets of patients and would respond to more targeted therapies.
Hackling, A. E. and H. Stark (2002). "Dopamine D3 receptor ligands with antagonist properties." Chembiochem 3(10): 946-61.
The dopamine D(3) receptor has been recognized to play an important role in the molecular mechanisms of various neuropsychiatric disorders. The development of new dopamine D(3) receptor selective antagonists is premised on the potentially improved therapeutic treatment of psychosis like schizophrenia. Partial agonists at dopamine D(3) receptors are supposed to be beneficial when administered to drug abusers or in Parkinson's disease. The structural basis for most compounds is at least a basic, aryl-substituted alkanamine part with an alkyl moiety, which in many compounds forms a spacer to another aryl residue. Structural variety among the amine moiety includes aminotetralins, tetrahydroisoquinolines, isoindoles, benzazepines, and aminoindans, as well as pyrrolidines, pyrroles, and 4-phenylpiperazines. Various ways for lead optimization are shown in different classes of compounds. Promising ligands with high D(3) receptor affinity often lack sufficient selectivity or display deficits in the required in vivo parameters. Structure-activity relationships for dopamine D(3) receptor antagonists and partial agonists are discussed here, along with the outlook for their potential therapeutic application.
Haeusler, G., H. Leitich, et al. (2002). "Drug therapy of urinary urge incontinence: a systematic review." Obstet Gynecol 100(5 Pt 1): 1003-16.
OBJECTIVE: To review the efficacy of drug therapy for urinary urge incontinence by examining the published literature. METHODS OF STUDY SELECTION: In October 1999, we searched the medical databases MEDLINE, EMBASE, and Cochrane Controlled Trials Register to identify prospective randomized, double-blind, placebo-controlled clinical trials in the English literature evaluating drug therapy (except hormonal therapy) of urinary urge incontinence. Trials were categorized by type of drug and outcome variables. TABULATION, INTEGRATION, AND RESULTS: Forty-seven trials were identified. Twenty-four, 12, and 11 trials evaluated anticholinergic drugs, drugs with anticholinergic and calcium antagonistic properties, and alternative regimens, respectively. Data regarding treatment effects of anticholinergic drugs are consistent with a high therapeutic efficacy and characteristic side effects. Therapeutic efficacy and side effect patterns of terodiline, an agent with anticholinergic and calcium antagonistic properties, were comparable to those of anticholinergic agents. Terodiline, however, has been withdrawn from the market because of its association with cardiac arrhythmia. Of the investigated alternative drug regimens, the papaverine-like smooth muscle relaxant flavoxate was reported to be ineffective. Studies investigating the dopamine agonist bromocryptine, the alpha-adrenoceptor blocker prazosin, or the gamma-aminobutyric acid receptor agonist baclofen showed subjective and/or objective improvement of symptoms without reaching statistical significance, whereas the tricyclic antidepressant doxepin, the neurotoxin capsaicin, and the prostaglandin synthase inhibitor flurbiprofen led to statistically significant subjective and/or objective improvement of symptoms. No data for subjective and/or objective improvement of symptoms could be extracted from the studies using the anticholinergic and calcium antagonistic agent propiverine and the calcium antagonist thiphenamil. CONCLUSION: Published trials support anticholinergic drugs as efficacious therapy for urinary urge incontinence, with predictable side effects. At present, these agents represent the pharmacological treatment of choice for this condition. The potential value of selected alternative drugs is underscored by the available data.
Halpert, A. G., M. C. Olmstead, et al. (2002). "Mechanisms and abuse liability of the anti-histamine dimenhydrinate." Neurosci Biobehav Rev 26(1): 61-7.
The over-the-counter anti-emetic dimenhydrinate (DMH) (Gravol or Dramamine) has been reported to be abused for non-medicinal purposes. Street drug users abuse DMH for the acute effects of euphoric sensations and hallucinations, while psychiatric patients abuse DMH for its anxiolytic or anti-cholinergic effects. DMH is an H(1) histamine receptor antagonist, but it interacts either directly or indirectly with other neurotransimitter systems, including those using acetylcholine, serotonin, norepinephrine, dopamine, opioids or adenosine. Animal behavioural studies, such as self-administration, conditioned place preference, drug discrimination, and modulation of operant responding, show that anti-histamines have abuse potential. Further support comes from reports of acute and chronic abuse of DMH by humans. Collectively, results confirm the abuse liability of DMH.
Hartvig, P., M. Bergstrom, et al. (2002). "Positron emission tomography and brain monoamine neurotransmission -- entries for study of drug interactions." Curr Pharm Des 8(16): 1417-34.
Monoamine neurotransmission is a complicated process with interactions between individual neurotransmitter pathways, multiple receptors with different responses and a variety of feedback loops regulating neurotransmitter synthesis, release, reuptake and effect on receptors. The system is further affected by a range of enzymes with co-factors controlling synthesis and degradation of monoamines. Positron emission tomography (PET) has evolved to a very versatile tool for the in vivo imaging and characterisation of physiology and biochemistry. The basis for its expansion during the last years has been a rapid development of labelling methods, allowing a range of tracer molecules to be generated and used in human and research animal studies. The most important PET radionuclide is (11)C with a short half-life of approximately 20 minutes. This radionuclide is ideal for the labelling of organic molecules and for multi-tracer applications in research and drug development studies. PET has been used for a range of explorative studies on the monoamine neurotransmission, as exemplified by studies on the expression of dopamine and serotonin receptors as well as the rate of dopamine and serotonin synthesis. The present article gives examples of studies where PET has been used for the characterization of monoamine transmitter systems in experimental animals and in humans, both in healthy individuals and in patients with diseases affecting neurotransmission.
Heinz, A. (2002). "Dopaminergic dysfunction in alcoholism and schizophrenia--psychopathological and behavioral correlates." Eur Psychiatry 17(1): 9-16.
Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of schizophrenia as well as drug and alcohol dependence. Different drugs of abuse stimulate dopamine release in the ventral striatum and thus reinforce drug consumption. Increased subcortical dopamine release has also been associated with the pathogenesis of positive symptoms in schizophrenia and may be driven by a prefrontal dopaminergic dysfunction. These seemingly heterogeneous findings may be explained by recent research in non-human primates. According to these studies, reward anticipation but not anticipated reward consumption is accompanied by a phasic dopamine release in the striatum and prefrontal cortex. In the striatum, phasic dopamine release primarily affects motivation, psychomotor activation and reward craving, while in the prefrontal cortex, dopaminergic stimulation is involved in the activation of working memory and reward anticipation. In alcoholism, previously neutral stimuli that have been associated with alcohol intake can become conditioned cues which activate phasic dopamine release and reward craving. In schizophrenia, stress-induced or chaotic activation of dopamine release may attribute incentive salience to otherwise irrelevant stimuli and thus be involved in the pathogenesis of delusional mood and other positive symptoms. Studies in humans and non-human primates emphasize the role of dopaminergic neurotransmission in reward anticipation and its dysfunction in different neuropsychiatric diseases.
Heiser, P. and H. Remschmidt (2002). "[Selective serotonin reuptake inhibitors and newer antidepressive substances in child and adolescent psychiatry]." Z Kinder Jugendpsychiatr Psychother 30(3): 173-83.
OBJECTIVES: Since the first report on a selective serotonin reuptake inhibitor (SSRI) in 1974, not only have new substances in the group of the SSRI been developed, but also completely new groups of antidepressants. Among these newer groups, characterised by their pharmacological properties, are the serotonin2-antagonists/serotonin reuptake inhibitors (SARI), the noradrenergic and specific serotonergic antidepressants (NaSSA), the noradrenaline and dopamine reuptake inhibitors (NDRI) and the serotonin and noradrenaline reuptake inhibitors (SNRI). This review describes the properties and side effects of the newer antidepressants and compares them to those of the older substance groups like tricyclic antidepressants (TCA), MAO inhibitors (MAOI) and SSRI. Studies of antidepressants in children and adolescents with depression are presented and compared for differences between the older and newer substances. METHODS: A Medline search was performed up to and including January 2002. RESULTS: Three double-blind, placebo-controlled studies of SSRI and one double-blind, placebo-controlled study of the newer antidepressant venlafaxine in children and adolescents with depression have been conducted. However, there is a great number of prospective and retrospective studies. Furthermore, seven double-blind, placebo-controlled studies of SSRI, as well as several prospective and retrospective of the newer antidepressants have been carried out in children and adolescents with other psychiatric disorders. CONCLUSIONS: The studies of the SSRI and the newer antidepressants conducted to date are promising. Nonetheless, further double-blind, placebo-controlled studies are necessary.
Hening, W. A. (2002). "Restless legs syndrome: a sensorimotor disorder of sleep/wake motor regulation." Curr Neurol Neurosci Rep 2(2): 186-96.
Restless legs syndrome (RLS) remains an underappreciated sensorimotor disorder of sleep/wake regulation. It is one of the few sensorimotor disorders that is provoked by rest and that also follows a clear circadian pattern. Recent epidemiologic studies have verified that the condition is common in populations derived from the north and west of Europe, and have begun to uncover some of the genetic substrate of the disorder. New instruments have been developed to facilitate diagnosis and assessment of severity. The pathogenesis of the condition remains uncertain, but recent discoveries implicate areas of the nervous system from the spinal cord up to the basal ganglia. A current hypothesis undergoing vigorous exploration is that the condition results from a deficiency of dopaminergic function based on abnormalities of iron transport and storage. Therapeutically, studies have shown the dopamine agonists to be the most reliable treatment for severe cases, whereas other recent studies have successfully utilized a number of other medications, including levodopa, opioids, and anticonvulsants. New standards provide guidelines for management of RLS and make specific pharmacotherapeutic recommendations.
Herndon, C. M., K. C. Jackson, 2nd, et al. (2002). "Management of opioid-induced gastrointestinal effects in patients receiving palliative care." Pharmacotherapy 22(2): 240-50.
Opioid-induced gastrointestinal side effects, namely, nausea and constipation, are bothersome yet often easy to manage. Due to their widespread frequency, it is imperative that prophylactic and treatment modalities be understood. Although many pharmacotherapeutic agents are available with which to prevent or treat these side effects, few randomized, placebo-controlled studies have been conducted in terminally ill patients, thus limiting most treatment decisions to empiric therapies based on extrapolated data. A strong understanding of the pathophysiology of the sequelae is therefore paramount. Common agents administered for nausea are butyrophenones, phenothiazines, metoclopramide, and serotonin-receptor antagonists. Those given to manage constipation are stimulant laxatives and stool softeners, individually or in combination.
Hirata, Y. (2002). "Manganese-induced apoptosis in PC12 cells." Neurotoxicol Teratol 24(5): 639-53.
Manganese has been known to induce neurological disorders similar to parkinsonisms for a long time. Dopamine deficiency has been demonstrated in Parkinson's disease and in chronic manganese poisoning, suggesting that the mechanisms underlying the neurotoxic effects of the metal ion are related to dysfunction of the extrapyramidal system. However, the details of the mechanisms have yet to be elucidated. In an effort to learn more about the toxicity of manganese, we have employed an in vitro model that uses the PC12 catecholaminergic cell line. In this model, manganese induces apoptosis in PC12 cells. In this paper, experiments conducted with this model, the cellular biochemical changes, and the mechanism of the cell death are reviewed.
Hiroi, N., A. B. Martin, et al. (2002). "Molecular dissection of dopamine receptor signaling." J Chem Neuroanat 23(4): 237-42.
The use of genetically engineered mice has provided substantial new insights into the functional organization of the striatum. Increasing evidence suggests that specific genes expressed within the striatum contribute to its functional activity. We studied the dopamine (DA) D1 receptor gene and one of its downstream targets, the transcription factor c-Fos. We have evaluated the functional interaction between the D1 and D2 DA receptor subtypes at the cellular and behavioral levels. Our results show that haloperidol, a DA D2-class receptor antagonist, activates c-Fos predominantly in enkephalin-positive striatal neurons, which project to the globus pallidus and are thought to mediate motor inhibition. Deletion of the DA D1 receptor increased the responsiveness of enkephalin neurons to haloperidol, in that haloperidol-induced increases in c-Fos and catalepsy were enhanced in D1 receptor knockout mice. These results suggest a functionally opposing role of the D1 receptor against the D2 DA-class receptors in the striatum.
Hoerr, R. and M. Noeldner (2002). "Ensaculin (KA-672 HCl): a multitransmitter approach to dementia treatment." CNS Drug Rev 8(2): 143-58.
Ensaculin, a novel benzopyranone substituted with a piperazine moiety, showed memory-enhancing effects in paradigms of passive and conditioned avoidance in both normal and artificially amnesic rodents. It exhibited neuroprotective activities in an NMDA toxicity model and neurotrophic effects in primary cultured rat brain cells. The compound could be characterized as a weak NMDA receptor-operated channel blocker. In receptor-binding studies, ensaculin was found to have high affinities to serotonergic 5-HT(1A) and 5-HT(7) receptors, adrenergic alpha(1), and dopaminergic D(2) and D(3) receptors. Due to its unique pharmacodynamic profile, ensaculin may have potential as an antidementia agent acting on various transmitter systems.
Homann, C. N., K. Wenzel, et al. (2002). "Sleep attacks in patients taking dopamine agonists: review." Bmj 324(7352): 1483-7.
OBJECTIVES: To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinson's disease, the type of drugs implicated, and strategies for prevention and treatment. DESIGN: Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic-like attacks were discussed in patients with Parkinson's disease. RESULTS: 124 patients with sleep events were found in 20 publications. Overall, 6.6% of patients taking dopamine agonists who attended movement disorder centres had sleep events. Men were over-represented. Sleep events occurred at both high and low doses of the drugs, with different durations of treatment (0-20 years), and with or without preceding signs of tiredness. Sleep attacks are a class effect, having been found in patients taking the following dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists (apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32, ropinirole in 38). Reports suggest two distinct types of events: those of sudden onset without warning and those of slow onset with prodrome drowsiness. CONCLUSION: Insufficient data are available to provide effective guidelines for prevention and treatment of sleep events in patients taking dopamine agonists for Parkinson's disease. Prospective population based studies are needed to provide this information.
Homberg, U. (2002). "Neurotransmitters and neuropeptides in the brain of the locust." Microsc Res Tech 56(3): 189-209.
As part of continuous research on the neurobiology of the locust, the distribution and functions of neurotransmitter candidates in the nervous system have been analyzed particularly well. In the locust brain, acetylcholine, glutamate, gamma-aminobutyric acid (GABA), and the biogenic amines serotonin, dopamine, octopamine, and histamine most likely serve a transmitter function. Increasing evidence, furthermore, supports a signalling function for the gaseous molecule nitric oxide, but a role for neuroptides is so far suggested only by immunocytochemistry. Acetylcholine, glutamate, and GABA appear to be present in large numbers of interneurons. As in other insects, antennal sensory afferents might be cholinergic, while glutamate is the transmitter candidate of antennal motoneurons. GABA is regarded as the principle inhibitory transmitter of the brain, which is supported by physiological studies in the antennal lobe. The cellular distribution of biogenic amines has been analyzed particularly well, in some cases down to physiologically characterized neurons. Amines are present in small numbers of interneurons, often with large branching patterns, suggesting neuromodulatory roles. Histamine, furthermore, is the transmitter of photoreceptor neurons. In addition to these "classical transmitter substances," more than 60 neuropeptides were identified in the locust. Many antisera against locust neuropeptides label characteristic patterns of neurosecretory neurons and interneurons, suggesting that these peptides have neuroactive functions in addition to hormonal roles. Physiological studies supporting a neuroactive role, however, are still lacking. Nitric oxide, the latest addition to the list of neurotransmitter candidates, appears to be involved in early stages of sensory processing in the visual and olfactory systems.
Hrnciar, J. (2002). "[Cor thyreotoxicum. Part I--new findings about its etiopathogenesis and diagnosis. Overview of problems based on 35 years' experience]." Vnitr Lek 48(1): 38-44.
In the seventies thyrotoxic heart accounted for 3% of all hospitalized cardiac patients and was found on average in 30% of all cases of hyperthyroidism. It presented most frequently by tachyfibrillation and resistant cardiac decompensation. It affected men four times as frequently as women. The incidence correlated with age, toxic nodose goitre, but its development did not correlate with concurrent thyrotoxic rhizomyelic myopathy nor with the extent of deviation of thyroid laboratory parameters (T4, T3, indexes FT4). At present the incidence of thyrotoxic heart declined due to early detection and more adequate diagnosis and treatment of hyperthyroidism, as well as due to the decline of oligosymptomatic toxic nodose goitres even in old age due to preventive iodization of table salt. However, there was an increase of hyperthyroidism induced by amiodarone and other iodine preparations (X-ray contrast materials) associated with primary heart disease and arrhythmias. (Up to 2% of amiodarone treated patients). The ratio of so-called real subclinical thyrotoxicoses in the development of thyrotoxic heart is negligible. Isolated reduction of TSH in hospital screening is a frequent finding but is conditioned most frequently by: a) the 1st stage of the low thyroxin syndrome, b) the 1st stage of subacute thyroiditis, c) the influence of various drugs (iodine preparations, overdosage of T4 substitution, pharmacotherapy with glucocorticoids, dopamine etc.), d) methodical artefacts, e) natural pulsed secretion of TSH etc. Hospital screening of hyperthyroidism and thyrotoxic heart even in older people above 60 years by T4 and/or TSH (2nd generation equipment) is not effective because it is detected in 20% of current hospital admissions and in 60% of those admitted to intensive care unitpathologic values of T4 and/or TSH most frequently without non-thyroid causes (stages of the low thyroxin syndrome) are recorded. This hospital screening has a satisfactory sensitivity but low specificity and in a large number of people calls for further diagnostic steps. Therefore it is more suitable only after clinical examination of the patient to confirm suspected hyperthyroidism to examine FT4 and TSH (IRMA 3rd generation) or possibly supplement FT3 and other aimed tests.
Hummel, M. and E. M. Unterwald (2002). "D1 dopamine receptor: a putative neurochemical and behavioral link to cocaine action." J Cell Physiol 191(1): 17-27.
Cocaine is one of the most abused psychostimulants known to man and as such, researchers have been steadfast in their attempts to understand the neurobiological mechanisms responsible for its abuse. Cocaine undoubtedly wreaks havoc on a number of mammalian neuronal neurotransmitter systems, and it is maintained that this dysregulatory effect supports cocaine abuse. Cocaine's mechanism of action has been well described. Cocaine binds differentially to the dopamine, serotonin, and norepinephrine transport proteins and directly prevents the re-uptake of dopamine, serotonin, and norepinephrine into pre-synaptic neurons (Heikkila et al., 1975, Biochem Pharmacol 24(8):847-852; Reith et al., 1986, Biochem Pharmacol 35(7):1123-1129; Ritz et al., 1987, Science 237:1219-1223). Inhibition of re-uptake subsequently elevates the synaptic concentrations of each of these neurotransmitters. In addition to this direct effect, cocaine also produces a number of indirect actions, which alter other neuromodulatory systems (i.e., opioidergic, glutamatergic, and GABAergic systems). Many of these effects are just beginning to be elucidated, but nonetheless contribute to this agent's diverse pharmacological profile. Interestingly, it is the indirect actions of this mellifluous molecule, which mediate most of its sought and unsought effects. The intricacy with which cocaine produces neuronal alterations beyond its direct effects on neurotransmitter re-uptake appear to be most relevant to cocaine abuse, and hence the phenomenon of addiction. In light of cocaine's multifarious effects on numerous neuronal systems, its effect on dopaminergic neurotransmission has attracted the most attention, particularly because of the implicated role of dopamine in brain reward. Pharmacologically, the psychostimulant effects of cocaine appear to be mediated by its ability to enhance dopaminergic activity within the mesocorticolimbic circuit (Roberts et al., 1977, Pharmacol Biochem Behav 6(6):615-620). Additionally, it is the intensity with which cocaine produces alterations in dopaminergic circuitry that have enabled this drug to prevail as one of the most addictive substances known to man. This review will summarize findings relevant to cocaine-induced alterations in dopamine-mediated signal transduction. Specifically, it will concentrate on the D1 dopamine receptor and intracellular signaling mediated by this receptor subtype. It will describe cocaine-induced cellular and behavioral alterations relevant to this pathway and how these changes potentially effect gene transcription and protein expression. This article too will review a common behavioral manifestation associated with repeated cocaine exposure, sensitization, and why the D1 dopamine receptor and its associated signaling pathway have been implicated in this phenomenon. Lastly, this article will discuss how targeting the D1 dopamine receptor and its signaling pathway may offer some insight into understanding cocaine addiction, a somewhat elusive brain disease.
Hunt, R. and D. Osborn (2002). "Dopamine for prevention of morbidity and mortality in term newborn infants with suspected perinatal asphyxia." Cochrane Database Syst Rev(3): CD003484.
BACKGROUND: Perinatal asphyxia remains an important condition with significant mortality and long-term morbidity. Multisystem involvement including hypotension and low cardiac output is common in infants with perinatal asphyxia. Dopamine is commonly used for infants with hypotension of any etiology, with the goal of improving cardiac output and preventing its detrimental consequences. OBJECTIVES: To determine if dopamine, compared to placebo, no treatment, volume or another inotrope reduces morbidity and mortality in term newborn infants with suspected perinatal asphyxia. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. Searches were conducted of the Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002), MEDLINE (1966 to March 2002), previous reviews including cross references, abstracts and conference proceedings (Perinatal Society of Australia and New Zealand 1998-2002 and Pediatric Academic Societies meetings 1998-2001). SELECTION CRITERIA: Randomised controlled trials comparing dopamine with placebo, no treatment, other inotropic agents, or volume in infants greater than 36 weeks gestation. Perinatal asphyxia could be suspected on the basis of a cord blood pH < 7.0, cord blood base excess < -16 mEq/L or 5 minute Apgar score < 6. DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Neonatal Review Group with use of relative risk (RR), risk difference (RD) and weighted mean difference (WMD). The fixed effects model using RevMan 4.1 was used for meta-analysis. Data from individual studies were only eligible for inclusion if at least 75% of participants were followed up. MAIN RESULTS: Only one study (DiSessa 1981) was eligible. This study compared low dose dopamine at 2.5 mcg/kg/min with placebo (dextrose in water). This study enrolled 14 term infants with a 5 minute Apgar <6 and a systolic BP >=50 mmHg at a mean of 10 hours age. Seven infants only were randomised to treatment with dopamine and seven to receive placebo. No significant differences between these two groups were found for mortality or long term neurodevelopmental outcome. Length of hospitalisation was not significantly different between the two groups. No study was found that examined the effect of dopamine in infants with evidence of cardiovascular compromise, nor were any studies identified in which dopamine was compared to other inotropic agents for term infants with suspected asphyxia. REVIEWER'S CONCLUSIONS: There is currently insufficient evidence from randomised controlled trials that the use of dopamine in term infants with suspected perinatal asphyxia improves mortality or long-term neurodevelopmental outcome. The question of whether dopamine improves outcome for term infants with suspected perinatal asphyxia has not been answered. Further research is required to determine whether or not the use of dopamine improves mortality and long-term morbidity for these infants and if so, issues such as which infants, at what dose and with what co-interventions should be addressed.
Ichise, J. and K. Yokokawa (2002). "[Preclinical studies of apomorphine hydrochloride]." Nippon Rinsho 60 Suppl 6: 452-6.
Ikemoto, K. (2002). "[Human striatal D-neurons and their significance]." Nihon Shinkei Seishin Yakurigaku Zasshi 22(4): 131-5.
It has recently been reported that the human striatum, especially its ventral part, the nucleus accumbens, contains numerous neurons immunoreactive for aromatic L-amino acid decarboxylase (AADC; the second-step monoamine synthesizing enzyme), but not for tyrosine hydroxylase (TH; the first-step catecholamine synthesizing enzyme) or tryptophan hydroxylase (TPH; the first-step serotonin synthesizing enzyme). These AADC (+)/TH(-)/TPH(-) neurons are named D-neurons. AADC is also the rate-limiting synthesizing enzyme of phenylethylamine (PEA). Although the functions of striatal D-neurons are yet unclear, their functions were discussed in the present review based on recent findings in the literature. D-neurons may participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by uptaking monoamine precursors, including L-dopa or droxidopa (L-threo-DOPS), and by converting them to dopamine (DA) or noradrenaline (NA), respectively. Because the nucleus accumbens is one of the brain regions involved in the pathogenesis of schizophrenia and drug dependence, D-neurons might be related to the etiology of these mental disorders. It has also been suggested that striatal D-neurons are the pluripotential cells that have compensating functions against aging or degeneration. Further studies should be conducted to elucidate the functions of this unique cell group in the human striatum.
Isacson, O. (2002). "Models of repair mechanisms for future treatment modalities of Parkinson's disease." Brain Res Bull 57(6): 839-46.
Parkinson's disease is one of the most likely neurological disorders to be fully treatable by drugs and new therapeutic modalities. The age-dependent and multifactorial nature of its pathogenesis allows for many strategies of intervention and repair. Most data indicate that the selectively vulnerable dopaminergic neurons in the substantia nigra of patients that have developed Parkinson's disease can be modified by protective and reparative therapies. First, the oxidative stress, protein abnormalities, and cellular inclusions typically seen could be dealt with by anti-oxidants, trophic factors, and proteolytic enhancements. Secondly, if the delay of degeneration is not sufficient, then immature dopamine neurons can be placed in the parkinsonian brain by transplantation. Such neurons can be derived from stem cell sources or even stimulated to repair from endogenous stem cells. Novel molecular and cellular treatments provide new tools to prevent and alleviate Parkinson's disease.
Ishihara, K. and M. Sasa (2002). "[Modulation of neuronal activities in the central nervous system via sigma receptors]." Nihon Shinkei Seishin Yakurigaku Zasshi 22(1): 23-30.
Sigma receptors have recently been the target of drug development related to psychiatric disorders, including schizophrenia and depression, as well as cognitive enhancers. This paper focused on the sigma-receptor-mediated modulation of neuronal activity, especially the effects on aminergic neuron and hippocampal neuron activity. Dopaminergic neuron activities in the substantia nigra and ventral tegmental area (VTA) are variously modified by the systemic administration of sigma ligands. When applied with microiontophoresis, they are reported to increase dopaminergic neuron activity in the VTA. This activity may be involved in the psychotropic or antipsychotic effects of these ligands. Moreover, serotonergic neurons in the raphe nucleus and noradrenergic neurons in the locus coeruleus were activated by sigma ligands. These effects are probably related to the antidepressant activity of sigma receptor ligands. In the hippocampus, sigma ligands suppressed CA1 neuronal activity in vitro. The effects were suggested to be due to an increase in the threshold of action potential and decreased synaptic transmission efficacy. NMDA receptor function was modified in biphasic fashion related to doses of sigma ligands, that is, a lower dose facilitated the NMDA receptor functions, and a higher dose inhibited them. These effects on the hippocampal neurons may contribute to their neuroprotective and antiamnesic actions. Further studies are needed to elucidate the relation between the physiological function of sigma receptor and psychiatric diseases by the use of sigma receptor ligands and molecular techniques.
Ito, C. (2002). "Analysis of overall gene expression induced by amphetamine and phencyclidine: novel targets for the treatment of drug psychosis and schizophrenia." Curr Pharm Des 8(2): 147-53.
Although the etiology of drug psychosis or schizophrenia is still unknown, molecular and biochemical researches have recently made significant advances in the search for the candidate genes of these disorders. Among such studies are animal models of drug psychosis or schizophrenia such as amphetamine-induced behavioral sensitization or phencyclidine-treated animals. In this review, it is suggested that amphetamine or phencyclidine change the gene expressions related to not only neurotransmitter systems such as dopamine or glutamic acid, transcription factors, cell proliferation, apoptosis, cell adhesion, but also the synapse. These alterable gene expressions may lead to the discovery of candidate genes of drug psychosis or schizophrenia and thus to novel antipsychotics.
James, J. H. (2002). "Branched chain amino acids in heptatic encephalopathy." Am J Surg 183(4): 424-9.
BACKGROUND: Early theories or hepatic encephalopathy focused on ammonia-driven disruption of the Krebs cycle and cellular energy production. The "false-neurotransmitter" theory directed attention toward the interactions of amino acids, metabolism, the blood-brain barrier and neurotransmission. As they evolved, these studies revealed surprising and subtle effects of ammonia on brain amino acid uptake. DATA SOURCES: Research over a 15-year period in Josef E. Fischer's laboratory explored many aspects of these interactions. Subsequent studies by others have confirmed and extended them into other areas. Insights from this work continue to stimulate attempts to confirm or disprove the clinical utility of branched chain amino acids. CONCLUSIONS: Increased understanding of the factors affecting ammonia, amino acid and neurotransmitter disturbances in chronic liver failure have made a significant and ongoing contribution to the study of metabolism in health and disease.
Jardemark, K., M. L. Wadenberg, et al. (2002). "Dopamine D3 and D4 receptor antagonists in the treatment of schizophrenia." Curr Opin Investig Drugs 3(1): 101-5.
The findings that dopamine D3 and D4 receptors are highly expressed in limbic and cortical areas (D4 more than D3), and the fact that the atypical drug clozapine has preferential affinity for the D4 receptors have suggested an involvement of these receptors in schizophrenia. Subsequently, many pharmaceutical companies have pursued the approach of developing selective dopamine D3 or D4 antagonists as potential antipsychotics. This review will discuss the current status of selective dopamine D3 and D4 receptor antagonists for the treatment of schizophrenia.
Jellinger, K. A. (2002). "Recent developments in the pathology of Parkinson's disease." J Neural Transm Suppl(62): 347-76.
Parkinson's disease (PD) is morphologically characterized by progressive loss of neurons in the substantia nigra pars compacta (SNpc) and other subcortical nuclei associated with intracytoplasmic Lewy bodies and dystrophic (Lewy) neurites mainly in subcortical nuclei and hippocampus und, less frequently in cerebral cortex. SN cell loss is significantly related to striatal dopamine (DA) deficiency as well as to both the duration and clinical severity of disease, The two major clinical subtypes of PD show different morphologic lesion patterns: the akinetic-rigid form has more severe cell loss in the ventrolateral part of SN with negative correlation to DA loss in the posterior putamen, and motor symptoms related to overacitivty of the GABAergic "indirect" motor loop, which causes inhibition of the glutamatergic thalamocortical pathway and reduced cortical activation. The tremor-dominant type shows more severe cell loss in the medial SNpc and retrorubal field A 8, which project to the matrix of the dorsolateral striatum and ventromedial thalamus, thus causing hyperactivity of thalamomotor and cerebellar projections. These and experimental data suggesting different pathophysiological mechanisms for the major clinical subtypes of PD may have important therapeutic implications. Lewy bodies, the morphologic markers of PD, are composed of hyperphosphorylated neurofilament proteins, lipids, redox-active iron, ubiquitin, and alpha-synuclein, showing a continuous accumulation in the periphery and of ubiquitin in the central core. Alpha-synuclein, is usually unfolded in alpha-helical form. By gene mutation, environmental stress or other factors it can be transformed to beta-folding which is sensible to self-aggregation in filamentous fibrils and formation of insoluble intracellular inclusions that may lead to functional disturbances and, finally, to death of involved neurons. While experimental and tissue culture studies suggest that apoptosis, a genetically determined form of programmed cell death, represents the most common pathway in neurodegeneration, DNA fragmentation, overexpression of proapoptotic proteins and activated caspase-3, the effector enzyme of the terminal apopoptic cascade, have only extremely rarely been detected in SN of PD brains. This is in accordance with the rapid course of apoptotis and the extremely slow progression of the neurodegenerative process in PD. The biological role of Lewy bodies and other intracellular inclusions, the mechanisms of the intracellular aggregation of insoluble protein deposits, and their implication for cellular dysfunction resulting in neurodegeneration and cell demise are still unresolved. Further elucidation of the basic molecular mechanisms of cytoskeletal lesions will provide better insight into the pathogenesis of neurodegeneration in PD and related disorders.
Jin, G. Z., Z. T. Zhu, et al. (2002). "(-)-Stepholidine: a potential novel antipsychotic drug with dual D1 receptor agonist and D2 receptor antagonist actions." Trends Pharmacol Sci 23(1): 4-7.
Johannsen, B. and H. J. Pietzsch (2002). "Development of technetium-99m-based CNS receptor ligands: have there been any advances?" Eur J Nucl Med Mol Imaging 29(2): 263-75.
By virtue of its ideal nuclear physical characteristics for routine nuclear medicine diagnostics and its ready availability, technetium-99m is of outstanding interest in the development of novel radiopharmaceuticals. The potential for the development of 99mTc-based radioligands for the study the receptor function in the central nervous system (CNS) is also well recognised despite the difficulties to be overcome. A fundamental challenge is the pharmacologically acceptable integration of the transition metal technetium, with its specific coordination chemistry, into the molecular entity of CNS receptor ligands. Conceptually, the ligand molecule can be assembled by three building blocks: a small neutral chelate unit, an organic linker that may also serve as a pharmacological modifier and a receptor-binding region derived from selective receptor antagonists. The recent introduction of novel technetium chelate units, particularly mixed-ligand complexes and low-valency organometallic compounds of technetium, provides an impetus for the further development of CNS receptor ligands. Moreover, progress in receptor pharmacology and the experience gained with positron emission tomography radiotracers have facilitated the design of numerous 99mTc-based CNS receptor ligands. The formidable challenge of developing 99mTc probes as single-photon emission tomography imaging agents targeting CNS receptors can be viewed with optimism given the successful development of [99mTc]TRODAT-1 as a 99mTc complex for imaging dopamine transporters in the brain, although there are a number of receptor-specific imaging agents that have so far resisted all efforts to develop them. This review presents recent advances and discusses the remaining hurdles in the design of 99mTc-based CNS receptor imaging agents.
Johansen, E. B., H. Aase, et al. (2002). "Attention-deficit/hyperactivity disorder (ADHD) behaviour explained by dysfunctioning reinforcement and extinction processes." Behav Brain Res 130(1-2): 37-45.
Inattentiveness, overactivity and impulsiveness are presently regarded as the main clinical symptoms of attention-deficit/hyperactivity disorder (ADHD). Inattention is, however, a characteristic of most psychiatric disorders. It is argued that the ADHD Inattentive subtype may have heterogeneous origins and be qualitatively different from the ADHD Hyperactive/Impulsive subtype. At the neurobiological level, ADHD symptoms may to a large extent be caused by a dysfunctioning dopamine system: A dysfunctioning meso-limbo-cortical dopamine branch will produce altered reinforcement and extinction processes, on a behavioural level giving rise to deficient sustained attention, hyperactivity, motor and cognitive impulsiveness. A dysfunctioning nigro-striatal dopamine branch will cause 'extrapyramidal' symptoms. Our model disentangles the behaviours usually explained by 'executive functions' into cognitive impulsiveness, motor impulsiveness and deficient motor control. The various dopaminergic branches may not be equally dysfunctional in all individuals with ADHD. Etiologically, dopamine dysfunctioning will probably mainly be genetically determined while sometimes be induced by environmental factors like drugs of abuse or pollutants, which may explain geographical differences in prevalence rates.
Johnston, A. J., J. Ascher, et al. (2002). "Pharmacokinetic optimisation of sustained-release bupropion for smoking cessation." Drugs 62 Suppl 2: 11-24.
Sustained-release bupropion (bupropion SR) is a unique, non-nicotine smoking cessation aid that is hypothesised to act upon neurological pathways involved in nicotine dependence. Pharmacokinetic and metabolism studies reveal that bupropion SR is metabolised by multiple pathways with no single pathway predominating. When one pathway is inhibited, others are available to compensate. Therefore, only a few clinically relevant drug-drug interactions involving bupropion SR have been observed, although the potential for interactions exists, as with any extensively metabolised drug. Population pharmacokinetic/pharmacodynamic analyses of data from patients receiving daily oral doses of 100mg, 150mg, or 300mg reveal that the anti-smoking efficacy of bupropion SR is directly related to dose. The incidences of dry mouth and insomnia were directly related to bupropion plasma concentrations while the incidence of anxiety was inversely proportional to bupropion plasma concentrations. To maximise efficacy (with an acceptable safety profile), the optimal daily dose for the majority of patients is 300mg.
Jones, H. M. and L. S. Pilowsky (2002). "Dopamine and antipsychotic drug action revisited." Br J Psychiatry 181: 271-5.
Jones, S. and J. L. Gutlerner (2002). "Addictive drugs modify excitatory synaptic control of midbrain dopamine cells." Neuroreport 13(2): A29-33.
Jorenby, D. (2002). "Clinical efficacy of bupropion in the management of smoking cessation." Drugs 62 Suppl 2: 25-35.
Nicotine addiction is a chronic relapsing condition that can be difficult to treat. Until recently, pharmacological options for the treatment of tobacco dependence were primarily limited to nicotine replacement therapy (NRT). Sustained-release bupropion (bupropion SR) is the first non-nicotine pharmacological treatment approved for smoking cessation. Bupropion SR is recommended for first-line pharmacotherapy alongside NRT in the updated US Clinical Practice Guidelines and the UK Health Education Authority Guidelines. The UK National Institute of Clinical Excellence recommends NRT and bupropion SR for smokers who have expressed a desire to quit smoking. This review presents evidence that bupropion SR is an effective first-line therapy for smoking cessation in a wide range of patient populations. It is associated with significantly higher smoking cessation rates compared with placebo in patients with or without a history of prior bupropion SR or NRT use, and its effect is independent of gender. Bupropion SR treatment is effective in the prevention of relapse to smoking in those patients who have successfully quit, and re-treatment is effective in smokers who recommence smoking after a previous course of bupropion SR. Bupropion SR treatment relieves the symptoms of craving and nicotine withdrawal, and attenuates the weight gain that often occurs after smoking cessation. Data collected from motivational support programmes and employer-based studies provide strong evidence of the effectiveness of bupropion SR as an aid to smoking cessation in 'real life' situations, and confirm the efficacy seen in clinical trials.
Jose, P. A., G. M. Eisner, et al. (2002). "Dopamine receptor-coupling defect in hypertension." Curr Hypertens Rep 4(3): 237-44.
Dopamine synthesized in non-neural tissues, eg, renal proximal tubule, functions in an autocrine or paracrine manner. The effects of dopamine are transduced by two classes of receptors (D1- and D2-like) that belong to the superfamily of G protein-coupled receptors. In genetic hypertension, the D1 receptor, a member of the D1-like receptor family, is uncoupled from its G protein complex, resulting in a decreased ability to regulate renal sodium transport. The impaired D1 receptor/G protein coupling in renal proximal tubules in genetic hypertension is secondary to abnormal phosphorylation and desensitization of the D1 receptor caused by activating single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK type 4.
Jose, P. A., G. M. Eisner, et al. (2002). "Role of dopamine receptors in the kidney in the regulation of blood pressure." Curr Opin Nephrol Hypertens 11(1): 87-92.
Regulation by dopamine of cardiovascular function, renal function and systemic blood pressure regulation is multifaceted. Each of the five dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors regulate blood pressure by influencing the central or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents. The D1, D3, and D4 receptors interact with the renin-angiotensin system, while the D2 and D5 receptors interact with the sympathetic nervous system to regulate blood pressure.
Jucaite, A. (2002). "[Dopaminergic modulation of cerebral activity and cognitive functions]." Medicina (Kaunas) 38(4): 357-62.
Alterations in dopaminergic system are known to lie in the basis of such diseases as Parkinson's disease, Huntington's disease, Attention Deficit/Hyperactivity Disorder, Tourette syndrome, schizophrenia and drug abuse. This induced broad investigations of dopaminergic system in nearly all the areas of neuroscience. New insights into the pathogenesis of neuropsychiatric diseases have emerged. Research in the field of dopaminergic neurotransmission and memory was awarded Nobel prize in the year 2000. New avenues for the development of more selective drugs have been opened. In their daily practice clinicians are often prescribing medications acting on presynaptic or postsynaptic sites of dopaminergic units. Thus the aim of this review was to renew some knowledge on the architecture of dopaminergic system and also to glance through some of the studies implying its modulating effect on cognitive functions.
Kaasinen, V. and J. O. Rinne (2002). "Functional imaging studies of dopamine system and cognition in normal aging and Parkinson's disease." Neurosci Biobehav Rev 26(7): 785-93.
Modern functional imaging methods, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), provide non-invasive, quantitative tools for the direct measurement of neurotransmitter function in the living human brain. The dopamine system has been of key interest; first, because it has a prominant role in several cognitive and motor processes, and secondly because the tracers currently available for the dopamine system enable an effective investigation of various pre, post- and intra-synaptic processes. Recent functional imaging findings indicate that certain cognitive deficits associated with both normal aging and Parkinson's disease are modulated by changes in the brain dopamine system. This review covers the literature related to age-associated phenomena in the dopamine system studied with in vivo imaging. In particular, the focus is on describing and discussing the relationships between aging, cognition and the dopaminergic system in healthy subjects and in patients with Parkinson's disease.
Kanner, A. M. and A. Balabanov (2002). "Depression and epilepsy: how closely related are they?" Neurology 58(8 Suppl 5): S27-39.
Article abstract Depressive disorders (DDs) are the most common type of psychiatric co-morbidity in patients with epilepsy. They are more likely to occur in patients with partial seizure disorders of temporal and frontal lobe origin and are more frequent among patients with poorly controlled seizures. Despite their relatively high prevalence, DDs remain unrecognized and untreated in a large proportion of patients. This article highlights the evidence of a close association between DDs and epilepsy, beginning with the bi-directional relationship between the two disorders. Not only are patients with epilepsy more likely to experience a DD, but a history of DD preceding the onset of the seizure disorder is more likely to be identified in patients with epilepsy than in a control group. In support of these observations, we review data from animal models of epilepsy showing that decreased activity of serotonin, norepinephrine, dopamine, and GABA facilitate the kindling process of seizure foci, worsen seizure frequency and severity, and are reversed or blocked by antidepressant drugs. Decreased activity of these neurotransmitters is a pivotal pathogenic mechanism of DDs and forms the basis of their pharmacotherapy. Thus, DDs and epilepsy may share common pathogenic mechanisms that facilitate the occurrence of one in the presence of the other. Contrary to long-held beliefs by patients and clinicians alike, in the sense that DDs are a "normal reaction" to the obstacles posed by epilepsy, we review evidence that points to their biologic or endogenous nature. We find a genetic predisposition to DDs, as evidenced by the frequent family history of mood disorders in these patients. Neuroimaging and neuropsychological data support a frontal lobe dysfunction in DDs, and a recent study documents concomitant dysfunction of mesial temporal structures. Depressive disorders have various clinical presentations, some typical of the different types of mood disorders in non-epileptic patients, others constituting rather frequent atypical presentations that can easily go unrecognized. A review of the pharmacologic treatment of DDs in epilepsy highlights the lack of scientific data and points to the empirical form in which these patients have been treated up to the present time. Contrary to clinicians' fears, most antidepressant drugs are safe in patients with epilepsy.
Kasper, S., J. Tauscher, et al. (2002). "Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette's disorder--implications for psychopharmacology." World J Biol Psychiatry 3(3): 133-46.
Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. To determine patterns of brain dysfunction and to uncover the mechanism of action of centrally active compounds we used single photon emission computerized tomography (SPECT) as well as positron emission tomography (PET) in patients diagnosed with schizophrenia, depression, bulimia and Tourette's disorder. Striatal D2 and 5-HT1A receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-naive or drug free, or we studied the influence of specifically acting compounds on receptor/transporter occupancy. We could demonstrate that atypical antipsychotics have a dose-dependent (with the exception of clozapine and quetiapine) lower striatal D2 receptor occupancy rate compared with typical neuroleptics, paralleling the more favourable extrapyramidal side effects of atypical antipsychotics. However, no association between striatal D2 receptor occupancy rates and antipsychotic efficacy has been found. The measurement of 5-HT1A receptors in drug-naive schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HT1A receptor binding potential in schizophrenia. beta-CIT as a ligand for measurement of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared to age- and sex-matching healthy controls, a measurement that has also been obtained for bulimia. We also documented seasonal variations in brain serotonergic function by our finding of reduced brain 5-HTT availability in winter (compared to summer) in healthy controls. Furthermore, displaceable [123I] beta-CIT binding in the area corresponding to the left striatum (representing predominantly the density of dopamine transporters) was significantly reduced in SAD patients compared to healthy controls. In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the beta-CIT binding potential, however, no significant dose relationship has been obtained in depression. Genotyping depressed patients for the serotonin transporter promoter gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects. In patients suffering from Tourette's disorder (TD) we were unable to detect differences of dopamine transporter densities between psychotropic drug-naive TD patients and controls. Furthermore, no difference could be found between currently treated (with antipsychotics) and psychotropic drug-naive TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments.
Katugampola, S. D., J. J. Maguire, et al. (2002). "Discovery of recently adopted orphan receptors for apelin, urotensin II, and ghrelin identified using novel radioligands and functional role in the human cardiovascular system." Can J Physiol Pharmacol 80(5): 369-74.
Using novel synthetic radioligands, we have discovered receptors for the recently paired apelin (APJ orphan receptor), ghrelin (GHS orphan receptor), and urotensin II (orphan GPR14) in the human cardiovascular system and determined their anatomical localisation. In addition, we have established functional vasoactive properties for these three peptides as potential vasoconstrictor/vasodilator mediators and provided evidence for alteration of receptor density in cardiovascular disease. We find that receptors for apelin, ghrelin, and urotensin II are widely distributed in human cardiovascular tissue, suggesting perhaps vasoactive roles for these peptides in human vascular physiology and a potential role in pathophysiology. Apelin and urotensin II are potent vasoconstrictors with low efficacy, consistent with their low receptor density. Ghrelin receptor density was increased (approximately three- to fourfold) with atherosclerosis of coronary artery disease and accelerated atherosclerosis of saphenous vein grafts, compared with normal vessels, highlighting a potentially beneficial role for this novel vasodilator peptide in human vascular disease. Our approach has demonstrated one successful strategy for translating genetic information encoding recently paired orphan receptor ligands into discovery of function. This study has the advantage of focussing on the actual disease processes, which allow the more precise identification of novel therapeutic targets.
Katzenschlager, R. and A. J. Lees (2002). "Treatment of Parkinson's disease: levodopa as the first choice." J Neurol 249 Suppl 2: II19-24.
The introduction of levodopa in the 1960s revolutionised the treatment of Parkinson's disease (PD), and it continues to be the most effective symptomatic therapy. The vast majority of PD patients who start treatment with L-dopa experience good to excellent functional benefit.In vitro studies with high doses of L-dopa and absent glia had shown that it may be neurotoxic, but other tissue culture studies show L-dopa to be neuroprotective. Most studies in animal models and clinico-pathological and mortality studies in humans failed to show evidence in favour of accelerated dopaminergic neuronal loss with long-term L-dopa therapy.L-dopa continues to be beneficial throughout the course of PD, although as the disease progresses, escape of some symptoms from adequate control may occur and refractory disabilities such as impaired balance, dysarthria, cognitive decline and hallucinations may emerge. Treatment of advanced PD may also be complicated by the emergence of motor fluctuations and dyskinesias. Studies in animal models and in humans show that these motor complications are not specific to a particular dopaminergic agent, but that they are related both to the extent of the striatal lesion and to the mode of application of dopaminergic agents: Pulsatile administration of L-dopa and of the dopamine agonist apomorphine causes more motor complications than continuous striatal dopaminergic receptor stimulation, and continuous administration can alleviate existing dyskinesias and fluctuations.Several controlled studies comparing levodopa and dopamine agonists as initial treatment have attempted to answer the question whether delaying L-dopa therapy can reduce the occurrence of motor complications. Three medium-term (3-5 years) and one 10-year study showed less dyskinesia in the first five years of treatment in patients who had started therapy with a dopamine agonist. However, these studies also consistently showed that levodopa provided better functional improvement in the first years of treatment. Ten-year follow-up data in patients randomised to L-dopa or bromocriptine also showed a slightly lower incidence of motor complications in the bromocriptine arm. However, this difference was not significant for the clinically relevant moderate and severe forms of dyskinesias and fluctuations, and was achieved at the expense of significantly worse disability scores during the first years of therapy. Furthermore, the relative impact of motor disability and dyskinesias on patients' quality of life remains to be established.Concordance is essential in the optimum treatment of PD and patients should be informed of the various therapeutic options available. Treatment should respect individual patients' needs and take into account their particular functional disabilities and specific handicaps. Low-dose L-dopa therapy (up to 400 mg/day), however, remains the most effective initial treatment of choice for the majority of patients.
Keating, G. M. and D. P. Figgitt (2002). "Dexmethylphenidate." Drugs 62(13): 1899-904; discussion 1905-8.
Dexmethylphenidate comprises only the d-enantiomer (the pharmacologically effective isomer) of racemic methylphenidate and is indicated for the treatment of patients aged > or =6 years with attention deficit hyperactivity disorder (ADHD). In a 4-week, double-blind trial in 132 children with ADHD, significantly greater improvements from baseline in teacher-rated Swanson, Nolan and Pelham (SNAP)-ADHD scores were seen in dexmethylphenidate and methylphenidate recipients, compared with placebo recipients. In addition, significantly more dexmethylphenidate and methylphenidate recipients, compared with placebo recipients, were much improved or very much improved according to Clinical Global Impression-Improvement of Illness scale scores. In the same study, parent-rated SNAP-ADHD scores had decreased by a significantly greater extent in dexmethylphenidate recipients at 3pm and 6pm and in methylphenidate recipients at 3pm, compared with placebo recipients. Significantly fewer dexmethylphenidate than placebo recipients failed treatment in a double-blind, treatment-withdrawal trial in 75 children with ADHD (17.1 vs 61.5%). In a noncomparative study in 22 children with ADHD, symptoms of ADHD, as assessed by teachers and parents, were controlled during the entire school day in 68 and 86% of dexmethylphenidate recipients, respectively, with a median duration of effect of 6.3 and 7.5 hours, respectively. Dexmethylphenidate was generally well tolerated in children with ADHD; adverse events were consistent with those known to be associated with agents containing methylphenidate.
Kelley, A. E. and K. C. Berridge (2002). "The neuroscience of natural rewards: relevance to addictive drugs." J Neurosci 22(9): 3306-11.
Kellum, J. A. and M. R. Pinsky (2002). "Use of vasopressor agents in critically ill patients." Curr Opin Crit Care 8(3): 236-41.
Distributive shock is a common problem in intensive care. Systemic hypotension is a medical emergency and will cause end-organ injury if not reversed. There are relatively few medications available to treat distributive shock. Catecholamines are most widely used for this indication and work by stimulating alpha- and/or beta-adrenergic receptors. Vasopressin and corticosteroids may have a role in reversing refractory shock and work primary through nonadrenergic mechanisms. Shock is difficult to define using hemodynamic criteria, because the same hemodynamic values can be normal in one patient, yet represent shock in another. Thus, the appropriate therapeutic endpoints for vasopressor therapy are not uniform for all patients. Similarly, the available evidence comparing vasopressor agents in terms of safety and efficacy is limited. When used at doses necessary to reverse distributive shock, less potent vasoconstrictors (eg, dopamine) do not appear to be safer than more potent ones (eg, norepinephrine) and do not appear to be as effective.
Keltner, N. L., K. M. McAfee, et al. (2002). "Mechanisms and treatments of SSRI-induced sexual dysfunction." Perspect Psychiatr Care 38(3): 111-6.
SSRI-induced sexual dysfunction affects 30% to 50% or more of individuals who take these drugs for depression. Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5HT2 and 5HT3 receptors; decreased dopamine; blockade of cholinergic and alpha-1 adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels. Five approaches to treatment include conservative approaches such as wait and see, decrease dosage, and drug holidays. More aggressive strategy for treating SSRI-induced sexual dysfunction are changing antidepressants and augmentation.
Kita, T. and T. Nakashima (2002). "[A recent trend in methamphetamine-induced neurotoxicity]." Nihon Shinkei Seishin Yakurigaku Zasshi 22(2): 35-47.
The neurotoxic damage caused by methamphetamine (METH) is characterized by nerve terminal destruction and/or degeneration of the dopaminergic and serotonergic systems in striatum and hippocampus. It has been hypothesized that intraneural dopamine (DA) redistribution from synaptic vesicles to cytoplasmic compartments produced by METH is an important factor for its neurotoxicity. The METH-induced redistribution of DA is thought to occur after an increased production of DA-based reactive oxygen species (ROS) (e.g., oxygen radicals and hydroxyl radicals) by auto-oxidation or enzymatic degradation, and METH-induced ROS produces an oxidative stress and depletion of energy stores. Furthermore, the glutamatergic system and nitric oxide (NO) may also contribute to METH-induced neurotoxicity. Recently, studies using several knockout strains of mice lacking the DA transporter, the monoamine vesicle transporter-2, c-fos, or neuronal NO synthase confirm a possible role of these factors in METH-induced neurotoxicity. Moreover, it has been proposed that METH causes the apoptosis and activation of cell-death-related genes. For example, METH-induced neurotoxicity is reduced in bcl-2-over expressing neural cell and p53 knockout mice and also induces the activation of caspase 3. Therefore in this review, we discuss the relationship between ROS formation, oxidative stress, and apoptosis in METH-induced neurotoxicity.
Kitamura, Y., J. Kakimura, et al. (2002). "Antiparkinsonian drugs and their neuroprotective effects." Biol Pharm Bull 25(3): 284-90.
In Parkinson's disease, while dopamine (DA) replacement therapy, such as with L-DOPA (levodopa), improves the symptoms, it does not inhibit the degeneration of DA neurons in the substantia nigra. Numerous studies have suggested that both endogenous and environmental neurotoxins and oxidative stress may participate in this disease, but the detailed mechanisms are still unclear. Recent genetic studies in familial Parkinson's disease and parkinsonism have shown several gene mutations. This new information regarding its pathogenesis offers novel prospects for effective strategies involving the neuroprotection of vulnerable DA neurons. This review summarizes current findings regarding the pathogenesis and antiparkinsonian drugs, and discusses their possibilities of targets to develop novel neuroprotective drugs.
Klein-Schwartz, W. (2002). "Abuse and toxicity of methylphenidate." Curr Opin Pediatr 14(2): 219-23.
The therapeutic use of methylphenidate for the management of attention-deficit hyperactivity disorder in children is increasing. As therapeutic use increases, the risk increases of unintentional overdoses, medication errors, and intentional overdoses caused by abuse, misuse, or suicide gestures and attempts. Side effects during therapy, which include nervousness, headache, insomnia, anorexia, and tachycardia, increase linearly with dose. Clinical manifestations of overdoses include agitation, hallucinations, psychosis, lethargy, seizures, tachycardia, dysrhythmias, hypertension, and hyperthermia. Methylphenidate tablets can be abused orally, or they can be crushed and the powder injected or snorted. Despite its abuse potential, there is disagreement regarding the extent to which methylphenidate is being diverted from legitimate use to abuse in preteens and adolescents.
Kofman, O. (2002). "The role of prenatal stress in the etiology of developmental behavioural disorders." Neurosci Biobehav Rev 26(4): 457-70.
Substantial evidence from preclinical laboratory studies indicates that prenatal stress (PS) affects the hormonal and behavioural development of offspring. In the following review, the effects of PS in rodents and non-human primates on hypothalamic-pituitary-adrenal (HPA) reactivity to stress, morphological changes in the brain, motor behaviour and learning are surveyed. PS has been found to alter baseline and stress-induced responsivity of the HPA axis and levels and distribution of regulatory neurotransmitters, such as norepinepherine, dopamine, serotonin and acetylcholine and to modify key limbic structures. In rodents and non-human primates, PS affected learning, anxiety and social behaviour. The relevance of these findings to humans is discussed with respect to (a) the effect of administration of exogenous corticosteroids in pregnancy and (b) maternal state and trait anxiety during gestation and its relation to foetal autonomic regulation as putative predisposing factors in the pathogenesis of behavioural developmental delays in children.
Kolk, S. M., B. M. Kramer, et al. (2002). "Multiple control and dynamic response of the Xenopus melanotrope cell." Comp Biochem Physiol B Biochem Mol Biol 132(1): 257-68.
Some amphibian brain-melanotrope cell systems are used to study how neuronal and (neuro)endocrine mechanisms convert environmental signals into physiological responses. Pituitary melanotropes release alpha-melanophore-stimulating hormone (alpha-MSH), which controls skin color in response to background light stimuli. Xenopus laevis suprachiasmatic neurons receive optic input and inhibit melanotrope activity by releasing neuropeptide Y (NPY), dopamine (DA) and gamma-aminobutyric acid (GABA) when animals are placed on a light background. Under this condition, they strengthen their synaptic contacts with the melanotropes and enhance their secretory machinery by upregulating exocytosis-related proteins (e.g. SNAP-25). The inhibitory transmitters converge on the adenylyl cyclase system, regulating Ca(2+) channel activity. Other messengers like thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH, from the magnocellular nucleus), noradrenalin (from the locus coeruleus), serotonin (from the raphe nucleus) and acetylcholine (from the melanotropes themselves) stimulate melanotrope activity. Ca(2+) enters the cell and the resulting Ca(2+) oscillations trigger alpha-MSH secretion. These intracellular Ca(2+) dynamics can be described by a mathematical model. The oscillations travel as a wave through the cytoplasm and enter the nucleus where they may induce the expression of genes involved in biosynthesis and processing (7B2, PC2) of pro-opiomelanocortin (POMC) and release (SNAP-25, munc18) of its end-products. We propose that various environmental factors (e.g. light and temperature) act via distinct brain centers in order to release various neuronal messengers that act on the melanotrope to control distinct subcellular events (e.g. hormone biosynthesis, processing and release) by specifically shaping the pattern of melanotrope Ca(2+) oscillations.
Kondo, T. (2002). "Initial therapy for Parkinson's disease: levodopa vs. dopamine receptor agonists." J Neurol 249 Suppl 2: II25-9.
Levodopa therapy is essential for patients in the advanced stages of Parkinson's disease. However, at early stages, DA agonist therapy has similar efficacy in the treatment of parkinsonism and a lower incidence of motor complications compared to levodopa therapy several years after the initiation of the therapy. The main factors causing motor complications have been speculated to be a severe reduction of dopaminergic nerve terminals because of disease progression, and a pulsatile stimulation of DA receptors using a drug with a short plasma half-life. DA agonists have longer plasma half-lifes than levodopa; therefore, they are expected to have a favorable effect on motor complications. Moreover, two clinical reports confirmed the potential neuroprotection by DA agonists. Although the patient's conditions should be considered in the selsction of a drug, DA agonist therapy is recommended as the initial therapy for Parkinson's disease.
Korczyn, A. D. and M. Nussbaum (2002). "Emerging therapies in the pharmacological treatment of Parkinson's disease." Drugs 62(5): 775-86.
The pharmacological management of Parkinson's disease is a complex and dynamic task; there is no one 'right' strategy indicating which drugs should be used at a particular stage of the disease. There are now many different drugs belonging to several classes that may be effective, and there are still differences of opinion among leading clinicians about the best course of treatment. This review focuses on drug therapy for the motor impairment in Parkinson's disease. Current and future research directions are summarised by taking inventory of recent and innovative areas of development in the field, representing each category with at least one of its featured treatments. The main research efforts are being directed towards delaying the use of levodopa or finding therapies to be used as adjunct to it, in order to postpone motor complications and, in particular, dyskinesias. One of the recent trends is early employment of dopamine agonists. Additional efforts are being directed towards protecting and restoring dopamine neurons. Novel therapies acting on non-dopaminergic systems are also being researched.
Kosten, T. R., T. P. George, et al. (2002). "The potential of dopamine agonists in drug addiction." Expert Opin Investig Drugs 11(4): 491-9.
The use of dopamine agonists in alcohol, stimulant and nicotine dependence has been examined. The direct agonists, such as bromocriptine and pergolide, have not shown utility in alcohol or cocaine abuse and dependence in larger controlled trials. Indirect agents, such as selegiline, may be helpful in cocaine or nicotine abuse and larger clinical trials are underway. Disulfiram may also raise dopamine levels and has shown promise for cocaine dependence. Other indirect agents, such as mazindol and methylphenidate, have not proven effective for cocaine addiction but have not been tested in alcohol or nicotine abuse. Agents for subtypes of dopamine receptors, such as D3, and the use of partial agonists may be useful future treatment approaches. Animal studies also suggest that tailoring treatment to subgroups of patients based on genotype may improve responses.
Kosten, T. A. and E. Ambrosio (2002). "HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats." Psychoneuroendocrinology 27(1-2): 35-69.
Much research supports a link between stress and its concomitant hypothalamic-pituitary-adrenal (HPA) axis responses with behavioral sensitivity to psychoactive drugs. Our research demonstrates that Lewis inbred rats more readily acquire drug self-administration than Fischer 344 (F344) inbred rats and, compared to this strain, Lewis rats have hyporesponsive HPA axis responses to stress exposure. This association appears to conflict with investigations using outbred rats and suggests that the relationship between drug sensitivity and HPA axis responsiveness is more complicated than originally thought. It is essential to better understand this relationship because of its relevance to vulnerability and relapse to drug abuse. Thus, this paper reviews the literature in which these two inbred strains have been compared. We discuss strain differences in HPA axis function, in characteristics of the mesolimbic dopamine system, and in behaviors thought to reflect emotionality. Strain differences in unconditioned and conditioned effects of psychoactive drugs are then reviewed. Next, we discuss the possible role of sex and gonadal hormones on responsiveness to psychoactive drugs in these strains. Finally, a comparison of results obtained from these strains to three other comparator groups (e.g., high and low responders) suggests that a non-monotonic relationship between behavioral sensitivity to drugs and HPA axis responsiveness can explain much of the discrepancies in the literature.
Kotwica, J., M. Bogacki, et al. (2002). "Neural regulation of the bovine corpus luteum." Domest Anim Endocrinol 23(1-2): 299-308.
The ovarian noradrenergic stimulation or noradrenaline (NA) administration directly to the ovary in cow increases ovarian oxytocin (OT) release and post-translational processing of OT synthesis within a few minutes has been established in both in vivo and in vitro studies. Furthermore, NA affects progesterone secretion and its synthesis by an increase of cytochrome P450scc and 3beta-hydroxysteroid dehydrogenase activity. This effect is mediated via luteal cell beta(1)- and beta(2)-receptors. Their total amount correlates with peripheral progesterone concentrations during the luteal phase and this reflects the ability of the ovary to react to beta-stimulation. On the other hand, ovarian denervation causes a decrease of steroidogenic activity in the CL, an increase of beta-receptors on luteal cells, a delay in follicular development and the disruption of cyclicity. Moreover, decrease of progesterone secretion by 20-30% was seen after brief pharmacological blockade of ovarian beta-receptors in the mid-cycle of cattle. We assume that tonic beta-stimulation of the CL ensures the basal secretion of progesterone, whereas acute noradrenergic activation supports the CL during stressful situations which could impair its function. Conversely, long-lasting increase in blood catecholamine concentrations markedly decreases the number of beta-receptors in CL, presumably due to their down-regulation. Concentrations of dopamine (DA) within the CL are highly correlated with those of NA during the estrous cycle, and are higher in the newly-formed than in the developed corpus luteum, the regressed corpus luteum or the corpus luteum of pregnant females. Bovine CL can synthesise de novo NA from DA as a precursor. Concluding, presented data indicate that noradrenergic stimulation can be an important part of mechanism supporting secretory function of CL.
Koutsilieri, E., S. Sopper, et al. (2002). "Parkinsonism in HIV dementia." J Neural Transm 109(5-6): 767-75.
A great number of human immunodeficiency virus (HIV)-infected patients develop a central nervous system disorder, commonly called HIV dementia or AIDS dementia complex (ADC). HIV dementia is independent of opportunistic infections and is due to the virus itself. Symptoms include psychomotor slowing, apathy and motor disorders similar to the bradykinesia and postural and gait abnormalities observed in late Parkinson's disease. Consequently, HIV has been discussed during the last few years as an additional cause for parkinsonism, and parkinsonian syndromes as manifestations of HIV dementia. Moreover, the early phase of HIV infection gains increasing interest because of studies which report subtle neurological symptoms at this stage. Accordingly, we found in SIV-infected monkeys that dopamine is reduced by 44% within as few as two months of infection, indicating that changes during early infection must be thoroughly evaluated. In this short review, we discuss alterations in the nigrostriatal dopaminergic system during early and late immunodeficiency virus infection and the common clinical and biochemical features shared by HIV dementia and Parkinson's disease.
Koutsilieri, E., C. Scheller, et al. (2002). "The pathogenesis of HIV-induced dementia." Mech Ageing Dev 123(8): 1047-53.
Koutsilieri, E., S. Sopper, et al. (2002). "Involvement of dopamine in the progression of AIDS Dementia Complex." J Neural Transm 109(3): 399-410.
HIV compromises immunological functions. Immune responses are regulated to a great extent by several molecules such as cytokines, neurotransmitters and hormones which interact with different immune effector cells and ultimately mediate the homeostatic responses to disease. Among these mediators, dopamine plays an important role. In this article we review AIDS Dementia Complex (ADC) and describe lines of evidence implying increased dopamine availability as a potent mediator of neurologic deficits in HIV infection and a factor exhibiting adverse effects on the progression of ADC.
Krebs, M. O. (2002). "[Genetic hypothesis of schizophrenia]." Rev Prat 52(11): 1208-11.
It is now well demonstrated from family, adoption or twin studies, that genetic factors are involved in schizophrenia. Yet, the nature of these factors remains unknown. The disappointing results of the classical linkage studies are explained by the complex non mendelian inheritance, involving several genes interacting with environmental and/or maturation processes, and the heterogeneity of the clinical expression. The identification of genes having an influence on schizophrenia requires thus new strategies including statistical analysis with no assumption on the inheritance mode (non parametric methods) and the dissection of the heterogeneous syndrome using endophenotypes and/or relevant clinical features. Beside the hypothesis of a dysfunctional neurotransmission in schizophrenia (i.e. dopaminergic), evidence suggests that genes involved in neurodevelopment could also be candidate. The observation of caryotypic anomalies could also lead to new candidate regions or genes.
Krizaj, D. and D. R. Copenhagen (2002). "Calcium regulation in photoreceptors." Front Biosci 7: d2023-44.
In this review we describe some of the remarkable and intricate mechanisms through which the calcium ion (Ca2+) contributes to detection, transduction and synaptic transfer of light stimuli in rod and cone photoreceptors. The function of Ca2+ is highly compartmentalized. In the outer segment, Ca2+ controls photoreceptor light adaptation by independently adjusting the gain of phototransduction at several stages in the transduction chain. In the inner segment and synaptic terminal, Ca2+ regulates cells' metabolism, glutamate release, cytoskeletal dynamics, gene expression and cell death. We discuss the mechanisms of Ca2+ entry, buffering, sequestration, release from internal stores and Ca2+ extrusion from both outer and inner segments, showing that these two compartments have little in common with respect to Ca2+ homeostasis. We also investigate the various roles played by Ca2+ as an integrator of intracellular signaling pathways, and emphasize the central role played by Ca2+ as a second messenger in neuromodulation of photoreceptor signaling by extracellular ligands such as dopamine, adenosine and somatostatin. Finally, we review the intimate link between dysfunction in photoreceptor Ca2+ homeostasis and pathologies leading to retinal dysfunction and blindness.
Kuhl, D. A. (2002). "Current strategies for managing the patient with sepsis." Am J Health Syst Pharm 59 Suppl 1: S9-13.
Key elements of the current approach to treating sepsis are reviewed, and examples are given to illustrate the difficulty of designing and evaluating trials in sepsis. A patient with sepsis is likely to have symptoms characteristic of the systemic inflammatory response syndrome. Initially, ruling out noninfective causes, locating the site of infection, and obtaining cultures before beginning antimicrobial therapy are critical. Aggressive fluid resuscitation and hemodynamic support are used to restore tissue perfusion and normalize cellular metabolism. Vasopressor therapy with dopamine or norepinephrine is needed in patients unresponsive to fluid resuscitation. Dobutamine should be administered in patients whose cardiac output is inadequate despite optimization of fluids and pressors. Supportive care includes deep vein thrombosis prophylaxis, nutrition support, stress ulcer prophylaxis, and management of acute lung injury. Attempts to modify the sepsis response and improve the outcome in these patients have yielded limited benefits. Recent small studies have shown benefits with low-dose hydrocortisone in patients with refractory sepsis. One challenge in study design is that a therapy may target a subset of patients that cannot be identified at the outset. Management of patients with suspected or documented sepsis focuses on hemodynamic support, appropriate antimicrobial therapy, and other supportive care.
Kurup, R. K. and P. A. Kurup (2002). "Central role of hypothalamic digoxin in conscious perception, neuroimmunoendocrine integration, and coordination of cellular function: relation to hemispheric dominance." Int J Neurosci 112(6): 705-39.
Alteration in the isoprenoid metabolites--digoxin, ubiquinone, and dolichol--have been reported in neuronal degeneration (Parkinson's disease), oncogenesis (central nervous system glioma), functional neuropsychiatric disorders (schizophrenia and epilepsy), and immune-mediated disorders (multiple sclerosis). The coexistence of these disorders has been documented in literature and a central dysfunction related to digoxin and the isoprenoid pathway may underlie all these disorders. A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms, syndrome X, rheumatoid arthritis, and epilepsy has been described. The psychological behavioral patterns of the family were: creativity and high IQ, hypersexual behavior, reduced appetite and eating behavior, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less bonding and affectionate behavior, and left handedness/right hemispheric dominance. Digoxin, an endogenous Na(+)-K+ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and red blood cell (RBC) membrane Na(+)-K+ ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine, resulting in increased levels of depolarizng tryptophan catabolites, serotonin, quinolinic acid, strychnine, and nicotine, and decreased levels of hyperpolarizing tyrosine catabolites, dopamine, noradrenaline, and morphine, contributing to membrane Na(+)-K+ ATPase inhibition in all the above disorders and the indexed family. Digoxin-induced membrane Na(+)-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced Mg2+ levels, leading on to glutamate excitotoxicity, oncogene activation, and immune activation. Digoxin-induced altered Ca2+/Mg2+ ratios, reduced ubiquinone, and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure, and mitochondrial function, leading to the diverse disorders described above, including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/LH dominant and left-handed/RH dominant individuals. The left-handed/RH dominant individuals compared to right-handed/LH dominant individuals had elevated hydroxymethylglutarylcoenzyme A reductase activity, with increased serum digoxin and dolichol levels. The serum ubiquinone, serum Mg2+ and RBC Na(+)-K+ ATPase activity were reduced in left-handed/RH dominant individuals. The left-handed/RH dominant individuals compared to right-handed/LH dominant individuals had elevated levels of serum tryptophan, quinolinic acid, serotonin, nicotine, and strychnine. The levels of tyrosine, dopamine, noradrenaline, and morphine were low in left-handed/RH dominant compared to right-handed/LH dominant individuals. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and coordinate the functions of various cellular organelles.
Lalonde, R. (2002). "The neurobiological basis of spontaneous alternation." Neurosci Biobehav Rev 26(1): 91-104.
When placed in a T-maze, rats or mice possess a strong tendency of alternating arm choices on successive trials. The exploration of novel environmental stimuli is dependent on the integrity of limbic and non-limbic pathways, including the basal forebrain, the hippocampus, the thalamus, the prefrontal cortex, and the dorsal striatum, as well as the vestibular system and cerebellum. Neurochemical pathways using acetylcholine, gamma-amino-butyric acid, and dopamine in the septum and hippocampus have been implicated in the exploration of novel maze arms. In addition to the delineation of interactions between neurotransmitters, the spontaneous alternation test is sensitive to the consequences of normal and pathological aging.
Lara, D. R. (2002). "Inhibitory deficit in schizophrenia is not necessarily a GABAergic deficit." Cell Mol Neurobiol 22(3): 239-47.
1. Current evidence strongly supports the idea of an inhibitory deficit as a central pathophysiological mechanism in schizophrenia. This deficit has been well documented in sensory gating and paired-pulse studies and may be related to decreases in inhibitory interneurons found in schizophrenic patients. 2. The GABAergic system has been repeatedly postulated to mediate this deficit, but the findings are controversial, at least in some areas, and mostly negative regarding treatment with drugs enhancing GABAergic activity. Therefore, the scope of mediators of this inhibitory deficit should be widened and the neuromodulator adenosine is proposed as a candidate to be further studied. 3. A state of adenosinergic hypoactivity in schizophrenia is compatible not only with the inhibitory deficit but also with symptoms, clinical response to antipsychotics, impaired sensory gating, deteriorating course, increased smoking, and sleep alterations reported in schizophrenia. 4. It is concluded that although the GABAergic system should be further studied, especially in sensory gating model in humans, emphasis on other inhibitory mechanisms may prove useful and provide more effective treatment.
Laviano, A., M. Russo, et al. (2002). "Neurochemical mechanisms for cancer anorexia." Nutrition 18(1): 100-5.
Under normal conditions, the homeostasis of energy intake is maintained in the hypothalamus by 1) transducing metabolic and sensorial inputs arising from the periphery into neuronal response, 2) integrating the information originating from different tissues, and 3) triggering the appropriate feeding responses. If cancer anorexia is considered a disruption of the physiologic mechanisms controlling energy intake, it is conceivable that its pathogenesis may lie in an abnormal input of information to the hypothalamus, its defective transduction and integration, or the induction of exaggerated and inappropriate feeding responses. Currently available data suggest that the pathogenesis of cancer anorexia is multifactorial and involves most of the neuronal signaling pathways modulating energy intake. Thus, a number of factors has been proposed as putative mediators of cancer anorexia, including hormones (e.g., leptin), neuropeptides (e.g., neuropeptide Y), cytokines (e.g., interleukin-1, interleukin-6, tumor necrosis factor), and neurotransmitters (e.g., serotonin and dopamine). However, it is unlikely that they represent separate and distinct pathogenic mechanisms; rather, it appears that close interrelationships may exist among them. In line with this reasoning, consistent experimental and human data suggest that hypothalamic monoaminergic neurotransmission and serotonergic activity in particular may represent a major target on which different anorexia-related factors converge. Thus, interfering pharmacologically with hypothalamic serotonin synthesis and activity has been tested as a therapeutic strategy in anorectic cancer patients with encouraging results. However, more clinical options will be available by revealing the complex interactions between the many factors participating in controlling energy intake under normal and pathologic conditions. Further, modulation of hypothalamic activity also might result in reduced catabolic signals to skeletal muscles, thus improving the cachexia associated with cancer.
Le, H. N. and D. M. Frim (2002). "Gene therapy for Parkinson's disease." Expert Opin Biol Ther 2(2): 151-61.
Significant progress has been made in the field of gene therapy for Parkinson's disease (PD). Successful vehicles for gene transfer into the central nervous system have been developed and clinical efficacy and safety have both been shown in various animal models of PD. Further optimisation of dosing, timing and location of gene therapy delivery as well as the ability to regulate and prolong gene expression will be important for the commencement of human trials. Current gene therapy models for PD have focused on two treatment strategies. One is the replacement of biosynthetic enzymes for dopamine synthesis and the second strategy is the addition of neurotrophic factors for protection and restoration of dopaminergic neurones. Concepts of neuroprotection and restoration of the nigrostriatal pathway will become important themes for future genetic treatment strategies for PD and may include, in addition to neurotrophic factors, genes to prevent apoptosis or detoxify free radical species. This review will highlight the recent literature on gene therapy for PD and summarise general approaches to gene therapy.
Lederer, S. R., T. Sitter, et al. (2002). "[Treatment of acute renal failure]." Dtsch Med Wochenschr 127(3): 89-93.
Lende, D. H. and E. O. Smith (2002). "Evolution meets biopsychosociality: an analysis of addictive behavior." Addiction 97(4): 447-58.
Evolutionary theory can inform the biopsychosocial approach to addictive behavior through the use of adaptationist thinking, or how natural selection has shaped the mechanisms and processes underlying addiction. Covering how evolutionary theory relates to biology, psychology and sociality, this paper examines three components to drug use and abuse: a biological mechanism (mesolimbic dopamine), a developmental trajectory (attachment) and a social phylogeny (dominance, submission, social dependence). The paper argues for a salience (or wanting) view of the function of dopamine; outlines how attachment affects time perspective, closure of internal models and self-regulation; and examines how inequality affects drug abuse and how social dependence and manipulative behaviors can play a role in relationships with drugs. The article concludes with an analysis of how the adaptive approach applies to interventions against addictive behavior.
Leon-Carrion, J., P. van Eeckhout, et al. (2002). "The locked-in syndrome: a syndrome looking for a therapy." Brain Inj 16(7): 555-69.
A review of the scientific literature on locked-in syndrome (LIS) is offered. The clinical features, diagnosis and prognosis of LIS are reviewed, and methods regarding the differential diagnosis of LIS with severe disorders of consciousness are considered. Effective treatment, physiotherapy, and methods of communication are reviewed. Although progress in the field of communication for patients with LIS is promising, it is concluded that there are new possibilities to be pursued and that a more positive outlook in the area of professional care of the patients, as well as more extensive imaginative research will facilitate new and positive strategies for this syndrome.
Lerner, A. G., M. Gelkopf, et al. (2002). "Flashback and Hallucinogen Persisting Perception Disorder: clinical aspects and pharmacological treatment approach." Isr J Psychiatry Relat Sci 39(2): 92-9.
One unique characteristic of lysergic acid diethylamide (LSD) and LSD-like substances is the recurrence of some of the symptoms which appeared during the intoxication after the immediate effect of the hallucinogen has worn off. This recurring syndrome, mainly visual, has not been clearly understood, appreciated or distinguished from other clinical entities by clinicians. The terms Flashback and Hallucinogen Persisting Perception Disorder (HPPD) are used interchangeably in the professional literature. Flashback is a usually short-term, non-distressing, spontaneous, recurrent, reversible and benign condition accompanied by a pleasant affect. In contrast, HPPD is a generally long-term, distressing, spontaneous, recurrent, pervasive, either slowly reversible or irreversible, non-benign condition accompanied by an unpleasant dysphoric affect. Flashback and HPPD appear to be part of a vast and broad spectrum of non-psychopathological and psychopathological states reported by hallucinogen users. Pharmacological agents such as clonidine, perphenazine and clonazepan have been shown to ameliorate this syndrome in some of the individuals seeking treatment.
Levant, B. (2002). "Novel drug interactions at D(2) dopamine receptors: modulation of [3H]quinpirole binding by monoamine oxidase inhibitors." Life Sci 71(23): 2691-700.
D(2) dopamine receptors are the principal target of drugs used to treat schizophrenia and Parkinson's disease. Recent findings suggest novel drug interactions at D(2) receptors, specifically interactions of monoamine oxidase inhibitors (MAOIs) at a novel binding site that modulates the binding of [3H]quinpirole to the D(2) receptor. That MAOIs inhibit [3H]quinpirole binding challenges the traditional understanding of ligand interactions at dopamine receptors and may shed light on the mechanism of behavioral sensitization to psychostimulants and the pharmacology and toxicity of MAOIs.
Levy, A. (2002). "Physiological implications of pituitary trophic activity." J Endocrinol 174(2): 147-55.
A complete inventory of pituitary trophic responses depends on precise estimates of mitotic activity and apoptotic events, and accurate characterization and quantification of pituitary cell subtypes irrespective of previous and current physiological demand. For a discrete structure that has been so extensively studied, it is disappointing but perhaps not surprising that none of these measures is available and therefore that the relative contributions to changes in the proportions of pituitary cellular subpopulations of trophic activity, differentiation of pluripotent cells and variations in the secretory profiles of apparently committed cells remain almost impossible to determine. To fully appreciate the extent of this dilemma, it should be remembered that conservative estimates of the proportion of corticotrophs in the rat anterior pituitary under basal conditions vary over twofold and that it is still not clear whether the apparent threefold increase in mammotrophs during pregnancy is the result of maturation of uncommitted cells, transdifferentiation of other cells such as somatotrophs, cell division, or a mixture of all three. Equally, while it has been known for some time that adrenalectomy results in a transient increase in anterior pituitary mitotic activity and appropriately timed supraphysiological glucocorticoid replacement with a wave of apoptosis, the precise identity of the cells involved in both of these responses is open to question. Thus, although many of the physiological stimuli associated with apparent changes in the proportions of pituitary cellular subpopulations are known, the precise mechanism of the changes and the consequences of the same remain obscure. This review summarizes the limited literature on pituitary trophic activity and asks what, if anything, analysis of pituitary trophic activity using current technology can tell us.
Lieb, K., Y. Treffurth, et al. (2002). "Substance P and affective disorders: new treatment opportunities by neurokinin 1 receptor antagonists?" Neuropsychobiology 45 Suppl 1: 2-6.
Substance P (SP) is a neuropeptide which is abundant in the periphery and the central nervous system, where it is colocalized with other neurotransmitters such as serotonin or dopamine. SP has been proposed to play a role in the regulation of pain including migraine and fibromyalgia, asthma, inflammatory bowel disease, emesis, psoriasis as well as in central nervous system disorders. This review summarizes our current knowledge of the role of SP in the pathogenesis of neuropsychiatric disorders with special emphasis on affective disorders including bipolar disorders. It also reviews current treatment approaches with neurokinin 1 receptor antagonists which appear to be promising drugs for the future treatment of affective disorders.
Loscher, W. (2002). "Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy." CNS Drugs 16(10): 669-94.
Since its first marketing as an antiepileptic drug (AED) 35 years ago in France, valproate has become established worldwide as one of the most widely used AEDs in the treatment of both generalised and partial seizures in adults and children. The broad spectrum of antiepileptic efficacy of valproate is reflected in preclinical in vivo and in vitro models, including a variety of animal models of seizures or epilepsy. There is no single mechanism of action of valproate that can completely account for the numerous effects of the drug on neuronal tissue and its broad clinical activity in epilepsy and other brain diseases. In view of the diverse molecular and cellular events that underlie different seizure types, the combination of several neurochemical and neurophysiological mechanisms in a single drug molecule might explain the broad antiepileptic efficacy of valproate. Furthermore, by acting on diverse regional targets thought to be involved in the generation and propagation of seizures, valproate may antagonise epileptic activity at several steps of its organisation. There is now ample experimental evidence that valproate increases turnover of gamma-aminobutyric acid (GABA) and thereby potentiates GABAergic functions in some specific brain regions thought to be involved in the control of seizure generation and propagation. Furthermore, the effect of valproate on neuronal excitation mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors might be important for its anticonvulsant effects. Acting to alter the balance of inhibition and excitation through multiple mechanisms is clearly an advantage for valproate and probably contributes to its broad spectrum of clinical effects. Although the GABAergic potentiation and glutamate/NMDA inhibition could be a likely explanation for the anticonvulsant action on focal and generalised convulsive seizures, they do not explain the effect of valproate on nonconvulsive seizures, such as absences. In this respect, the reduction of gamma-hydroxybutyrate (GHB) release reported for valproate could be of interest, because GHB has been suggested to play a critical role in the modulation of absence seizures. Although it is often proposed that blockade of voltage-dependent sodium currents is an important mechanism of antiepileptic action of valproate, the exact role played by this mechanism of action at therapeutically relevant concentrations in the mammalian brain is not clearly elucidated. By the experimental observations summarised in this review, most clinical effects of valproate can be explained, although much remains to be learned at a number of different levels about the mechanisms of action of valproate. In view of the advances in molecular neurobiology and neuroscience, future studies will undoubtedly further our understanding of the mechanisms of action of valproate.
Lotharius, J. and P. Brundin (2002). "Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein." Nat Rev Neurosci 3(12): 932-42.
Ludin, H. P. (2002). "[Fatigue, daytime somnolence and sleep disorders in Parkinson patients]." Schweiz Rundsch Med Prax 91(10): 407-10.
Many patients suffering from Parkinson's disease complain about chronic fatigue and daytime somnolence. During the last few years attention has been drawn to "sleep attacks", which are supposed to be due mainly to dopamine agonists. Sleep disturbances during the night are quite frequent. It is important to search for the probable causes in each individual case in order to be able to install an efficacious treatment.
Lykkebo, S. and P. H. Jensen (2002). "Alpha-synuclein and presynaptic function: implications for Parkinson's disease." Neuromolecular Med 2(2): 115-29.
This article focuses on alpha-synuclein's role in normal and pathological axonal and presynaptic functions and its relationship to Parkinson's disease. It is not possible to mention all the contributions to aspects of this area. Readers interested in alpha-synuclein's relation to aggregation, Lewy lesions, and pathological modifications are referred to the many reviews (see Goldberg and Lansbury 2000; Galvin 2001a; Goedert 2001).
Madras, B. K., G. M. Miller, et al. (2002). "The dopamine transporter: relevance to attention deficit hyperactivity disorder (ADHD)." Behav Brain Res 130(1-2): 57-63.
The dopamine transporter is elevated in adults with attention deficit hyperactivity disorder (ADHD) compared with healthy controls [Lancet 354 (1999) 2132]. The findings have been confirmed by others in a different population using a different probe for the dopamine transporter. Notwithstanding the need to confirm these findings in a multi-center trial, several hypotheses are presented to account for these observations. A premise that elevated transporter levels result from medication is not supported by current data. Other possibilities, including hypertrophy of dopamine neuronal terminals in the striatum, dysfunctional regulation of dopamine or dopamine receptors, or anomalies in the dopamine transporter gene are presented as hypotheses. The feasibility of exploring these mechanisms in animal models or in human subjects is explored.
Maev, I. V. (2002). "[Non-ulcer dyspepsia syndrome]." Eksp Klin Gastroenterol(2): 37-42.
Magee, L. A., P. Mazzotta, et al. (2002). "Evidence-based view of safety and effectiveness of pharmacologic therapy for nausea and vomiting of pregnancy (NVP)." Am J Obstet Gynecol 185(5 Suppl Understanding): S256-61.
OBJECTIVE: Our goal was to review the safety and effectiveness of available antiemetics for treatment of nausea and vomiting of pregnancy. STUDY DESIGN: We performed a quantitative and qualitative overview of observational controlled studies for drug safety in pregnancy and randomized controlled trials for drug effectiveness for nausea and vomiting in pregnancy. RESULTS: All of the following are safe and effective for treatment of varying degrees of nausea and vomiting in pregnancy: Bendectin/Diclectin (doxylamine, pyridoxine, dicyclomine), antihistamine (H(1)) blockers, and phenothiazines; however, the magnitude of effect, particularly for phenothiazines, is in question and may differ among individual agents. Pyridoxine and vitamin B(12)are safe and may be effective. Metoclopramide, droperidol, and ondansetron may be effective, but safety data are insufficient to recommend them as first-line agents. Corticosteroids may not be as beneficial as first thought, and there may be a small teratogenic risk. The relative effectiveness of various agents is largely unknown. CONCLUSION: Many medications, particularly H(1)-antagonists and phenothiazines, are safe and effective for treatment of varying degrees of NVP.
Maldonado, R. and F. Rodriguez de Fonseca (2002). "Cannabinoid addiction: behavioral models and neural correlates." J Neurosci 22(9): 3326-31.
The use of cannabis sativa preparations as recreational drugs can be traced back to the earliest civilizations. However, animal models of cannabinoid addiction allowing the exploration of neural correlates of cannabinoid abuse have been developed only recently. We review these models and the role of the CB1 cannabinoid receptor, the main target of natural cannabinoids, and its interaction with opioid and dopamine transmission in reward circuits. Extensive reviews on the molecular basis of cannabinoid action are available elsewhere (Piomelli et al., 2000; Schlicker and Kathmann, 2001).
Mancama, D., M. J. Arranz, et al. (2002). "Genetic predictors of therapeutic response to clozapine: current status of research." CNS Drugs 16(5): 317-24.
Clozapine is one of the most clinically potent drugs currently available for treating the symptoms of schizophrenia. Compared with conventional antipsychotics it surpasses its predecessors in its ability to treat a wider range of symptoms in otherwise refractory patients, while possessing a low propensity to produce extrapyramidal symptoms. Despite its significant advantages, not all patients benefit from treatment. Some patients react adversely to therapy while others fail to respond adequately. If those most likely to benefit from clozapine could be identified prior to treatment, this would significantly improve the clinical management of these patients. Genetic alterations in drug-metabolising enzymes have previously been demonstrated to influence the efficacy of clinically relevant drugs. It is possible that similar alterations in these and other systems may influence the response variability of patients to clozapine. Pharmacogenetic studies are at present investigating genes encoding drug receptors, drug-metabolising enzymes and neurotransmitter transporters to identify genetic variants that may be important. To date polymorphisms within serotonergic and dopaminergic pathways have been implicated, though the involvement of similar variants in other candidate systems is also likely. This information will ultimately enable the genetic prediction of patients most likely to benefit from the drug, and in the process would alleviate the unnecessary exposure of predisposed individuals to potentially serious adverse effects.
Mansvelder, H. D. and D. S. McGehee (2002). "Cellular and synaptic mechanisms of nicotine addiction." J Neurobiol 53(4): 606-17.
The tragic health effects of nicotine addiction highlight the importance of investigating the cellular mechanisms of this complex behavioral phenomenon. The chain of cause and effect of nicotine addiction starts with the interaction of this tobacco alkaloid with nicotinic acetylcholine receptors (nAChRs). This interaction leads to activation of reward centers in the CNS, including the mesoaccumbens DA system, which ultimately leads to behavioral reinforcement and addiction. Recent findings from a number of laboratories have provided new insights into the biologic processes that contribute to nicotine self-administration. Examination of the nAChR subtypes expressed within the reward centers has identified potential roles for these receptors in normal physiology, as well as the effects of nicotine exposure. The high nicotine sensitivity of some nAChR subtypes leads to rapid activation followed in many cases by rapid desensitization. Assessing the relative importance of these molecular phenomena in the behavioral effects of nicotine presents an exciting challenge for future research efforts.
Marik, P. E. (2002). "Low-dose dopamine: a systematic review." Intensive Care Med 28(7): 877-83.
OBJECTIVE: To determine the magnitude of the treatment effect of low-dose dopamine on renal function in patients at risk of and in patients with early renal injury. DATA SOURCES: MEDLINE, citation review of relevant primary and review articles, personal files, and contact with expert informants. STUDY SELECTION: Randomized controlled studies that compared low-dose dopamine with placebo for the prevention or treatment of acute renal dysfunction. From 122 articles screened, 21 met the inclusion criteria for this meta-analysis. Of these six, were excluded. DATA EXTRACTION: Fifteen studies containing 970 subjects were analyzed. Descriptive and outcome data were extracted. The main outcome measure was the absolute change in serum creatinine. In addition the number of patients who developed an acute decline in renal function was recorded. The meta-analysis was performed using the random effects model. DATA SYNTHESIS: The meta-analysis demonstrated no significant difference between the absolute change in serum creatinine (5.1 micromol/l, 95% CI of -6.5 to +16.7) and the incidence of acute renal dysfunction (31% vs 33%, relative risk 1.01, 95% CI of 0.79-1.28) between those patients receiving low-dose dopamine and the control group. In addition, no sub-group of patients showed improved renal function with low-dose dopamine. CONCLUSIONS: The results of this meta-analysis confirms that low-dose dopamine has no reno-protective effect. Considering the potential side-effects of dopamine this agent should not be used for this indication.
Marinelli, M. and P. V. Piazza (2002). "Interaction between glucocorticoid hormones, stress and psychostimulant drugs." Eur J Neurosci 16(3): 387-94.
In this review we summarize data obtained from animal studies showing that glucocorticoid hormones have a facilitatory role on behavioural responses to psychostimulant drugs such as locomotor activity, self-administration and relapse. These behavioural effects of glucocorticoids involve an action on the meso-accumbens dopamine system, one of the major systems mediating the addictive properties of drugs of abuse. The effects of glucocorticoids in the nucleus accumbens are site-specific; these hormones modify dopamine transmission in only the shell of this nucleus without modifying it in the core. Studies with corticosteroid receptor antagonists suggest that the dopaminergic effects of these hormones depend mostly on glucocorticoid, not on mineralocorticoid receptors. These data suggest that an increase in glucocorticoid hormones, through an action on mesolimbic dopamine neurons, could increase vulnerability to drug abuse. We also discuss the implications of this finding with respect to the physiological role of glucocorticoids. It is proposed that an increase in glucocorticoids, by activating the reward pathway, could counteract the aversive effects of stress. During chronic stress, repeated increases in glucocorticoids and dopamine would result in sensitization of the reward system. This sensitized state, which can persist after the end of the stress, would render the subject more responsive to drugs of abuse and consequently more vulnerable to the development of addiction.
Martinez, M., L. Devenport, et al. (2002). "Drug-associated heat stroke." South Med J 95(8): 799-802.
During the June 1998 heat wave in New Orleans, 8 patients came to the emergency department of a large public hospital over a 14-day period. They were subsequently admitted to the intensive care unit with a diagnosis of heat stroke. On each of these days, the ambient temperature exceeded 33.3 degrees C (91.9 degrees F). Although the highest recorded temperature was only 35.6 degrees C (96 degrees F), the heat index reached a high of 44.5 degrees C (112 degrees F). Weather-related heat illnesses are well documented, but the reports rarely address contributing medications or drugs. In this series, 6 patients (75%) had been using medication or drugs known to induce or worsen hyperthermia. A seventh patient had been prescribed a phenothiazine, but actual use could not be established. An eighth patient had an unidentified agent detected on toxicologic screening. The most common drug identified was cocaine. Other drugs included diphenhydramine, tricyclic antidepressants, and phenothiazines. Six patients (75%) had rhabdomyolysis; 3 of them also had disseminated intravascular coagulation. There were 2 deaths, yielding a 25% mortality rate.
Maruyama, W., Y. Akao, et al. (2002). "Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes." Neurotoxicol Teratol 24(5): 675-82.
In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT.
Matsubara, K., K. Aoyama, et al. (2002). "N-methylation underlying Parkinson's disease." Neurotoxicol Teratol 24(5): 593-8.
The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) leads to the hypothesis that Parkinson's disease (PD) is maybe initiated or precipitated by environmental or endogenous toxins by the mechanism similar to that of MPTP in genetically-predisposed individuals. Endogenous analogs of MPTP, such as beta-carbolines (betaCs) and tetrahydroisoquinolines, have been proposed as possible causative candidates causing PD and are bioactivated into potential neurotoxins by N-methylation enzyme(s). These N-methylated betaCs and tetrahydroisoquinoline have been higher cerebrospinal levels in parkinsonian patients than age-matched controls. Thus, there is a hypotheses to influence the pathogenesis of PD, that is, the excess enzyme activity to activate neurotoxins, such as N-methyltransferase, might be higher in PDs. Indeed, simple betaCs, via N-methylation steps, induced bradykinesia with the decreased dopamine contents in the striatum and midbrain in C57/BL mice. In younger (65 years old) PD patients, the excretion amount of N(1)-methyl-nicotinamaide was significantly higher than that in younger controls. The protein amount of nicotinamide N-methyltransferase (NNMT) was also significantly higher in younger PD patients than that in younger controls. These findings described here would indicate that the excess N-methylation ability for azaheterocyclic amines, such as betaCs, before the onset had been implicated in PD pathogenesis. On the other hand, the contribution of aberrant cytochrome P450 or aldehyde oxidase activity acting on the pyridine ring, that could act as detoxification routes of endogenous neurotoxins, would be small in the etiology of PD.
Matsubara, E., M. Shoji, et al. (2002). "[The treatment of Parkinson's disease--adenosine A2A receptor antagonists]." Nippon Rinsho 60(1): 112-6.
The primary pathology of Parkinson's disease is the degeneration of dopaminergic neurons in the nigrostriatal pathway, resulting in a significant reduction in striatum dopamine concentration which is responsible for the altered motor functions. With time and disease progression, efficacy of dopaminergic therapy becomes unpromising. Since adenosine A2A receptor is selectively localized in striatum for controlling motor activity, it appeared to be an attractive target for a novel treatment in Parkinson's disease. Several lines of evidence indicated that KW-6002, highly selective antagonist of adenosine A2A receptor, showed anti-parkinsonian effect in vivo and in vitro without any problematic side effect which is observed in dopaminergic therapy. Further investigation will be necessary to make sure the effect in ongoing progressive nature of Parkinson's disease or the long treatment periods in Parkinson's disease.
Matsuzawa, S. and T. Suzuki (2002). "[Psychological stress and rewarding effect of alcohol]." Nihon Arukoru Yakubutsu Igakkai Zasshi 37(3): 143-52.
It has long been postulated that an interaction between ethanol and stress may play an important role in the etiology of alcoholism. In the present review, we focused on an interaction between ethanol and stress in the mechanism of psychological dependence on ethanol. Ethanol with conditioned fear stress (CFS), but not without the stress, induced a significant place preference. These results suggest that psychological stress may play an important role in the rewarding effect of ethanol. It has been hypothesized that activation of the mesolimbic dopamine system mediated by the endogenous opioid system may be particularly important in the rewarding mechanism of ethanol. It appeared that mu- and delta-opioid receptors might play critical roles in the development of the rewarding effect of ethanol under the stress. Under psychological stress, the rewarding effect of ethanol through the activation of mu- and/or delta-opioid receptors was found to results the activation of dopamine D1 and/or D2 receptors. Additionally, a subtype of serotonin (5-HT) receptors, 5-HT3 receptor, was shown to be involved in the rewarding mechanism of ethanol through the activation of mu- and delta-opioid receptors. In conclusion, psychological stress may be an important factor in the development of the rewarding effect of ethanol and may potentiate the rewarding mechanism. 5-HT3 receptor, is likely to be involved in the rewarding mechanism of ethanol under stress. Dopamine D1 and D2 receptors may also be implicated in the rewarding mechanism of ethanol under stress.
Maurice, T., R. Martin-Fardon, et al. (2002). "Sigma(1) (sigma(1)) receptor antagonists represent a new strategy against cocaine addiction and toxicity." Neurosci Biobehav Rev 26(4): 499-527.
Cocaine is a highly addictive substance abused worldwide. Its mechanism of action involves initially inhibition of neuronal monoamine transporters in precise brain structures and primarily the dopamine reuptake system located on mesolimbic neurons. Cocaine rapidly increases the dopaminergic neurotransmission and triggers adaptive changes in numerous neuronal circuits underlying reinforcement, reward, sensitization and the high addictive potential of cocaine. Current therapeutic strategies focus on counteracting the cocaine effects directly on the dopamine transporter, through post-synaptic D(1), D(2) or D(3) receptors or through the glutamatergic, serotoninergic, opioid or corticotropin-releasing hormone systems. However, cocaine administration also results in the activation of numerous particular targets. Among them, the sigma(1) (sigma(1)) receptor is involved in several acute or chronic effects of cocaine. The present review will first bring concise overviews of the present strategies followed to alleviate cocaine addiction and animal models developed to analyze the pharmacology of cocaine addiction. Evidence involving activation of the sigma(1) receptor in the different aspects of cocaine abuse, will then be detailed, following acute, repeated, or overdose administration. The therapeutic potentials and neuropharmacological perspectives opened by the use of selective sigma(1) receptor antagonists in cocaine addiction will finally be discussed.
McBride, W. J. (2002). "Central nucleus of the amygdala and the effects of alcohol and alcohol-drinking behavior in rodents." Pharmacol Biochem Behav 71(3): 509-15.
This article will review key literature on the effects of alcohol on the amygdala and the involvement of the amygdala in regulating alcohol drinking in mice and rats. Special emphasis will be placed on the central nucleus of the amygdala (CeA) because this nucleus is a major component of the extended amygdala, which has been implicated in regulating alcohol-drinking behavior. Immunocytochemical and in situ hybridization studies indicate that acute high-dose ethanol administration increases c-fos expression in GABAergic neurons within the CeA of the rat, suggesting activation of these neurons by ethanol. A similar high-dose (4 g/kg ethanol) effect on c-fos expression in the CeA of C57 mice was also observed, whereas the DBA mice showed increased c-fos expression in the CeA in the dose range of 1.25-4.0 g/kg. Studies with DBA x C57 F2 intercross mice suggest that there may be a relationship between the neuronal activating effects of ethanol in the CeA and the locomotor stimulating effects of ethanol. Studies with rats examining the effects of acute ethanol or chronic alcohol drinking on local cerebral glucose utilization (LCGU) rates (as a measure of synaptic activity) indicated that (a) acute ethanol (0.25-2.0 g/kg) had little effect on LCGU rates in the CeA; (b) basal LCGU rates were reduced in the CeA as a result of chronic alcohol drinking; and (c) oral self-administration of ethanol increased LCGU values within the CeA. Microdialysis studies demonstrated that acute ethanol (2 g/kg) injection increased dopamine (DA) and serotonin (5-HT) release in the CeA. Microinjection studies indicate that GABA(A) receptors within the CeA are involved in oral ethanol self-administration. Overall, the findings from the various studies support a role for the CeA in mediating the stimulating actions of alcohol in mice and regulating alcohol-drinking behavior in mice and rats.
Meaney, M. J., W. Brake, et al. (2002). "Environmental regulation of the development of mesolimbic dopamine systems: a neurobiological mechanism for vulnerability to drug abuse?" Psychoneuroendocrinology 27(1-2): 127-38.
Repeated periods of maternal separation in the early life of rats decreased dopamine transporter expression and significantly increased dopamine responses to stress, and behavioral responses to either stress or cocaine. As adults, maternal separation animals showed increased sensitivity to the effects of cocaine on locomotor activity and greater sensitivity to stress-induced sensitization to the effects of amphetamine on locomotor activity. These findings raise the possibility that in addition to effects on stress reactivity, early life events might dispose individuals to illness in later life through effects on very specific neurotransmitter systems.
Melmed, S., F. F. Casanueva, et al. (2002). "Guidelines for acromegaly management." J Clin Endocrinol Metab 87(9): 4054-8.
Mena, M. A., S. de Bernardo, et al. (2002). "The role of astroglia on the survival of dopamine neurons." Mol Neurobiol 25(3): 245-63.
Glial cells play a key role in the function of dopamine (DA) neurons and regulate their differentiation, morphology, physiological and pharmacological properties, survival, and resistance to different models of DA lesion. Several studies suggest that glial cells may be important in the pathogenesis of Parkinson's disease (PD), a common neurodegenerative disorder characterized by degeneration of the nigrostriatal DA system. In this disease the role of glia could be due to the excessive production of toxic products such as nitric oxide (NO) or cytokines characteristic of inflammatory process, or related to a defective release of neuroprotective agents, such as small antioxidants with free radical scavenging properties or peptidic neurotrophic factors.
Mignot, E., S. Taheri, et al. (2002). "Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders." Nat Neurosci 5 Suppl: 1071-5.
Delineating the basic mechanisms that regulate sleep will likely result in the development of better treatments for sleep disorders. The hypothalamus is now recognized as a key center for sleep regulation, with hypothalamic neurotransmitter systems providing the framework for therapeutic advances. An increased awareness of the close interaction between sleep and homeostatic systems is also emerging. Progress has occurred in the understanding of narcolepsy--molecular techniques have identified the lateral hypothalamic hypocretin (orexin) neuropeptide system as key to the disorder. Other sleep disorders are now being tackled in the same way and are likely to yield to efforts combining basic and clinical research. Here we highlight the role of the hypothalamus in sleep physiology and discuss neurotransmitter systems, such as adenosine, dopamine, GABA, histamine and hypocretin, that may have therapeutic applications for sleep disorders.
Millan, M. J. (2002). "Descending control of pain." Prog Neurobiol 66(6): 355-474.
Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at alpha(2)-adrenoceptors (alpha(2)-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain.
Misu, Y., N. Furukawa, et al. (2002). "DOPA causes glutamate release and delayed neuron death by brain ischemia in rats." Neurotoxicol Teratol 24(5): 629-38.
DOPA seems to be a neuromodulator in striata and hippocampal CA1 and a neurotransmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii (NTS) and baroreflex pathways in the caudal ventrolateral medulla and rostral ventrolateral medulla in the brainstem of rats. DOPA recognition sites differ from dopamine (DA) D(1) and D(2) and ionotropic glutamate receptors. Via DOPA sites, DOPA stereoselectively releases by itself neuronal glutamate from in vitro and in vivo striata. In the cultured neurons, DOPA and DA cause neuron death via autoxidation. In addition, DOPA causes autoxidation-irrelevant neuron death via glutamate release. Furthermore, DOPA released by four-vessel occlusion seems to be an upstream causal factor for glutamate release and resultant delayed neuron death by brain ischemia in striata and hippocampal CA1. Glutamate has been regarded as a neurotransmitter of baroreflex pathways. Herein, we propose a new pathway that DOPA is a neurotransmitter of the primary aortic depressor nerve and glutamate is that of secondary neurons in neuronal microcircuits of depressor sites in the NTS. DOPA seems to release unmeasurable, but functioning, endogenous glutamate from the secondary neurons via DOPA sites. A common following pathway may be ionotropic glutamate receptors-nNOS activation-NO production-baroreflex neurotransmission and delayed neuron death. However, we are concerned that DOPA therapy may accelerate neuronal degeneration process especially at progressive stages of Parkinson's disease.
Misu, Y., Y. Goshima, et al. (2002). "Is DOPA a neurotransmitter?" Trends Pharmacol Sci 23(6): 262-8.
Historically, 3,4-dihydroxyphenylalanine (DOPA) has been considered to be an inert amino acid that alleviates the symptoms of Parkinson's disease by its conversion to dopamine via the enzyme aromatic L-amino acid decarboxylase. In contrast to this generally accepted idea, we propose that DOPA itself is a neurotransmitter and/or neuromodulator in addition to being a precursor of dopamine. Several criteria such as synthesis, metabolism, active transport, existence, physiological release, competitive antagonism and physiological or pharmacological responses must be satisfied before a compound is accepted as a neurotransmitter. Recent evidence suggests that DOPA fulfills these criteria in its involvement in baroreflex neurotransmission.
Mizuno, Y. (2002). "[Progress in diagnosis and therapy for Parkinson's disease]." Nippon Naika Gakkai Zasshi 91(8): 2344-8.
Moghaddam, B. (2002). "Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders." Biol Psychiatry 51(10): 775-87.
In most psychiatric disorders, stress is the major nongenomic factor that contributes to the expression or exacerbation of acute symptoms, recurrence or relapse after a period of remission, and treatment outcome. Delineation of mechanisms by which stress contributes to these processes is fundamental to understanding the disease process and for improving outcome. In this article, evidence is reviewed to indicate that many central aspects of stress response, including activation of the hypothalmic-pituitary-adrenal (HPA) axis and dopamine neurotransmission, are modulated, and in some cases mediated, by glutamate neurotransmission in the prefrontal cortex (PFC). It is suggested that activation of glutamatergic neurotransmission in the PFC presents a common mechanism by which stress influences normal and abnormal processes that sustain affect and cognition. Although monoamines, in particular dopamine, have been considered the major culprits in the adverse effects of stress in disorders such as addiction and schizophrenia, it is likely that in a vulnerable brain with an underlying PFC pathophysiology, abnormal stress-activated monoaminergic neurotransmission is secondary to anomalies in cortical glutamate neurotransmission. Thus, understanding the contribution of glutamate-mediated processes to stress response through the use of experimental models that involve disrupted PFC function can provide insights to the fundamental pathophysiology of stress-sensitive psychiatric disorders and lead to novel strategies for treatment and prevention.
Mohanakumar, K. P., B. Thomas, et al. (2002). "Nitric oxide: an antioxidant and neuroprotector." Ann N Y Acad Sci 962: 389-401.
Indirect evidence, including neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-neurotoxicity by nitric oxide synthase (NOS) inhibitors and resistance of transgenic animals deficient in NOS, is controversial. We have reviewed evidence in favor of oxidative stress during the development of MPTP-neurotoxicity and the influence of antioxidants, including nitric oxide (NO) and NO donors, on MPTP-induced dopaminergic neurotoxicity. Systemic administration of MPTP causes dose-dependent generation of hydroxyl radicals (OH) in vivo in the striatum in mice; OH scavengers protect dopaminergic neurons from this insult. On the other hand the role of NO in MPTP-neurotoxicity is controversial. Hitherto, no direct evidence for the involvement of NO in MPTP neurotoxicity has been available. MPTP does not affect inducible-NOS mRNA level or its expression in SN or the striatum. Nitroglycerine, a NO donor, can attenuate MPTP-induced dopamine depletion in the striatum by virtue of its OH scavenging action. Several other NO donors have also been shown to scavenge the OH generated, following Fenton chemistry in vitro, and to protect against in vivo dopaminergic neurotoxicity by small mass iron complex formation. This evidence suggests that NO renders protection against MPTP-induced OH-mediated nigrostriatal lesions, acting as an antioxidant.
Momiyama, T. (2002). "[Calcium channel subtypes mediating central synaptic transmission]." Nippon Yakurigaku Zasshi 119(4): 235-40.
It is well established that neurotransmitter release is triggered by Ca2+ entry into the presynaptic terminals through voltage-dependent Ca2+ channels. In the mammalian central nervous system, multiple types of Ca2+ channels including N-type, P/Q-type and other types mediate fast synaptic transmission. Electrophysiological studies using type-specific antagonists for Ca2+ channels have estimated the relative contribution of N-, P/Q- and other types of Ca2+ channels in excitatory and inhibitory synaptic transmission in the hippocampus, cerebellum, spinal cord, brain stem, and striatum. A recent study has demonstrated that activation of presynaptic dopamine D2-like receptors selectively block N-type Ca2+ channels to reduce GABA release onto cholinergic interneurons in the rat striatum. In addition, it has been recently clarified that the contribution of N-type Ca2+ channels to synaptic transmission is restricted to the early postnatal period at synapses in auditory brain stem, cerebellum, or thalamus. Advanced morphological studies are necessary for the further understanding of the subcellular localization of each subtype of Ca2+ channels and receptors modulating the transmitter release through Ca2+ channel activity in relation to the release sites in the presynaptic terminals.
Montgomery, E. B., Jr. (2002). "Two advances in the management of Parkinson disease." Cleve Clin J Med 69(8): 639-43.
Levodopa should generally be avoided early in the course of Parkinson disease; dopamine agonists, particularly second-generation agents such as ropinirole (Requip) and pramipexole (Mirapex), carry a smaller long-term risk of dyskinesia and should be used instead. Deep brain stimulation is remarkably effective in refractory cases and may well usher in a new era in the treatment of chronic neurologic disease.
Morris, D. and A. Grossman (2002). "The medical management of Cushing's syndrome." Ann N Y Acad Sci 970: 119-33.
Cushing's syndrome results from prolonged exposure to excessive circulating glucocorticosteroids, and is associated with significant morbidity and mortality. While the treatment of choice in most patients is surgical, the metabolic consequences of the syndrome, including increased tissue fragility, poor wound healing, hypertension, and diabetes mellitus, increase the risks of such surgery. The hypercortisolemia and its sequelae can be efficiently reversed using medical therapy, either as a temporary measure prior to definitive treatment, or longer term in more difficult cases. Drug treatment has been targeted at the hypothalamic/pituitary level, the adrenal glands, and also at the glucocorticoid receptor level. In this review we discuss the pharmacotherapeutic agents that have been used in Cushing's syndrome, and their efficacy, the monitoring of treatment, and potential therapies that may prove useful in the future in this complex endocrinological disorder.
Muller, W. E. (2002). "[How do clozapine and co. work? Pharmacologic mechanisms of atypical neuroleptics]." Pharm Unserer Zeit 31(6): 537-45.
Muller, U., D. Steinberger, et al. (2002). "Mutations of GCH1 in Dopa-responsive dystonia." J Neural Transm 109(3): 321-8.
Dopa responsive dystonia (DRD) is an autosomal dominant dystonia caused by mutations in the gene GCH1 in about 50% of cases. GCH1 codes for GTP cyclohydrolase I, a rate limiting enzyme in the synthesis of tetrahydrobiobterin (BH(4)) from GTP. There is reduced penetrance and pronounced variation in expressivity of GCH1 mutations in families with DRD. Correlations between given mutations in GCH1 and phenotypes cannot be established. Mutations in GCH1 appear to function as dominant-negatives but the exact mechanism remains unclear. Additional open questions in DRD include the molecular mechanisms resulting in highly variable expressivity of symptoms and the more likely occurrence of symptoms in a female than in a male carrier of a GCH1 mutation.
Muller-Vahl, K. R. (2002). "The treatment of Tourette's syndrome: current opinions." Expert Opin Pharmacother 3(7): 899-914.
Correct education of the patient is one of the most important aspects in the treatment of Tourette's syndrome. Pharmacotherapy is often unsatisfactory and therefore should be limited to those patients who are significantly impaired. Therapy must be individualised and the most troublesome symptom should be targeted first. In the treatment of tics, dopamine receptor blocking agents are currently the most effective drugs. It is currently unknown whether classic neuroleptics, such as pimozide, selective dopamine receptor antagonists, such as sulpiride, or newer atypical antipsychotics, such as risperidone, have the best adverse effect profile. Tiapride can be used as an alternative, particularly in children. Selective serotonin-re-uptake inhibitors are recommended for the treatment of obsessive-compulsive behaviour. In children suffering from attention deficit hyperactivity disorder, psychostimulants, such as methylphenidate, are the treatment of choice. Recent studies have provided increasing evidence that stimulants do not cause a significant increase in tics in the majority of patients.
Muramatsu, S., L. Wang, et al. (2002). "Recombinant adeno-associated viral vectors bring gene therapy for Parkinson's disease closer to reality." J Neurol 249 Suppl 2: II36-40.
The recombinant adeno-associated viral (rAAV) vector is a powerful tool for delivering therapeutic genes into mammalian brains. In rodents and non-human primates, a substantial number of striatal neurons can be transduced with high titer rAAV vectors by simple stereotaxic injection. Efficient and long-term expression of genes for dopamine (DA)-synthesizing enzymes in the striatum restored local DA production and achieved behavioral recovery in animal models of Parkinson's disease (PD). Moreover, sustained expression of a glial cell line-derived neurotrophic factor gene in the striatum rescued nigral neurons and led to functional recovery in a rat model of PD, even when treatment was delayed until after the onset of progressive degeneration. These results suggest that gene therapy using rAAV vectors may become a novel and feasible treatment for PD.
Nagai, A. and H. Kumon (2002). "[Clinical evaluation of apomorphine HCl]." Nippon Rinsho 60 Suppl 6: 457-60.
Nagatsu, T. (2002). "Amine-related neurotoxins in Parkinson's disease: past, present, and future." Neurotoxicol Teratol 24(5): 565-9.
Parkinson's disease (PD) is an aging-related movement disorder caused by a deficiency of the neurotransmitter dopamine (DA) in the striatum of the brain as a result of selective degeneration of nigrostriatal DA neurons. The molecular basis of the cell death of DA neurons is unknown, but one hypothesis is the presence of some amine-related neurotoxins that kill specifically nigrostriatal DA neurons over a long period of time. This neurotoxin hypothesis of PD started in the 1980s when 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was discovered to produce acutely PD-like symptoms. Two groups of natural MPTP-like and amine-related neurotoxins have been investigated as endogenous candidate compounds: isoquinolines (IQs) and beta-carbolines. These neurotoxins are speculated to cause oxidative stress, mitochondrial dysfunction, apoptotic cell death, and PD symptoms. However, since PD is a neurodegenerative disorder that progresses slowly over a period of many years, a long-term study may be required to elucidate the neurotoxicity of such neurotoxins in relation to PD.
Nagatsu, T. (2002). "Parkinson's disease: changes in apoptosis-related factors suggesting possible gene therapy." J Neural Transm 109(5-6): 731-45.
Specific degeneration of the nigrostriatal dopamine (DA) neurons of the substantia nigra pars compacta and the resulting loss of nerve terminals accompanied by DA deficiency in the striatum are responsible for most of the movement disturbances called parkinsonism, i.e., muscle rigidity, akinesia, and resting tremor, observed in Parkinson's disease (PD). We and other workers have found changes in the levels of cytokines, neurotrophins, and other apoptosis-related factors in the nigro-striatal region of postmortem brain and/or in the cerebrospinal fluid (CSF) from PD patients, or from animal models of PD such as 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP)-induced PD in mice or 6-hydroxydopamine (6-OHDA)-induced PD in rats. The most remarkable changes observed specifically in the nigrostriatal region were decreased levels of neurotrophins supporting DA neurons. These results indicate that the process of cell death in the nigrostriatal DA neurons in PD may be the so-called programmed cell death, i.e., apoptosis. Thus gene therapy for PD should aim both at supplementing the decreased striatal DA level by introducing the genes of DA-synthesizing enzymes into non-DA cells in the striatum and at supporting or restoring DA neurons by preventing apoptosis by introducing genes that block the process of apoptosis.
Naoi, M., W. Maruyama, et al. (2002). "Dopamine-derived endogenous N-methyl-(R)-salsolinol: its role in Parkinson's disease." Neurotoxicol Teratol 24(5): 579-91.
A dopamine-derived alkaloid, N-methyl-(R)-salsolinol [NM(R)Sal], enantioselectively occurs in human brains and accumulates in the nigrostriatal system. It increases in the cerebrospinal fluid (CSF) of parkinsonian patients and the activity of a neutral (R)-salsolinol [(R)Sal] N-methyltransferase, a key enzyme in the biosynthesis of this toxin, increases in the lymphocytes from parkinsonian patients, suggesting its involvement in the pathogenesis of Parkinson's disease (PD). The studies of animal and cellular models of PD proved that this isoquinoline is selectively cytotoxic to dopamine neurons. Using human dopaminergic SH-SY5Y cells, NM(R)Sal induces apoptosis by the activation of the apoptotic cascade initiated in mitochondria. In this article, we review the recent advance in proving our hypothesis that the dopamine-derived neurotoxin causes the selective depletion of dopamine neurons in PD.
Nath, A., K. F. Hauser, et al. (2002). "Molecular basis for interactions of HIV and drugs of abuse." J Acquir Immune Defic Syndr 31 Suppl 2: S62-9.
In certain populations around the world, the HIV pandemic is being driven by drug-abusing populations. Mounting evidence suggests that these patient populations have accelerated and more severe neurocognitive dysfunction compared with non-drug-abusing HIV-infected populations. Because most drugs of abuse are central nervous system stimulants, it stands to reason that these drugs may synergize with neurotoxic substances released during the course of HIV infection. Clinical and laboratory evidence suggests that the dopaminergic systems are most vulnerable to such combined neurotoxicity. Identifying common mechanisms of neuronal injury is critical to developing therapeutic strategies for drug-abusing HIV-infected populations. This article reviews 1) the current evidence for neurodegeneration in the setting of combined HIV infection and use of methamphetamine, cocaine, heroin or alcohol; 2) the proposed underlying mechanisms involved in this combined neurotoxicity; and 3) future directions for research. This article also suggests therapeutic approaches based on our current understanding of the neuropathogenesis of dementia due to HIV infection and drugs of abuse.
Newlin, D. B. (2002). "The self-perceived survival ability and reproductive fitness (SPFit) theory of substance use disorders." Addiction 97(4): 427-45.
A new theory of substance use disorders is proposed-the SPFit theory-that is based on evolutionary biology and adaptive systems. Self-perceived survival ability and reproductive fitness (SPFit) is proposed as a human psychobiological construct that prioritizes and organizes (i.e. motivates) behavior, but is highly vulnerable to temporary, artificial activation by drugs of abuse. Autoshaping/sign-tracking/feature positive phenomena are proposed to underlie the development of craving and expectations about drugs as the individual learns that abused drugs will easily and reliably inflate SPFit. The cortico-mesolimbic dopamine system and its modulating interconnections are viewed as the biological substrate of SPFit; it is proposed to be a survival and reproductive motivation system rather than a reward center or reward pathway. Finally, the concept of modularity of mind is applied to the SPFit construct. Although considerable empirical data are consistent with the theory, new research is needed to test specific hypotheses derived from SPFit theory.
Newman, A. H. and S. Kulkarni (2002). "Probes for the dopamine transporter: new leads toward a cocaine-abuse therapeutic--A focus on analogues of benztropine and rimcazole." Med Res Rev 22(5): 429-64.
In an attempt to discover a cocaine-abuse pharmacotherapeutic, extensive investigation has been directed toward elucidating the molecular mechanisms underlying the reinforcing effects of this psychostimulant drug. The results of these studies have been consistent with the inhibition of dopamine uptake, at the dopamine transporter (DAT), which results in a rapid and excessive accumulation of extracellular dopamine in the synapse as being the mechanism primarily responsible for the locomotor stimulant actions of cocaine. Nevertheless, investigation of the serotonin (SERT) and norepinephrine (NET) transporters, as well as other receptor systems, with which cocaine either directly or indirectly interacts, has suggested that the DAT is not solely responsible for the reinforcing effects of cocaine. In an attempt to further elucidate the roles of these systems in the reinforcing effects of cocaine, selective molecular probes, in the form of drug molecules, have been designed, synthesized, and characterized. Many of these compounds bind potently and selectively to the DAT, block dopamine reuptake, and are behaviorally cocaine-like in animal models of psychostimulant abuse. However, there have been exceptions noted in several classes of dopamine uptake inhibitors that demonstrate behavioral profiles that are distinctive from cocaine. Structure-activity relationships between chemically diverse dopamine uptake inhibitors have suggested that different binding interactions, at the molecular level on the DAT, as well as divergent actions at the other monoamine transporters may be related to the differing pharmacological actions of these compounds, in vivo. These studies suggest that novel dopamine uptake inhibitors, which are structurally and pharmacologically distinct from cocaine, may be developed as potential cocaine-abuse therapeutics.
Nguimfack Mbodie, P. C. (2002). "[Do the glutamate excitotoxicity theory and potential free radicals implication in schizophrenia aetiopathogenesis provide a new enlightenment to links between: genome, environment and biology in the determinism of that disorder?]." Encephale 28(2): 147-53.
The aetiopathogenesis of schizophrenia constitutes nowadays one of the major points of interest for researchers on this cosmopolitan disorder which involves about 1% of the world population and which significantly alters the social functioning of the individual. Numerous studies have focused on the role played by genome, environmental factors and biology in the development of symptoms. The neurodevelopmental theory is an illustration with the perinatal period considered as the main provider of environmental factors (hypertension, infections, bleedings during pregnancy, acute and chronic fetal distress.). Many authors found significant associations between such factors, the occurrence of brain lesions and finally schizophrenic symptoms. Although no convincing genetic model had been established to date for schizophrenia, nevertheless it appears that a predisposition not inheritable under the mendelian mode exists and authors showed that disease gets more and more severe over schizophrenic descendants. The risk to be schizophrenic being a first degree relative of the schizophrenic person is about ten time superior than in general population. Indeed, this risk is also about ten time superior in biological parents of schizophrenic adoptees than in biological parents of healthy adoptees. Studies done in monozygotic comparing to dizygotic twins are in favour of an important role played by genetic factors more than socioeducational or psychological factors. Concerning biology, the dopaminergic hypothesis remains shared by numerous authors although direct links with incriminated factors are not well established. Now is suspected the glutamate excitotoxicity with implication of free radicals in schizophrenia. These free radicals are products of various enzymatic activations led by overstimulation of post synaptic receptors (NMDA and AMPA) by the excess glutamate. Therefore, according to that concept, some amino acids as glutamate and derivatives could have through free radicals a noxious effect on neuronal synapses. This could be due to a failing of their recapture at the presynaptic level in addition to a dysfunctioning of the antioxidizing system (glutathion, carnosine, superoxide dismutase, aspartate) to which dopamine and other monoamines might participate. The question is whether or not this theory contributes to shed light on links between: genome, environmental factors and biology in schizophrenia. Through the review and discussion of genetical aspects of schizophrenia, environmental factors and the biological aspect, we intend to revive debate on that question. The articles and authors were selected with regard to the aptness of their publications on that subject, their evolving ideas and finally the interest of their works for neurosciences. This new approach perhaps is opening the way to new therapeutic perspectives in the treatment of schizophrenia based on the antioxidizing substances as shown for some neurological diseases (amyotrophic lateral sclerosis, Parkinson's disease and Huntington's chorea) for which experiments are going on.
Nieoullon, A. (2002). "Dopamine and the regulation of cognition and attention." Prog Neurobiol 67(1): 53-83.
Dopamine (DA) acts as a key neurotransmitter in the brain. Numerous studies have shown its regulatory role for motor and limbic functions. However, in the early stages of Parkinson's disease (PD), alterations of executive functions also suggest a role for DA in regulating cognitive functions. Some other diseases, which can also involve DA dysfunction, such as schizophrenia or attention deficit hyperactivity disorder (ADHD) in children, as shown from the ameliorative action of dopaminergic antagonists and agonists, respectively, also show alteration of cognitive functions. Experimental studies showed that selective lesions of the dopaminergic neurons in rats or primates can actually provide cognitive deficits, especially when the mesocorticolimbic component of the dopaminergic systems is altered. Data from the experiments also showed significant alteration in attentional processes, thus raising the question of direct involvement of DA in regulating attention. Since the dopaminergic influence is mainly exerted over the frontal lobe and basal ganglia, it has been suggested that cognitive deficits express alteration in these subcortical brain structures closely linked to cortical areas, more than simple deficit in dopaminergic transmission. This point is still a matter of debate but, undoubtedly, DA acts as a powerful regulator of different aspects of cognitive brain functions. In this respect, normalizing DA transmission will contribute to improve the cognitive deficits not only related to neurologic or psychiatric diseases, but also in normal aging. Ontogenic and phylogenetic analysis of dopaminergic systems can provide evidences for a role of DA in the development of cognitive general capacities. DA can have a trophic action during maturation, which may influence the later cortical specification, particularly of pre-frontal cortical areas. Moreover, the characteristic extension of the dopaminergic cortical innervation in the rostro-caudal direction during the last stages of evolution in mammals can also be related to the appearance of progressively more developed cognitive capacities. Such an extension of cortical DA innervation could be related to increased processing of cortical information through basal ganglia, either during the course of evolution or development. DA has thus to be considered as a key neuroregulator which contributes to behavioral adaptation and to anticipatory processes necessary for preparing voluntary action consequent upon intention. All together, it can be suggested that a correlation exists between DA innervation and expression of cognitive capacities. Altering the dopaminergic transmission could, therefore, contribute to cognitive impairment.
Nishikawa, T. (2002). "[Genetic study on schizophrenia and its recurrence utilizing pharmacological models]." Seishin Shinkeigaku Zasshi 104(6): 487-92.
Nyberg, L., J. Persson, et al. (2002). "Individual differences in memory enhancement by encoding enactment: relationships to adult age and biological factors." Neurosci Biobehav Rev 26(7): 835-9.
Numerous studies have demonstrated an age-related decline in episodic memory performance. However, both younger and older adults benefit from various kinds of encoding support, suggesting that memory functioning remains plastic in older age. The present review is concerned with encoding support in the form of enactment. Memory for simple commands is substantially higher if the commands are enacted during encoding than only read/heard. Such memory enhancement has been demonstrated for many age groups and patient groups, suggesting that it is a general effect. Analysis of the results from 1000 participants ranging in age between 35 and 80 years revealed that about 5% of the participants had low memory performance after enacted encoding and showed no enactment effect. The majority of these were older. Comparisons of participants that did or did not show an enactment effect for a select set of biological and neuropsychological factors provided tentative evidence that a failure to benefit from encoding enactment reflects a dysfunctional motor system. This is in agreement with findings from recent functional neuroimaging studies that associate the enactment effect with motor areas in the brain. Variation in the ability to benefit from encoding enactment is discussed in relation to an age-related decline in dopamine function.
O'Connell, F. (2002). "Central pathways for cough in man--unanswered questions." Pulm Pharmacol Ther 15(3): 295-301.
Central processing of afferent cough impulses occurs in a putative 'cough centre' in the dorsal medulla where the reflex is subject to considerable cortical control. Little is known about the central neurotransmitters and mediators which mediate cough in humans. Previous animal and human studies suggest that the antitussive effect of opiates may be mediated at central 5-HT receptors.In three studies in healthy human volunteers, we have investigated the potential role of central cholinergic and dopaminergic receptors in the mediation of cough, and the potential role of 5-HT receptors in the antitussive action of opiates. Intravenous administration of atropine or physostigmine had no effect on capsaicin-induced cough. Similarly, oral administration of L-dopa, bromocriptine or haloperidol had no effect on capsaicin-induced cough. Compared with saline, intravenous morphine significantly suppressed capsaicin-induced cough and increased drowsiness. Compared with placebo, pretreatment with oral pizotifen significantly attenuated the antitussive effect of morphine, but not the sedative effect. This suggests that in humans, an agonist action at 5-HT2 and/or 5-HT1 receptors may be involved in the antitussive effect of morphine, but not its sedative effect.Further knowledge of central cough pathways in humans must await the availability of more selective receptor agonists and antagonists for human studies. This offers the promise of effective antitussive therapy. The challenge is to find an antitussive agent which can return the abnormal sensitivity of the cough reflex to normal, without adverse effects.
Oades, R. D. (2002). "Dopamine may be 'hyper' with respect to noradrenaline metabolism, but 'hypo' with respect to serotonin metabolism in children with attention-deficit hyperactivity disorder." Behav Brain Res 130(1-2): 97-102.
Noradrenaline: Hechtman (J Psychiat Neurosci 1994;19:193) argued for a role for frontal dopamine (DA) and noradrenaline (NA) in ADHD, where Oades (Prog Neurobiol 1987;29:365) has described lateralised functional impairments. Mechanisms (e.g. via alpha-2 sites) for stimulating low NA activity in ADHD children (J Am Acad Child Adolesc Psychiatry 1997;36:1688) in order to promote interactions with mesocortical DA have been discussed (J Psychopharmacology 1997;11:151; Psychiatr Res 1994;52:305). We described with indicators of overall transmitter metabolism (monoamines, metabolites in 24 h urine samples (Behav Brain Res 1997;88:95)) significantly lower utilisation ratios (MHPG/NA) in ADHD children with respect to healthy controls. Interestingly, a comparison of between catecholamine levels (DA/NA) showed a correlation with the conditioned blocking measure of selective attention recorded at the time of collection. This measure was negatively associated with blocking in controls. These results are consistent with reports of lower DOPEG and increased DOPAC in ADHD urine (J Child Adolesc Psychopharmacol 1996;6:63) and indicate that the relatively hyperactive DA versus NA systems may have functional consequences. Serotonin: the relevance for ADHD of an association of impulsivity with low serotonin (5-HT) metabolism (Behav Brain Sci 1986;9:319) has long been played down. Yet, some symptoms have been related to CSF measures of the metabolite 5-HIAA, and in particular the HVA/5-HIAA ratio has been reported to correlate with ratings of activity (Psychiatr Res 1994;52:305). We find that while urinary measures of 5-HIAA are somewhat higher, the ratio HVA/5-HIAA is markedly lower in ADHD children versus controls. In these ADHD children 5-HIAA levels were negatively related to d-prime measures in a continuous performance task (CPTax), and the HVA/5-HIAA was negatively associated with conditioned blocking. These results suggest a relatively low DA versus 5-HT activity may have functional consequences, albeit in a subgroup of ADHD. This is consistent with drug-induced prolactin changes reported by Verbaten et al. (Eur Child Adolesc Psychiatry 1999;8:30).
Obata, T. (2002). "Dopamine efflux by MPTP and hydroxyl radical generation." J Neural Transm 109(9): 1159-80.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP(+)) by B-form monoamine oxidase (MAO) in the brain, which is one of the most potent dopamine (DA)-releasing agents. MPP(+) perfusion into the striatum increases extracellular DA levels and this increase may concomitantly induce the formation of reactive free oxygen radicals, such as hydroxyl radical (.OH). These elevations seem to induce lipid peroxidation of striatum membranes, as detected by increases non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) levels. Sustained increase in striatal DA efflux by MAO inhibition produce.OH generation by products of monoamine. Therefore, reserpine-induced DA depletion clearly decreased MPP(+)-induced.OH formation. Neuromelanine synthesis from DA produce highly reactive free radicals. Nitric oxide (NO) contributes to produce MPP(+)-induced.OH generation via NO synthase (NOS) activation by depolarization. The antioxidation effect of angiotensin converting enzyme (ACE) inhibitor protects against MPP(+)-induced.OH generation due to the suppression of the Ca(2+)-dependent release of DA. These findings may be useful in elucidating the actual mechanism of free radical formation in the pathogenesis of neurodegenerative brain disorders, including Parkinson's disease and traumatic brain injuries. This review describes the free radicals mechanisms involved in MPTP toxicity and their possible involvement in the the pathogenesis of Parkinson's disease.
Obata, T. (2002). "Environmental estrogen-like chemicals and hydroxyl radicals induced by MPTP in the striatum: a review." Neurochem Res 27(5): 423-31.
Oxygen free radical formation has been implicated in lesions caused by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron. Although MPTP produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP+) by type B monoamine oxidase (MAO) in the brain, the etiology of this disease remains obscure. This review focuses on the role of an environmental neurotoxin chemically related to MPP+-induced free radical generation in the pathogenesis of Parkinson's disease. Environmental-like chemicals, such as para-nonylphenol or bisphenol A, significantly stimulated hydroxyl radical (*OH) formation in the striatum. Allopurinol, a xanthine oxidase inhibitor, prevents para-nonylphenol and MPP+-induced *OH generation. Tamoxifen, a synthetic nonsteroidal antiestrogen, suppressed the *OH generation via dopamine efflux induced by MPP+. These results confirm that free radical production might make a major contribution at certain stages in the progression of the injury. Such findings may be useful in elucidating the actual mechanism of free radical formation in the pathogenesis of neurodegenerative brain disorders, including Parkinson's disease and traumatic brain injuries.
Obata, T. (2002). "Role of hydroxyl radical formation in neurotoxicity as revealed by in vivo free radical trapping." Toxicol Lett 132(2): 83-93.
Reactive oxygen species have been implicated in dopaminergic toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron. Although MPTP produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP(+)) by type B monoamine oxidase (MAO-B) in the brain, the etiology of this disease remains obscure. MPP(+) is a highly potent dopaminbergic-releasing agents and dopamine (DA) autoxidation catalyzed by iron and oxidative stress may be involved in the pathogenesis of Parkinson's disease. Neuromelanine synthesis from DA produce highly reactive free radicals. Although the controversy possible neurotoxin and/or neuroprotective roles of nitric oxide (NO) was discussed, NO contributes to oxidative injury to brain neurons in vivo. An environmental estrogen-like chemical also related to MPP(+)-induced *OH generation. This review describes actual mechanism of the free radicals formation by dialysis studies of in vivo free radical trapping in the pathogenesis of neurodegenerative disorders, including in the Parkinson's disease, Alzheimer disease and traumatic brain injuries.
Obata, T. (2002). "Nitric oxide and depolarization induce hydroxyl radical generation." Jpn J Pharmacol 88(1): 1-5.
Nitric oxide (NO) contributes to the extracellular potassium-ion concentration ([K+]o)-induced hydroxyl radical (*OH) generation. Cytotoxic free radicals such as peroxinitrite (ONOO-) and *OH may also be implicated in NO-mediated cell injury. NO is synthesized from L-arginine by NO synthase (NOS). NOS activation was induced by K+ depolarization. Oxidative modification of low-density lipoprotein (LDL) is thought to contribute to the production of oxygen derived-free radicals. However, LDL oxidation may be related to noradrenaline-induced *OH generation, but LDL oxidation may be unrelated to *OH generation via NOS activation. Abnormal levels of extracellular free dopamine (DA) and/or intraneuronal Ca2+ triggered by 1-methyl-4-phenylpyridinium ion (MPP+) may be detrimental to the functioning of dopaminergic nerve terminals in the striatum. Although [K+]o-induced depolarization enhances the formation of *OH product due to MPP+, the *OH generation via NOS activation may be unrelated to the DA-induced *OH generation. Depolarization enhances the formation of *OH products via NOS activation.
Obe, G. F. (2002). "Helping patients to stop smoking." Practitioner 246(1631): 74, 79-80.
Otani, K. (2002). "[Pharmacogenetic studies on psychotropic agents]." Seishin Shinkeigaku Zasshi 104(1): 71-5.
Overstall, P. W. and C. E. Clarke (2002). "Uncertainties in the pharmacotherapy of Parkinson's disease and how to solve them." Gerontology 48(1): 30-3.
The causative relationship between levodopa and the long-term motor complications of therapy, along with the possibility that levodopa may be toxic to dopaminergic neurones in vivo, has led to a move away from its use in early Parkinson's disease. Alternatives such as amantadine and the anticholinergics suffer from poor efficacy in comparison and a high side effect profile. Selegiline is probably less effective than levodopa and the issue of its safety versus neuroprotective properties remains unresolved. Long-term trials with the old and newer dopamine agonists as monotherapy have shown that as a class they can delay the development of dyskinesia and probably response fluctuations. However, major uncertainties remain about their use as monotherapy in all patients instead of levodopa. No data on their effect on quality of life and health care costs are available. Most of the trials were heavily biased towards younger patients with Parkinson's disease, so little data in the elderly are available. In later disease when patients have already developed motor complications on levodopa, the choice rests between adjuvant therapy with a dopamine agonist, a catechol-O-methyltransferase inhibitor (COMT; e.g. entacapone), and a monoamine oxidase B inhibitor (MAO B; e.g. selegiline). Trials with the former two classes have confirmed that they can reduce 'off' time, reduce levodopa dose, and improve motor impairments and disabilities with acceptable increases in adverse events including dyskinesia. Trials with selegiline as adjuvant therapy were less rigorous but it can allow a reduction in levodopa dose and motor impairments. No studies have compared these three classes of drug as adjuvant therapy so there is no evidence on which to base rational decisions in this type of patient. A large pragmatic trial which includes older patients is needed to clarify which treatment is best for different stages of the disease.
Owyang, C. and W. L. Hasler (2002). "Physiology and pathophysiology of the interstitial cells of Cajal: from bench to bedside. VI. Pathogenesis and therapeutic approaches to human gastric dysrhythmias." Am J Physiol Gastrointest Liver Physiol 283(1): G8-15.
This review describes recent advances in our knowledge about the pathogenesis and therapeutic approaches to human gastric dysrhythmias. A number of clinical conditions has been found to be associated with gastric slow-wave rhythm disturbances that may relate to the induction of nausea and vomiting. Human and animal studies indicate that multiple neurohumoral factors are involved in the generation of gastric dysrhythmias. Antral distension and increased intestinal delivery of lipids may cause slow-wave disruption and development of nausea. This may be mediated by cholinergic and serotonergic pathways. Similarly, progesterone and estrogen may also disrupt gastric slow-wave rhythm in susceptible individuals. Prostaglandin overproduction in gastric smooth muscle appears to mediate slow-wave disruption in diabetes and with tobacco smoking. On the other hand, central cholinergic pathways play an important role in the genesis of gastric dysrhythmias associated with motion sickness. This may be mediated by vasopressin released from the pituitary. Although it is difficult to ascribe with certainty a causative role of slow-wave rhythm disturbances in the genesis of nausea and vomiting, the search has begun for novel antiemetic therapies based on their abilities to ablate or prevent gastric dysrhythmia formation. This includes the use of prostaglandin synthesis inhibitors, central muscarinic receptor antagonists, and dopamine receptor antagonists. Finally direct gastric electrical stimulation using a surgically implanted neurostimulator has shown promise in reducing emesis in patients with gastroparesis and gastric dysrhythmias.
Ozdemir, V., J. Fourie, et al. (2002). "Aripiprazole (Otsuka Pharmaceutical Co)." Curr Opin Investig Drugs 3(1): 113-20.
Otsuka Pharmaceuticals in collaboration with Bristol-Myers Squibb is developing aripiprazole, a dual dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist, for the potential treatment of psychoses including schizophrenia [281327], [340364]. A regulatory filing for schizophrenia in the US was submitted at the end of 2001 [340364]. The compound entered phase III trials in Japan in 1995 [192966]. Although presynaptic dopamine autoreceptor agonists may be efficacious in the treatment of schizophrenia, they may also potentially increase the risk for exacerbation of psychosis through stimulation of postsynaptic dopaminergic receptors [245791], [350478], [350479]. However, earlier neuropharmacology studies have shown that aripiprazole can act as a presynaptic D2 agonist while displaying an antagonistic effect at the postsynaptic D2 receptors [281327], [337126], [350479], [424587], [424588]. In animal models, aripiprazole inhibits the apomorphine-induced stereotypy, without causing catalepsy [281327], [337126]. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in expression of the c-fos mRNA in the striatum, in agreement with the low risk for extrapyramidal side effects (EPS) during aripiprazole treatment [245781], [262096], [350481], [350483]. Collectively, aripiprazole is an important atypical antipsychotic candidate with a favorable safety profile. Moreover, the mechanism of action of aripiprazole differentiates it from both typical and atypical antipsychotics and hence, may provide important leads for pharmacotherapy of schizophrenia and other psychotic disorders. In January 2000, Lehman Brothers predicted peak sales of aripiprazole could reach US $500 million [357788]. In February 2001, Credit Suisse First Boston predicted sales of US $403 million in 2005 [399484].
Padmanabhan, R. (2002). "Renal dose dopamine--it's myth and the truth." J Assoc Physicians India 50: 571-5.
Renal dose dopamine is prescribed worldwide for the prevention and treatment of acute renal failure. It's use is based on selective renal vasodilatation (induced at low doses) observed in animal studies and normal subjects. But most clinical studies have failed to demonstrate convincingly the benefit of low dose dopamine in acute renal failure. Moreover adverse effects of dopamine have been recognised warranting its use only in specific situations where benefit is proved. The available data on renal dose dopamine are either poor or statistically underpowered to draw conclusion. Therefore, a prospective, controlled trial with adequate patient number is required, to confirm the benefits.
Paes-De-Carvalho, R. (2002). "Adenosine as a signaling molecule in the retina: biochemical and developmental aspects." An Acad Bras Cienc 74(3): 437-51.
The nucleoside adenosine plays an important role as a neurotransmitter or neuromodulator in the central nervous system, including the retina. In the present paper we review compelling evidence showing that adenosine is a signaling molecule in the developing retina. In the chick retina, adenosine transporters are present since early stages of development before the appearance of adenosine A1 receptors modulating dopamine-dependent adenylate cyclase activity or A2 receptors that directly activate the enzyme. Experiments using retinal cell cultures revealed that adenosine is taken up by specific cell populations that when stimulated by depolarization or neurotransmitters such as dopamine or glutamate, release the nucleoside through calcium-dependent transporter-mediated mechanisms. The presence of adenosine in the extracellular medium and the long-term activation of adenosine receptors is able to regulate the survival of retinal neurons and blocks glutamate excitoxicity. Thus, adenosine besides working as a neurotransmitter or neuromodulator in the mature retina, is considered as an important signaling molecule during retinal development having important functions such as regulation of neuronal survival and differentiation.
Pandey, C. K., N. Singh, et al. (2002). "Hepatorenal syndrome: pathophysiology and treatment." J Assoc Physicians India 50: 819-25.
The hepatorenal syndrome (HRS) is a unique form of acute renal failure with entirely normal renal histology in advanced liver disease. Its diagnosis is made by exclusion of all causes of renal failure and by all the five major criteria as set by the International Ascites Club. The presence of hepatomegaly, poor nutritional status, and oesophageal varices at endoscopy are associated with a high risk of HRS. The liver tests, the Child-Pugh score, are of no value in prediction of its occurrence. Contraction of the effective blood volume, which may lead to renal hypoperfusion with preferential renal cortical ischaemia, is proposed pathogenesis of the condition. Because understanding of the pathogenesis of HRS is incomplete, therapy is supportive only. Optimal fluid management is vital as there is almost invariably a reduction in effective arterial blood volume. Dopamine, frusemide and haemofiltration may be helpful in management of fluid overload but do not affect renal function. TIPS has been used successfully in small series of patients. The vasopressin analog also has been used with early excellent response. The treatment of HRS has been discouraging and the only proven cure for HRS is liver transplantation at this point of time.
Pani, L. and G. L. Gessa (2002). "The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia." Mol Psychiatry 7(3): 247-53.
In this paper the historical and scientific background that led to the use of substituted benzamides in two apparently unrelated clinical conditions namely dysthymic disorder and schizophrenia will be reviewed, in order to understand if a common mechanism of action may support this dual therapeutic indication. The dopaminergic antidepressant action of substituted benzamides such as sulpiride, has been proposed, since the late 1970s, by several authors and extensively explored in preclinical experiments by our group. In Italy the first marketing authorization obtained for the new substituted benzamide amisulpride, was with the sole indication of dysthymia and therefore a solid clinical experience exists in the use of substituted benzamides in mild forms of depression, with more than 1 000 000 patients being treated in the last 7 years. The proposed mechanism of action of substituted benzamides implies a selective modulation of the dopaminergic system in the mesocorticolimbic area, important for cognitive processing of internal and external cues, related to survival. The selective antagonism of dopamine D2-D3 receptors has been evoked to explain, in small to moderate doses (ie 50-100 mg day(-1)), the antidepressant effect and, in moderate to medium doses (100-400 mg day(-1)), the reported efficacy on negative symptoms of schizophrenia. Thus, substituted benzamides could represent the first class of atypical antipsychotics successfully employed for both depressive states and schizophrenia. Interestingly, recent evidence in the literature suggests that depressive episodes belonging to the bipolar spectrum are among "alternative indications" of other atypical antipsychotics such as olanzapine and risperidone.
Pare, D. (2002). "Mechanisms of Pavlovian fear conditioning: has the engram been located?" Trends Neurosci 25(9): 436-7; discussion 437-8.
Uncertainty persists as to whether the amygdala is a crucial site of plasticity for classically conditioned fear or merely a sensory relay to structures generating fear responses. A recent Nature study suggests that associative synaptic changes take place in neurons of the amygdala during fear conditioning, and that these changes require dopamine-mediated modulation. Nevertheless, these findings do not prove that the amygdala is a sufficient site of plasticity for fear memory.
Parmer, R. J. and O. Zinder (2002). "Catecholaminergic pathways, chromaffin cells, and human disease." Ann N Y Acad Sci 971: 497-505.
Recent studies demonstrate major effects of adrenal medullary and catecholaminergic pathways on a wide variety of normal physiologic and regulatory events. Alterations in these pathways, involving changes in catecholamines or in proteins and peptides costored and coreleased with catecholamines, may lead to profound changes in autonomic, cardiovascular, neuroendocrine, metabolic, nociceptive, and immune function. These findings have important implications for a variety of human disease states. In addition, molecules associated with catecholaminergic function may provide novel diagnostic and therapeutic strategies for human disease and suggest specific genetic loci as important and fruitful targets for further genetic and pharmacogenetic studies.
Parrott, A. C. (2002). "Recreational Ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity." Pharmacol Biochem Behav 71(4): 837-44.
The ring-substituted amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) or "Ecstasy" is widely used a recreational drug. It stimulates the release and inhibits the reuptake of serotonin (5-HT) and other neurotransmitters such as dopamine to a lesser extent. The acute boost in monoamine activity can generate feelings of elation, emotional closeness, and sensory pleasure. In the hot and crowded conditions of raves/dances, mild versions of the serotonin syndrome often develop, when hyperthermia, mental confusion, and hyperkinesia predominate. Rest in a cooler environment generally reverses these problems, although they can develop into medical emergencies, which occasionally prove fatal. This acute serotonergic overactivity is exacerbated by the high ambient temperatures, overcrowding (aggregate toxicity), and use of other stimulant drugs. The on-drug experience is generally followed by negative moods, with 80--90% of weekend Ecstasy users reporting 'midweek blues', due probably to monoaminergic depletion. Single doses of MDMA can cause serotonergic nerve damage in laboratory animals, with repeated doses causing extensive loss of distal axon terminals. Huether's explanatory model for this 5-HT neurotoxicity will be briefly described. There is an increasing body of evidence for equivalent neuropsychobiological damage in humans. Abstinent regular Ecstasy users often show: reduced cerebrospinal 5-HIAA, reduced density of 5-HT transporters, blunted response to a fenfluramine challenge, memory problems, higher cognitive deficits, various psychiatric disorders, altered appetite, and loss of sexual interest. Functional deficits may remain long after drug use has ceased and are consistent with serotonergic axonal loss in higher brain regions.
Pelissolo, A. and E. Corruble (2002). "[Personality factors in depressive disorders: contribution of the psychobiologic model developed by Cloninger]." Encephale 28(4): 363-73.
The psychobiological model of personality developed by Cloninger, including four dimensions of temperament and three dimensions of character, allows to explore personality factors associated with depressive disorders. The three main dimensions of temperament are Novelty Seeking (NS), ie the tendency towards excitement in response to novel or rewarding stimuli, Harm Avoidance (HA) hypothesized to represent the tendency to respond intensely to signals of adverse stimuli, and Reward Dependence reflecting the tendency to respond intensely to signals of reward and to maintain behavior previously associated with reward. These personality traits are hypothetically related to underlying neurotransmetter systems (especially NS to dopaminergic function and HA to serotonergic function). The two main dimensions of character are Self-Directedness (SD) and Cooperativeness (C), measuring maturity traits respectively concerning individual and social adaptation; thus they are negatively correlated with the risk of personality disorder for a given patient. Many studies have been carried out with the Temperament and Character Inventory (TCI), or with the previous Tridimensional Personality Questionnaire (TPQ), in depressive disorders with cross-sectional but also with short-term and long-term longitudinal designs. They show primarily that patients with history of depressive disorders, even in euthymic phase, have very high Harm Avoidance scores. In prospective studies conducted in depressive patients, even after remission of the depressive episodes, the Harm Avoidance scores are lower than before treatment, but still elevated compared to the general population. The patients who fail to respond to antidepressant treatments have generally higher Harm Avoidance scores before treatment than the others. Overall, various results support four types of potent relationships between Harm Avoidance and depression: an influence of state on trait measure, a pathoplastic effect of Harm Avoidance on depressive expression, a vulnerability model (Harm Avoidance representing a susceptibility factor for depression), and a scar model with elevated Harm Avoidance scores even after remission of acute depressive symptoms. Other temperament dimensions, Novelty Seeking and Reward Dependence, are not consistently associated with depression characteristics nor affected by state effects, but Self-Directedness character dimension is often low when compared to subjects without depressive disorders, reflecting maladaptive personalities frequently associated to depressive disorders. Some studies suggest that low Self-Directedness scores can be predictive of suicidal behaviors. In cross-sectional studies, Harm Avoidance scores are highly positively correlated with depression intensity (r=0.23 to 0.67) and Self-Directedness scores are highly negatively correlated with depression (r=- 0.37 to - 0.60). Some studies suggest that the temperamental dimensions assessed by the TCI could have a predictive value for the response to antidepressants treatments, but this result is controversial and needs further research. For example, a study conducted in 84 patients with major depressive disorder showed that temperament type based on TPQ traits explained 25% of the response to treatment variance: patients with high scores on both Harm Avoidance and Reward Dependence had a favourable response to either clomipramine or desipramine. Studies of the relationship of temperament dimensions to biological markers of depression have also been published. It has been shown for example that Reward Dependence and Harm Avoidance scores are significantly predictive of morning hypercortisolemia in depressed subjects. More specifically, correlations have been obtained between platelet serotonergic markers (5-HT2a receptors) and Harm Avoidance scores also in depressed patients. In conclusion, Harm Avoidance seems to be a vulnerability factor or at least an associated factor to depressive disorders. This temperament dimension is supposed to be highly heritable, and to be linked to the serotonergic system variations.
Pfeiffer, R. F. (2002). "Potential of transdermal drug delivery in Parkinson's disease." Drugs Aging 19(8): 561-70.
There has been a growing recognition that pulsatile stimulation of dopamine receptors may be an important mechanism in the generation of the motor fluctuations that often develop and compromise the effectiveness of long-term levodopa administration in persons with Parkinson's disease (PD). This has prompted investigation of treatment approaches that might provide more constant, and therefore physiological, dopamine receptor stimulation. Frequent levodopa administration, controlled-release levodopa preparations, inhibitors of levodopa metabolism, and duodenal, subcutaneous and even intravenous infusions of levodopa or dopamine agonists have all been employed with this goal in mind, but all have limitations. Transdermal drug delivery is a treatment approach that is not only capable of providing a constant rate of drug delivery, but is also non-invasive and relatively simple to use. However, developing a drug to be delivered transdermally for the treatment of PD has been anything but easy. Levodopa and many dopamine agonists are not sufficiently soluble to be administered via the transdermal route, and blind alleys have been encountered thus far in the investigation of suitably soluble drugs. Nevertheless, investigation continues and yet another candidate drug, rotigotine (N-0923), is currently under active investigation. Techniques designed to enhance skin permeation and thus improve the effectiveness of transdermal drug delivery are also potential sources for future treatment advances.
Picciotto, M. R., D. H. Brunzell, et al. (2002). "Effect of nicotine and nicotinic receptors on anxiety and depression." Neuroreport 13(9): 1097-106.
Nicotine has been shown to have effects on anxiety and depression in both human and animal studies. These studies suggest that nicotinic acetylcholine receptors (nAChRs) can modulate the function of pathways involved in stress response, anxiety and depression in the normal brain, and that smoking can result in alterations of anxiety level and mood. The effects of nicotine are complex however, and nicotine treatment can be either anxiolytic or anxiogenic depending on the anxiety model tested, the route of nicotine administration and the time course of administration. The paradoxical effects of nicotine on emotionality are likely due to the broad expression of nAChRs throughout the brain, the large number of nAChR subtypes that have been identified and the ability of nicotine treatment to both activate and desensitize nAChRs. Activation of nAChRs has been shown to modulate many systems associated with stress response including stress hormone pathways, monoaminergic transmission and release of classical neurotransmitters throughout the brain. Local administration studies in animals have identified brain areas that may be involved in the anxiogenic and anxiolytic actions of nicotine including the lateral septum, the dorsal raphe nuclei, the mesolimbic dopamine system and the hippocampus. The ensemble of studies to date suggest that under certain conditions nicotine can act as an anxiolytic and an antidepressant, but that following chronic use, adaptations to nicotine can occur resulting in increased anxiety and depression following withdrawal.
Pickel, V. M., M. Garzon, et al. (2002). "Electron microscopic immunolabeling of transporters and receptors identifies transmitter-specific functional sites envisioned in Cajal's neuron." Prog Brain Res 136: 145-55.
Neuronal arborizations that were so elegantly demonstrated in the early drawings of Santiago Ramon y Cajal can now be viewed by high resolution electron microscopic immunocytochemical localization of vesicular and plasmalemmal neurotransmitter transporters and receptors. The subcellular distribution of these proteins confers both chemical selectivity and functional specificity to the dendritic and axonal arborizations described by Cajal. This is illustrated by central dopaminergic and cholinergic neurons. Dopamine terminals in the striatum and ventral pallidum, as well as dendrites of midbrain dopaminergic neurons in the ventral tegmental area and substantia nigra express the plasmalemmal dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2). In forebrain regions, the dopamine D2 receptor (D2R) autoreceptor is localized to dopamine terminals, but also is targeted to pre- and postsynaptic neuronal profiles at a distance from the dopamine terminals. In somata and dendrites of the midbrain dopaminergic neurons, D2R labeling is expressed in most dendrites that contain VMAT2 storage vesicles, as well as in both excitatory and inhibitory afferents. Together, these observations indicate that dopamine is stored in and released from vesicles in both dendrities and axons, and may activate either local or more distant receptors through volume transmission. By analogy, the vesicular acetylcholine transporter (VachT) is similarly localized to the membranes of axon terminals and tubulovesicles in dendrities in the mesopontine tegmental cholinergic nuclei, suggesting that there also may be release of acetylcholine from both dendrities and axons. These results identify chemically selective functional sites for neuronal signaling envisioned by Cajal and redefined by modern technology.
Pierce, J. D., D. A. Morris, et al. (2002). "Understanding renal dose dopamine." J Infus Nurs 25(6): 365-71.
Low-dose dopamine is a widely administered drug used often in critical care settings to prevent or treat patients with low urinary output. There are new data to support that low-dose dopamine may have side effects and not always increase renal perfusion to the kidneys. This article is a review of the current use of low-dose dopamine, the role of dopamine in the kidneys, and the potential risks of infusing this drug to patients.
Pierce, S. R. and L. J. Buxbaum (2002). "Treatments of unilateral neglect: a review." Arch Phys Med Rehabil 83(2): 256-68.
OBJECTIVES: To review the existing literature on treatments of unilateral neglect, to synthesize findings, and to offer recommendations for future studies. DATA SOURCES: Computerized databases including MEDLINE and PsychINFO. STUDY SELECTION: All studies investigating treatment(s) of unilateral neglect. DATA EXTRACTION: Authors reviewed design and other methodologic issues. DATA SYNTHESIS: Unilateral neglect is a common consequence of right-hemisphere stroke. It is well recognized that the disorder is heterogeneous and has numerous subtypes. There have been numerous studies showing that arousal, hemispheric activation, and spatial attention treatments may all improve neglect, at least transiently. Despite these promising outcomes, little consensus exists as to whether 1 treatment is more efficacious than others, in part because cross-study differences in methodology render meta-analyses difficult, and in part because many studies fail to document duration of treatment effects or generalization to daily activities. One possibility is that these varied and diverse treatments may all be effective, reflecting redundancy in neural circuits devoted to attention and action in space, and consequent flexibility of the spatial processing system. It remains possible, however, that different subtypes of neglect may respond differentially to treatment of various sorts. Most existing studies of neglect have relied on very small populations of neglect patients, whose neglect is characterized only generally. CONCLUSION: Methodologic shortcomings hinder assessment of the efficacy of various types of neglect treatment. In the future, these shortcomings could be addressed with larger studies of well-characterized patients that evaluate duration of treatment effects and include functional measures. In addition, the role of overarching variables, such as reduced arousal, requires consideration. The ultimate goal of these studies might be the development of triaging strategies wherein neglect patients are assigned to treatments of most likely benefit on the basis of neuroanatomic and behavioral profiles.
Porter, M. C., L. S. Appiah-Kubf, et al. (2002). "Treatment of Parkinson's disease and restless legs syndrome with cabergoline, a long-acting dopamine agonist." Int J Clin Pract 56(6): 468-74.
Dopamine agonists have diverse chemical and physical properties that can directly stimulate the dopamine receptors, unlike levodopa which undergoes presynaptic breakdown to dopamine before dopaminergic effects in Parkinson's disease (PD). Cabergoline, a dopamine agonist effective given once daily, is being used as treatment for PD. In theory, therapy with cabergoline provides striatal intrasynaptic dopamine replacement of PD in a physiological manner because of its long half-life and the resultant sustained rather than pulsatile dopaminergic stimulation. Several placebo-controlled trials using cabergoline as adjunctive therapy in PD have shown that cabergoline significantly reduces 'off' time, improves motor function and reduces levodopa requirement. Cabergoline has also been used as monotherapy in PD and has been shown to be as effective as other dopamine agonists in improving motor function and to be superior to levodopa in reducing dyskinesias over a five-year period. Work from our group and others have also demonstrated the efficacy of cabergoline in PD patients with nocturnal disabilities and those with restless legs syndrome (RLS). More recently we have reported that cabergoline is a well-tolerated dopamine agonist in both young and elderly patients and has an acceptable side-effect profile.
Pralong, E., P. Magistretti, et al. (2002). "Cellular perspectives on the glutamate-monoamine interactions in limbic lobe structures and their relevance for some psychiatric disorders." Prog Neurobiol 67(3): 173-202.
Dopaminergic, serotonergic and noradrenergic nuclei form the trimonoamine modulating system (TMMS). This system modulates emotional/motivational activities mediated by the limbic circuitry, where glutamate is the major excitatory neurotransmitter. Two main concepts are the basis of this review. First, since 1950 and the discovery of the antipsychotic activity of the dopamine D2 receptor antagonist chlorpromazine, it appears that drugs that can modulate the TMMS possess therapeutic psychiatric properties. Second, the concept of glutamate/trimonoamine imbalance in the cortico-striato-thalamo-cortical loop that has been so successful in explaining the pathophysiology of Parkinson disease has been applied in the pathophysiology of schizophrenia. This review will focus on the complex interactions between the fast synaptic glutamatergic transmission and the TMMS in specific parts of the limbic lobe and we will try to link these interactions to some psychiatric disorders, mainly depression, schizophrenia and drug addiction.
Prasad, S., P. Semwal, et al. (2002). "Molecular genetics of schizophrenia: past, present and future." J Biosci 27(1 Suppl 1): 35-52.
Schizophrenia is a severe neuropsychiatric disorder with a polygenic mode of inheritance which is also governed by non-genetic factors. Candidate genes identified on the basis of biochemical and pharmacological evidence are being tested for linkage and association studies. Neurotransmitters, especially dopamine and serotonin have been widely implicated in its etiology. Genome scan of all human chromosomes with closely spaced polymorphic markers is being used for linkage studies. The completion and availability of the first draft of Human Genome Sequence has provided a treasure-trove that can be utilized to gain insight into the so far inaccessible regions of the human genome. Significant technological advances for identification of single nucleo-tide polymorphisms (SNPs) and use of microarrays have further strengthened research methodologies for genetic analysis of complex traits. In this review, we summarize the evolution of schizophrenia genetics from the past to the present, current trends and future direction of research.
Raggenbass, M. and D. Bertrand (2002). "Nicotinic receptors in circuit excitability and epilepsy." J Neurobiol 53(4): 580-9.
Neuronal nicotinic acetylcholine receptors belong to the family of excitatory ligand-gated channels and result from the assembly of five subunits. Functional heteromeric nictonic receptors are present in the hippocampus and neocortex, thalamus, mesolimbic dopamine system and brainstem motor nuclei, where they may play a role, respectively, in memory, sensory processing, addiction and motor control. Some forms of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have been found to be associated with mutations in the genes coding for the alpha 4 or beta2 subunits of the nicotinic receptor. Mutant receptors display an increased acetylcholine sensitivity with respect to normal receptors. Since the thalamus and the cortex are strongly innervated by cholinergic neurons projecting from the brainstem and basal forebrain, an unbalance between excitation and inhibition, brought about by the presence of mutant receptors, could generate seizures by facilitating and synchronizing spontaneous oscillations in thalamo-cortical circuits.
Ramaker, C. and J. J. Hilten (2002). "Bromocriptine/levodopa combined versus levodopa alone for early Parkinson's disease." Cochrane Database Syst Rev(2): CD003634.
BACKGROUND: Drugs that mimic dopamine such as bromocriptine were introduced as monotherapy or in a combination with LD in the hope that this approach would prevent or delay the onset of motor complications in patients with Parkinson's disease (PD). However, hitherto, the role of bromocriptine (BR) in this issue has remained controversial. The present study is a systematic review of all randomised controlled trials of bromocriptine/levodopa (BR/LD) combination therapy compared with levodopa (LD) monotherapy in PD. OBJECTIVES: To assess the efficacy and safety of BR/LD combination therapy in delaying the onset of motor complications associated with LD monotherapy in patients with PD. SEARCH STRATEGY: Sources including the Cochrane Library, the search strategy of the Movement Disorders Group (includes computerised searches of MEDLINE and EMBASE and hand searching of appropriate neurology journals), reference lists of the reviews found by the MEDLINE and EMBASE search-strategy, Sandoz -now Novartis- (manufacturer of BR), PPD Pharmaco, symposia reports, PD handbooks, contacts with colleagues who had co-ordinated trials on BR and reference lists of all included studies were used to identify randomised controlled trials (RCTs) of interest. SELECTION CRITERIA: Randomised trials were eligible for inclusion if they evaluated the efficacy of BR/LD combination therapy for delaying the onset of motor complications compared to LD monotherapy in PD patients. Outcome measures that were evaluated included occurrence and severity of motor complications, scores on impairment and disability, and the occurrence of side effects and dropouts. DATA COLLECTION AND ANALYSIS: To determine the feasibility of a quantitative systematic review two independent reviewers evaluated the methodological quality of identified trials. MAIN RESULTS: The methodological quality of five trials showed important shortcomings. All studies failed to adequately describe randomisation procedures. Only two were carried out according to a double-blind design. Differences between studies concerning the mean age of the patients, the BR titration phase, the maximum achieved daily dose of LD (62.5-1000 mg) and BR (5-50 mg), and the applied outcomes were found. Our results show no evidence of consistent differences concerning the occurrence and severity of motor complications, scores of impairment and disability and the occurrence of side effects between both treatment groups. REVIEWER'S CONCLUSIONS: This systematic review found no evidence in support of early bromocriptine/levodopa combination therapy as a strategy to prevent or delay the onset of motor complications in the treatment of PD.
Reddy, V. G. (2002). "Prevention of postoperative acute renal failure." J Postgrad Med 48(1): 64-70.
Postoperative acute renal failure (PO-ARF) is a serious complication resulting in a prolonged stay and high mortality. Patients may be at risk for this problem because of an underlying medical illness, nature of surgery, nephrotoxin exposure, or combinations of these factors. An increase in the intra abdominal pressure above 20-mm Hg is associated with an increase in the incidence of PO-ARF. Based on many clinical studies in high-risk surgical patients and patients undergoing renal transplantation, the only proven management strategies for prevention of PO-ARF are adequate volume expansion and avoidance of hypovolaemia. Drugs known to be nephrotoxic should be avoided or used with caution. Three main pharmacological agents namely mannitol, frusemide and dopamine have been extensively tried in the prevention of PO-ARF. Mannitol has proven of value only in the presence of adequate volume expansion in attenuating renal dysfunction in transplant patients. Frusemide converts oliguric renal failure to non-oliguric renal failure. The bulk of the data, including that from prospective studies indicate dopamine is only a diuretic. Fenoldopam, a dopamine analogue, has shown early promise in reports. Calcium channel blockers have not been shown to improve the outcome in renal transplantation or help in the prevention of contrast-induced nephropathy. Atrial natriuretic peptide has not been proven to be of benefit in established renal failure and its role in prevention has not been assessed.
Reeves, S., C. Bench, et al. (2002). "Ageing and the nigrostriatal dopaminergic system." Int J Geriatr Psychiatry 17(4): 359-70.
BACKGROUND: Brain dopamine has been the focus of numerous studies owing to its crucial role in motor function and in neurological and psychiatric disease processes. Whilst early work relied on postmortem data, functional imaging has allowed a more sophisticated approach to the quantification of receptor density, affinity and functional capacity. This review aims to summarise changes in the nigrostriatal dopaminergic system which accompany normal ageing. METHODS: A literature search focussed on postmortem and neuroimaging studies of normal ageing within the nigrostriatal dopaminergic tract. The functional significance of age-related effects was also considered. RESULTS: There are significant reductions in pre- and post-synaptic markers of brain dopamine activity during normal ageing: However the rate of decline (linear or exponential), the effects of gender and heterogeneity and the mechanisms by which these changes occur remain undetermined. Limited data suggest there is a significant association between postsynaptic receptor density and specific aspects of motor and cognitive function. CONCLUSION: The identification of strategies to improve dopaminergic transmission may delay the onset of motor and cognitive deficits associated with normal ageing. In order to develop effective preventative strategies, the causative mechanisms underlying age-related changes and the interaction between synaptic structure and function need to be more clearly elucidated.
Reiner, A. (2002). "Functional circuitry of the avian basal ganglia: implications for basal ganglia organization in stem amniotes." Brain Res Bull 57(3-4): 513-28.
Histochemical, pathway tracing, and neuropeptide/neurotransmitter localization studies in birds, reptiles and mammals during the 1970s and 80s clearly showed that the telencephalon in all amniotes consists of a prominent ventrally situated subpallial region termed the basal ganglia, and a large overlying region involved in higher order information processing termed the pallium or cortex. These studies also showed that the basal ganglia in all extant amniote groups possessed neurochemically and hodologically distinct striatal and pallidal territories. More recently, studies of the localization of genes controlling regional brain development have confirmed the homology of the basal ganglia among amniotes. In our ongoing studies, we have identified several aspects of the functional organization of the basal ganglia that birds also share with mammals. These include: (1) an extensive glutamatergic "cortico"-striatal input and distinctive, cell-type specific localization of glutamate receptor subtypes; (2) an extensive, presumptively glutamatergic intralaminar thalamic input to striatal neurons; (3) an extensive dopaminergic input from the midbrain targeting both substance P (SP) type and enkephalin (ENK) type striatal projection neurons, with SP-type striatal neurons seemingly richer in the D-1 type dopamine receptor; and (4) SP+ and ENK+ striatal outputs giving rise to functionally distinct so-called direct and indirect motor output pathways, with the direct pathway having a pallido-thalamo-motor cortex loop and the indirect pathway relaying back to the direct circuit via the subthalamic nucleus. These findings suggest that the major aspects of the cellular organization and functional circuitry of the basal ganglia in stem amniotes were already as observed in living amniotes, as therefore presumably was its key role in movement control. Because the organization of the basal ganglia of anamniotes is clearly less elaborate than in amniotes, and because the basal ganglia and cortex in amniotes are clearly extensively interconnected structures, it seems likely that stem amniotes were characterized by a major step forward in the grade of telencephalic organization of both the basal ganglia and the pallium.
Reingardiene, D. (2002). "[Neuroleptic malignant syndrome]." Medicina (Kaunas) 38(1): 1-5.
The neuroleptic malignant syndrome (NMS) is a rare but potentially lethal form of neuroleptic drug-induced hyperthermia, altered level of consciousness, extrapyramidal effects, autonomic instability and muscle rigidity. The present review describes pathophysiology, frequency, course, outcome, mortality and management of NMS in prehospital care and emergency department care. Review discusses clinical features, diagnosis differentiation of this hyperpyretic-rigidity syndrome from other disorders and prevention of this serious iatrogenic condition as life-threatening disorder.
Rose, S. D., T. Lejen, et al. (2002). "Molecular motors involved in chromaffin cell secretion." Ann N Y Acad Sci 971: 222-31.
Neurosecretory cells, including chromaffin cells, possess a mesh of filamentous actin underneath the plasma membrane. It has been proposed that filamentous actin network separates the secretory vesicles into two compartments: the reserve pool and the release-ready vesicle pool. Disassembly of chromaffin cell cortical filamentous actin in response to stimulation allows the movement of vesicles from the reserve pool into the release-ready vesicle pool. Electron microscopy of cytoskeletons revealed the presence of polygonal areas almost devoid of actin filaments in stimulated cells. The percentage of stimulated cells showing disrupted cytoskeleton correlates well with the increase in secretion in these cells. Fine filaments also remain in these areas of disassembly, and these reacted with actin antibodies, as demonstrated by immunogold staining. In addition, the movement of vesicles between pools requires Ca(2+) and ATP, a condition for activation of a molecular motor. Confocal microscopy images demonstrated colocalization of myosin Va with dopamine-beta-hydroxylase. Cell depolarization induced the dissociation of myosin Va from chromaffin vesicles. 2,3-Butadione-2-monoxime (BDM), an inhibitor of myosin ATPase, inhibited secretion, suggesting a blockage for chromaffin vesicle transport between the reserve pool and the release-ready vesicle pool. On the other hand, myosin II subcellular distribution was not affected by cell depolarization. Confocal microscopy images show myosin II to be localized in the cell cortex and in some perinuclear structures. Chromaffin vesicles were not stained by myosin II antibody.
Rosenzweig, P., M. Canal, et al. (2002). "A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers." Hum Psychopharmacol 17(1): 1-13.
Amisulpride binds selectively to dopamine D(2) and D(3) receptors in the limbic system. Low doses of amisulpride preferentially block presynaptic D(2)/D(3)-dopamine autoreceptors, thereby enhancing dopaminergic transmission, whereas higher doses block postsynaptic receptors, thus inhibiting dopaminergic hyperactivity. Amisulpride is clinically effective on the negative symptoms of acute schizophrenia exacerbations at low dosages (50-300 mg/day), and also on the positive symptoms of the disease at high dosages (400-800 mg/day). Nineteen clinical studies involving 358 volunteers have investigated the pharmacokinetics, pharmacodynamics and tolerability of amisulpride. Amisulpride shows linear pharmacokinetics, a bioavailability of 48%, low protein binding (17%) and an elimination half-life of approximately 12 h. It is predominantly eliminated in the urine as the parent compound. It exhibits no significant detrimental effects in psychometric or memory tests up to the dose of 400 mg/day, inducing only mild impairment at high doses, whereas EEG data suggest an alertness-enhancing effect at low doses (<or= 50 mg). Moreover, amisulpride does not potentiate the depressant effects on the central nervous system of alcohol and lorazepam. This tolerability profile is clearly better than that of haloperidol 4 mg/day and is consistent with a weak blocking effect on striatal D(2) receptors. In summary, studies in humans have shown that amisulpride is free of behavioural toxicity at doses exerting clear antipsychotic efficacy and confirm that its CNS effects may vary with the dose administered.
Rossi Fanelli, F. and A. Laviano (2002). "Cancer anorexia: a model for the understanding and treatment of secondary anorexia." Int J Cardiol 85(1): 67-72.
Under normal conditions, food intake is controlled in the hypothalamus by: (i) transducing metabolic/sensorial inputs arising from the periphery into neuronal response; (ii) integrating the information originating from different tissues; and (iii) triggering the appropriate feeding responses. Thus, the anorexia associated with a number of chronic diseases, including cancer, may result from an abnormal input of information to the hypothalamus, or in its defective transduction and integration, or in the induction of exaggerated and inappropriate feeding responses. Currently available data suggest that the pathogenesis of secondary anorexia is multifactorial, and involves most of the neuronal signalling pathways modulating energy intake, including hormones (e.g. leptin), neuropeptides (e.g. NPY), cytokines (e.g. IL-1, IL-6, TNF) and neurotransmitters (e.g. serotonin and dopamine). However, it is unlikely that they represent separate and distinct pathogenic mechanisms, rather it appears that close interrelationships may exist among them. In line with this reasoning, consistent experimental and human data suggest that the hypothalamic serotonergic neurotransmission may represent a major target on which different anorexia-related factors converge. Thus, interfering pharmacologically with hypothalamic serotonin synthesis and activity may represent an effective therapeutic strategy in anorectic patients, as suggested by recent preliminary clinical data.
Russell, V. A. (2002). "Hypodopaminergic and hypernoradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder--the spontaneously hypertensive rat." Behav Brain Res 130(1-2): 191-6.
Evidence supports dysfunction of dopaminergic and noradrenergic systems in patients with attention-deficit hyperactivity disorder (ADHD). Noradrenergic and dopaminergic systems exert distinct modulatory actions on the transfer of information through neural circuits that connect functionally distinct cortical areas with separate striatal regions and remain segregated in parallel striato-pallidal-thalamic and striato-substantia nigra pars reticulata-thalamic pathways. Prefrontal cortex performance is maximal at moderate stimulation of postsynaptic dopaminergic and noradrenergic receptors, and is reduced by either higher or lower levels of receptor stimulation. Spontaneously hypertensive rats (SHR) are generally considered to be a suitable genetic model for ADHD, since they display hyperactivity, impulsivity, poor stability of performance, impaired ability to withhold responses and poorly sustained attention, when compared with their normotensive Wistar-Kyoto (WKY) control rats. Evidence suggests that terminals of mesocortical, mesolimbic and nigrostriatal dopaminergic neurons of SHR release less dopamine in response to electrical stimulation and/or depolarization as a result of exposure to high extracellular K+ concentrations, than WKY. Vesicular storage of dopamine was suggested to be impaired in SHR, causing leakage of dopamine into the cytoplasm and increased d-amphetamine-induced transporter-mediated release. While electrically stimulated release of dopamine appears to be decreased in prefrontal cortex of SHR suggesting hypodopaminergic function, autoreceptor-mediated inhibition of norepinephrine release appears to be impaired in SHR, suggesting that noradrenergic function may be poorly regulated in the prefrontal cortex of the SHR. These findings are consistent with the hypothesis that the behavioral disturbances of ADHD are the result of an imbalance between noradrenergic and dopaminergic systems in the prefrontal cortex, with inhibitory dopaminergic activity being decreased and noradrenergic activity increased relative to controls.
Rye, D. B. and J. Jankovic (2002). "Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD." Neurology 58(3): 341-6.
Saaresranta, T. and O. Polo (2002). "Hormones and breathing." Chest 122(6): 2165-82.
A number of hormones, including hypothalamic neuropeptides acting as neurotransmitters and neuromodulators in the CNS, are involved in the physiologic regulation of breathing and participate in adjustment of breathing in disease. In addition to central effects, some hormones also control breathing at peripheral chemoreceptors or have local effects on the lungs and airways. Estrogen and progesterone seem to protect from sleep-disordered breathing, whereas testosterone may predispose to it. Progesterone and thyroxine have long been known to stimulate respiration. More recently, several hormones such as corticotropin-releasing hormone and leptin have been suggested to act as respiratory stimulants. Somatostatin, dopamine, and neuropeptide Y have a depressing effect on breathing. Animal models and experimental human studies suggest that also many other hormones may be involved in respiratory control.
Sanchez-Pernaute, R., A. L. Brownell, et al. (2002). "Functional imaging of the dopamine system: in vivo evaluation of dopamine deficiency and restoration." Neurotoxicology 23(4-5): 469-78.
Dopamine deficiency causes a severe impairment in motor function in patients with Parkinson's disease (PD) and in experimental animal models. Recent developments in neuroimaging techniques provide a means to assess in vivo the state of the dopamine system. From a functional perspective, four levels need to be operative and integrated in the system: the dopamine cell (pre-synaptic), the striatal dopamine receptors (post-synaptic), adequate release of dopamine (intra-synaptic), and the cortico-subcortical motor projections. Neuroimaging functional methods can be used to estimate, at these four levels, dopamine cell degeneration, adaptive responses to injury and, importantly, the effect of therapeutic interventions. In this respect, data from functional imaging studies at clinical and pre-clinical stages, support the idea that cell replacement therapy might achieve a more physiological restoration of the dopamine motor system than other therapies (such as ablative surgery, administration of precursor, deep brain stimulation) that currently are equally or more effective in relieving motor symptoms.
Sasai, Y. (2002). "Generation of dopaminergic neurons from embryonic stem cells." J Neurol 249 Suppl 2: II41-4.
Neuronal transplantation is considered to be a promising therapeutic approach to neurodegenerative diseases. In addition to fetal tissues and neural stem cells, embryonic stem cells are good candidates for the creation of neurons. We have recently identified a stromal cell-derived inducing activity that promotes neural differentiation of mouse embryoric stem cells. This activity accumulated on the surface of PA6 stromal cells and induced efficient neuronal differentiation of co-cultured embryonic stem cells under serum-free conditions without the use of either retinoic acid or embryoid bodies. A high proportion of tyrosine hydroxylase-positive neurons producing dopamine are obtained. Induction of neurons with stromal cell-derived inducing activity may be a useful new method for basic neuroscience research and therapeutic applications, including cell transplantation therapy for Parkinson's disease.
Sasaki, H., H. Arai, et al. (2002). "[Progress in the field of pulmonary medicine in the last 100 years: Medical history of aspiration pneumonitis]." Nippon Naika Gakkai Zasshi 91(6): 1790-3.
Sato, M. (2002). "[Basic and clinical studies on methampetamine-related psychosis]." Seishin Shinkeigaku Zasshi 104(3): 179-90.
Sawa, A. and S. H. Snyder (2002). "Schizophrenia: diverse approaches to a complex disease." Science 296(5568): 692-5.
Schizophrenia is a debilitating mental illness that affects 1% of the population. Despite intensive study, its molecular etiology remains enigmatic. Like many common diseases, schizophrenia is multifactorial in origin, with both genetic and environmental contributions likely playing an important role in the manifestation of symptoms. Recent advances based on pharmacological studies, brain imaging analyses, and genetic research are now converging on tantalizing leads that point to a central role for several neurotransmitters, including dopamine, glutamate, and serotonin, that may interface with neurodevelopmental defects reflecting disease-related genetic aberrations. Here, we provide a brief overview of the parallel approaches being used to identify the molecular causes of schizophrenia and discuss possible directions for future research.
Schafer, J. A. (2002). "Abnormal regulation of ENaC: syndromes of salt retention and salt wasting by the collecting duct." Am J Physiol Renal Physiol 283(2): F221-35.
Although the aldosterone-responsive segments of the nephron together reabsorb <10% of the filtered Na+, certain single-gene defects that affect the epithelial Na+ channel (ENaC) in the luminal membrane of the collecting duct (CD) or its regulation by aldosterone cause severe hypertension, whereas others cause salt wasting and hypotension. These rare defects illustrate the key role of the distal nephron in maintaining normal extracellular volume and blood pressure. Genetic defects that increase the Cl- conductance of the junctional complexes may also lead to salt retention and hypertension. Less dramatic alterations in regulatory actions of other hormones such as vasopressin (VP), either alone or with other genetic variations, diet, or environmental factors, may also produce Na+ retention or loss. Although VP acts primarily to regulate water balance, it is also an antinatriuretic hormone. Elevated basal plasma VP levels, and/or augmented VP release with increased Na+ intake, have been linked to essential hypertension in humans and in animal models of congestive heart failure and cirrhosis. Norepinephrine, dopamine, and prostaglandin E2 can inhibit the antinatriuretic effects of VP, and changes in the actions of these autocrine and paracrine regulators may also be involved in abnormal regulation of Na+ reabsorption.
Schmidt, M., F. Jockenhovel, et al. (2002). "[Assessment of endocrine disorders of the hypothalamic-pituitary axis by nuclear medicine techniques]." Nuklearmedizin 41(2): 80-90.
The following article reviews nuclear medicine techniques which can be used for assessment of endocrine disorders of the hypothalamic-pituitary axis. For planar and SPECT imaging somatostatin-receptor- and dopamine-D2-receptor-scintigraphy are the most widely distributed techniques. These nuclear medicine techniques may be indicated in selected cases to answer differential diagnostic problems. They can be helpful to search for presence and localization of receptor positive tissue. Furthermore they can detect metastasis in the rare cases of a pituitary carcinoma. Scintigraphy with Gallium-67 is suitable for further diagnostic evaluation in suspected hypophysitis. Other SPECT radiopharmaca do not have relevant clinical significance. F-18-FDG as PET radiopharmacon is not ideal because obvious pituitary adenomas could not be visualized. Other PET radiopharmaca including C-11-methionine, C-11-tyrosine, F-18-fluoroethylspiperone, C-11-methylspiperone, and C-11-raclopride are available in specialized centers only. Overall indications for nuclear medicine in studies for the assessment of endocrine disorders of the hypothalamic-pituitary-axis are rare. Original studies often report only about a small number of patients. According to the authors' opinion the relevance of nuclear medicine in studies of clinically important endocrinologic fields, e.g. localization of small ACTH-producing pituitary adenomas, tumor localization in ectopic ACTH syndrome, localization of recurrent pituitary tissue, assessment of small incidentalomas, can not be definitely given yet.
Schmidt, R. E. (2002). "Age-related sympathetic ganglionic neuropathology: human pathology and animal models." Auton Neurosci 96(1): 63-72.
Systematic studies of the autonomic nervous system of human subjects and development of well-defined animal models have begun to substantially improve our understanding of the pathogenesis of autonomic dysfunction in aging and may eventually provide strategies for intervention. Neuropathological studies of the sympathetic ganglia of aged human subjects and rodent models have demonstrated that neuroaxonal dystrophy involving intraganglionic terminal axons and synapses is a robust, unequivocal and consistent neuropathological finding in the aged sympathetic nervous system of man and animals. Quantitative studies have demonstrated that markedly swollen argyrophilic dystrophic axon terminals develop in the prevertebral superior mesenteric (SMG) and coeliac, but to a much lesser degree in the superior cervical ganglia (SCG) as a function of age, sex (males more than females) and diabetes. Dystrophic axons were immunoreactive for neuropeptide Y, tyrosine hydroxylase, dopamine-beta-hydroxylase, trkA and p75NTR, an immunophenotype consistent with their origin from postganglionic sympathetic neurons, and contained large numbers of highly phosphorylated neurofilaments or tubulovesicular elements. The sympathetic ganglia of aged rodents also showed the hallmark changes of neuroaxonal dystrophy as a function of age and location (many more in the SMG than in the SCG). Plasticity-related synaptic remodeling could represent a highly vulnerable target of the aging process. The fidelity of animal models to the neuropathology of aged humans suggests that similar pathogenetic mechanisms may be involved in both and that therapeutic advances in animal studies may have human application.
Schneier, F. R., C. Blanco, et al. (2002). "The social anxiety spectrum." Psychiatr Clin North Am 25(4): 757-74.
Social anxiety disorder is well suited to the spectrum concept because it has trait-like qualities of early onset, chronicity, and no empirically derived threshold that demarcates normal from clinically significant trait social anxiety. Social anxiety disorder has been shown to respond to relatively specific pharmacologic and cognitive-behavioral therapies, which makes identification of other conditions that may lie on the social anxiety disorder spectrum important because of possible treatment implications. Biologic markers associated with social anxiety disorder also may be shared by similar but nonidentical traits, such as behavioral inhibition and detachment. Clarification of the trait spectrums associated with specific biologic systems offers an opportunity for improving the understanding of the origin of these conditions. Strong evidence exists that at least some forms of shyness, avoidant personality disorder, and selective mutism lie on a social anxiety disorder spectrum. For several other disorders that share a prominent focus on social comparison, significant subgroups of patients seem to have features of social anxiety disorder. These disorders include major depression (especially the atypical subtype), body dysmorphic disorder, and eating disorders. Several other disorders marked by social dysfunction or inhibition, including substance use disorders (especially alcoholism), paranoid disorder, bipolar disorder, autism, and Asperger's disorder, also may show some overlap with social anxiety disorder features (e.g., social anxiety as a cause or complication of substance abuse, social avoidance in paranoid disorder, social disinhibiton in bipolar disorder, and social communication deficits in autism and Asperger's disorder). Social anxiety disorder also is associated with other anxiety disorders in general and other phobias in particular. In respect to traits, a growing body of evidence links behavioral inhibition to the unfamiliar to a social anxiety disorder spectrum with some specificity. Biologic measures of dopamine system hypoactivity have been linked to social anxiety disorder, trait detachment, and general deficits in reward and incentive function. It remains to be clarified, however, whether this brain system function is best characterized by a social anxiety disorder spectrum or some variant that incorporates social reward deficits or social avoidance behavior. Social anxiety disorder, shyness, and behavioral inhibition all seem to have a genetic component, but more research is needed to attempt to identify a more specifically heritable temperament associated with these conditions. Finally, the emergent concept of a social anxiety spectrum needs maturation. Although the notion of a single social anxiety disorder spectrum currently has some clinical use, the authors believe that exclusive focus on the notion of a single continuum with two extremes--from social disinhibition in mania to the most severe form of social anxiety, avoidant personality disorder--is premature and limiting in respect to etiologic research. An alternative approach is to conceptualize multiple, probably overlapping spectra in this area of social psychopathology. Individual dimensions might be based on various core phenomenologic, cognitive, or biologic characteristics. A bottom-up biologic approach holds promise for identifying spectra with a common etiology that might respond to specific treatments. Taking a pluralistic view of the concept of spectrum at this stage may help accelerate our understanding of social anxiety and related disorders.
Schultz, W. (2002). "Getting formal with dopamine and reward." Neuron 36(2): 241-63.
Recent neurophysiological studies reveal that neurons in certain brain structures carry specific signals about past and future rewards. Dopamine neurons display a short-latency, phasic reward signal indicating the difference between actual and predicted rewards. The signal is useful for enhancing neuronal processing and learning behavioral reactions. It is distinctly different from dopamine's tonic enabling of numerous behavioral processes. Neurons in the striatum, frontal cortex, and amygdala also process reward information but provide more differentiated information for identifying and anticipating rewards and organizing goal-directed behavior. The different reward signals have complementary functions, and the optimal use of rewards in voluntary behavior would benefit from interactions between the signals. Addictive psychostimulant drugs may exert their action by amplifying the dopamine reward signal.
Schulz, G. M. (2002). "The effects of speech therapy and pharmacological treatments on voice and speech in Parkinson s disease: a review of the literature." Curr Med Chem 9(14): 1359-66.
The purpose of this paper was to examine the effects of speech therapy and various pharmacological treatment approaches on the voice and speech of persons with Parkinson s disease (PD). Approximately 80% of PD patients have voice and speech problems including reduced vocal intensity, reduced vocal pitch, monopitch and monoloudness, and imprecise articulation. Research prior to 1970's had not demonstrated significant improvements following speech therapy. However, recent research has shown that speech therapy (when persons with PD are optimally medicated) has proven to be the most efficacious therapeutic method for improving voice and speech function. Across research studies, pharmacological methods of treatment in isolation do not appear to significantly improve voice and speech function in PD. In a single subject study, however, the dopamine agonist Mirapex was shown to have beneficial effects on vocal intensity. Possible explanations for the differential responses to treatment are discussed. It is suggested that the goal of future studies should be investigations of the effects of combined treatment approaches.
Schwartz, L., M. Lander, et al. (2002). "Current management of depression in cancer patients." Oncology (Huntingt) 16(8): 1102-10; discussion 1110, 1114-5.
Depression is a common but treatable condition among cancer patients. Screening for depression can be done simply and effectively, and a variety of practical treatment strategies are available. Numerous factors should be considered when prescribing medications from an ever-growing antidepressant armamentarium, including selective serotonin-reuptake inhibitors, serotonin norepinephrine-reuptake inhibitors, serotonin antagonist-reuptake inhibitors, norepinephrine dopamine modulators, monoamine oxidase inhibitors, reversible inhibitors of monoamine oxidase type A, tricyclic antidepressants, and psychostimulants. Other treatment options include electroconvulsive therapy and numerous forms of psychotherapy. The judicious use of medication and supportive therapies should significantly alleviate depression and enable the patient to navigate the cancer course with dignity, purpose, and the best quality of life possible.
Scordalakes, E. M., D. B. Imwalle, et al. (2002). "Oestrogen's masculine side: mediation of mating in male mice." Reproduction 124(3): 331-8.
This review focuses on the role of oestrogen in male sexual behaviour using oestrogen receptor alpha and beta knockout (ERalphaKO and ERbetaKO) mouse models. ERbetaKO mice are capable of mating and producing offspring, whereas ERalphaKO mice are unable to do either. When ERalphaKO males are treated with testosterone or dihydrotestosterone (DHT), < 50% display mounting behaviour, few intromit and none ejaculate. However, concurrent treatment with testosterone and a dopamine agonist instates masculine sexual behaviour in both male and female ERalphaKO mice. Dopamine content in the preoptic area and associated regions is not affected by oestrogen receptor alpha gene disruption. However, expression of neuronal nitric oxide synthase immunoreactivity is severely reduced in ERalphaKO males compared with wild-type males. These findings, together with studies conducted in aromatase knockout mice, are at odds with the dogma that oestrogen is required during development for expression of male sexual behaviour in adults. However, they do support a role for oestrogens, mediated by oestrogen receptor alpha, in regulation and production of neuronal nitric oxide synthase, which in turn may control dopamine agonist release. As has been shown in male rats, in mice dopamine agonist release is likely to be an essential component of the neural pathway that mediates male sexual behaviour.
Seeman, P. (2002). "Atypical antipsychotics: mechanism of action." Can J Psychiatry 47(1): 27-38.
BACKGROUND: Although the principal brain target that all antipsychotic drugs attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by attaching to it, induce extrapyramidal signs and symptoms (EPS). They also, by binding to the D2 receptor, elevate serum prolactin. Atypical antipsychotics given in dosages within the clinically effective range do not bring about these adverse clinical effects. To understand how these drugs work, it is important to examine the atypical antipsychotics' mechanism of action and how it differs from that of the more typical drugs. METHOD: This review analyzes the affinities, the occupancies, and the dissociation time-course of various antipsychotics at dopamine D2 receptors and at serotonin (5-HT) receptors, both in the test tube and in live patients. RESULTS: Of the 31 antipsychotics examined, the older traditional antipsychotics such as trifluperazine, pimozide, chlorpromazine, fluphenazine, haloperidol, and flupenthixol bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. The newer, atypical antipsychotics such as quetiapine, remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all bind more loosely than dopamine to the dopamine D2 receptor and have dissociation constants higher than that for dopamine. These tight and loose binding data agree with the rates of antipsychotic dissociation from the human-cloned D2 receptor. For instance, radioactive haloperidol, chlorpromazine, and raclopride all dissociate very slowly over a 30-minute time span, while radioactive quetiapine, clozapine, remoxipride, and amisulpride dissociate rapidly, in less than 60 seconds. These data also match clinical brain-imaging findings that show haloperidol remaining constantly bound to D2 in humans undergoing 2 positron emission tomography (PET) scans 24 hours apart. Conversely, the occupation of D2 by clozapine or quetiapine has mostly disappeared after 24 hours. CONCLUSION: Atypicals clinically help patients by transiently occupying D2 receptors and then rapidly dissociating to allow normal dopamine neurotransmission. This keeps prolactin levels normal, spares cognition, and obviates EPS. One theory of atypicality is that the newer drugs block 5-HT2A receptors at the same time as they block dopamine receptors and that, somehow, this serotonin-dopamine balance confers atypicality. This, however, is not borne out by the results. While 5-HT2A receptors are readily blocked at low dosages of most atypical antipsychotic drugs (with the important exceptions of remoxipride and amisulpride, neither of which is available for use in Canada) the dosages at which this happens are below those needed to alleviate psychosis. In fact, the antipsychotic threshold occupancy of D2 for antipsychotic action remains at about 65% for both typical and atypical antipsychotic drugs, regardless of whether 5-HT2A receptors are blocked or not. At the same time, the antipsychotic threshold occupancy of D2 for eliciting EPS remains at about 80% for both typical and atypical antipsychotics, regardless of the occupancy of 5-HT2A receptors. RELEVANCE: The "fast-off-D2" theory, on the other hand, predicts which antipsychotic compounds will or will not produce EPS and hyperprolactinemia and which compounds present a relatively low risk for tardive dyskinesia. This theory also explains why L-dopa psychosis responds to low atypical antipsychotic dosages, and it suggests various individualized treatment strategies.
Segovia, J. (2002). "Gene therapy for Parkinson's disease: current status and future potential." Am J Pharmacogenomics 2(2): 135-46.
Parkinson's disease appears to be a good candidate for gene therapy. The primary biochemical defect associated with the disease has been clearly determined as an absence of dopamine in the caudate-putamen, and the anatomical region where the neuropathologic hallmark of the disease, death of the nigral dopamine-producing neurons, occurs, remains circumscribed. Based on the biochemical and anatomical information gathered on Parkinson's disease, different gene therapy strategies have been devised to treat it. The first, and most explored strategy so far, consists in engineering cells to produce levodopa or dopamine so they will replace dopaminergic neurotransmission. Several types of cells have been employed in these experiments, and behavioral recovery has been reported in animal models of the disease. However, this approach cannot prevent neuronal death, nor reconstruct brain circuits. Another strategy is to protect cells by transferring genes that encode neurotrophic factors. Effort is now being concentrated into this research area, and promising results have recently been reported. Finally, an additional strategy aims at generating cells with a dopaminergic phenotype so they will be capable of replacing the missing dopaminergic neurons in biochemical, anatomical and functional terms. This has the potential to become an important constituent for an effective cure. Gene therapy holds significant promise for the treatment of neurodegenerative disorders, and Parkinson's disease treatment will benefit greatly from the knowledge and information arising from gene therapy research.
Seta, K., H. W. Kim, et al. (2002). "Genomic and physiological analysis of oxygen sensitivity and hypoxia tolerance in PC12 cells." Ann N Y Acad Sci 971: 379-88.
The mechanisms by which cells adapt and respond to changes in oxygen tension remain largely unknown. Our laboratory has used the PC12 cell line to study both biophysical and molecular responses to hypoxia. This chapter summarizes our findings. We found that membrane depolarization that occurred when PC12 cells were exposed to reduced O(2) was mediated by a specific potassium channel, the Kv1.2 channel. The membrane depolarization leads to increased Ca(2+) conductance through a voltage-sensitive channel, which in turn mediates the release of the neurotransmitters dopamine, adenosine, glutamate, and GABA. In addition, increased intracellular Ca(2+) and other signaling systems regulate hypoxia-induced gene expression, which contributes to the adaptive response to reduced O(2+). We identified several critical signaling pathways that regulate a complex gene expression profile in PC12 cells during hypoxia. These include the cAMP-protein kinase A, Ca(2+)-calmodulin, p42/44 mitogen-activated protein kinase (MAPK), stress-activated protein kinase (SAPK; p38 kinase), and the phosphatidylinositol 3-kinase-AKT as regulators of gene expression. Several of these pathways regulate hypoxia-specific transcription factors that are members of the hypoxia-inducible factor (HIF) family. Recently, we have successfully used subtractive cDNA libraries and microarray analysis to identify the genomic profile that mediates the cellular response to hypoxia.
Shaikh, S. and R. W. Kerwin (2002). "Receptor pharmacogenetics: relevance to CNS syndromes." Br J Clin Pharmacol 54(4): 344-8.
Pharmacogenetic research dedicated to the investigation of inherited factors that influence drug response has produced exciting results over the past decade. Adding to the knowledge that genetic variation in metabolic enzymes may cause drug-related adverse reactions, recent studies indicate that variation in neurotransmitter receptors can also be the cause of treatment failure. In addition, recent studies have attempted to use genetic information for the prediction of treatment outcome. The aim of this review is to summarize the most significant findings in pharmacogenetic research in relation to CNS drugs and to outline how these studies could lead to the individualization of drug treatment.
Shields, P. G. (2002). "Molecular epidemiology of smoking and lung cancer." Oncogene 21(45): 6870-6.
Lung cancer is the single most common cause of death, and almost all of it is due to tobacco smoking. Before the widespread use of cigarettes in this century, lung cancer was a rare illness. Tobacco smoke is a complex mixture of numerous mutagens and carcinogens. Over the last 40 years, the type of cigarettes most frequently used has been changing, namely the increased use of low tar and nicotine cigarettes. This has been accompanied by an increased risk of lung cancer due to a smokers' need to maintain blood nicotine levels, which in turn causes the need for smoking more cigarettes per day and deeper inhalation. This phenomena has led to the increasing rates of lung adenocarcinoma, compared to squamous cell carcinoma. It also probably explains, in part, the greater risk of lung cancer in women compared to men (in addition to some biological differences). The study of lung cancer involves many types of biomarkers, including those that measure exposure, the biologically effective dose and harm. The use of these has allowed us to understand many parts of lung carcinogenesis. Genetic susceptibilities play a large role in lung cancer risk. They govern smoking behavior (affecting dopamine reward mechanisms due to nicotine and nicotine metabolism), carcinogen metabolism and detoxification, DNA repair, cell cycle control and other cellular responses. The need for the study of lung cancer is highlighted by the need to improve cessation rates and reduce exposure among persons who cannot quit smoking, for better prevention strategies for former smokers and an understanding of environmental tobacco smoke risk.
Shintaku, H. (2002). "Disorders of tetrahydrobiopterin metabolism and their treatment." Curr Drug Metab 3(2): 123-31.
Tetrahydrobiopterin (BH4) deficiencies are disorders affecting phenylalanine metabolism in liver and neurotransmitters biosynthesis in brain. BH4 is the essential cofactor in the enzymatic hydroxylation of 3 aromatic amino acids (phenylalanine, tyrosine, and tryptophan). BH4 is synthesized from guanosine triphosphate (GTP) catalyzed by GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase, and sepiapterin reductase (SPR), and in aromatic amino acids hydoxylating system is regenerated by pterin-4a-carbinolamine dehydratase (PCD) and dihydropteridine reductase (DHPR). To date, 4 enzyme deficiencies (GTPCH, PTPS, DHPR, PCD) have been reported and they all follow an autosomal recessive mode of inheritance. The incidence of BH4 deficiency is at 1 in 1,000,000, except that in Taiwanese (much higher than in Japanese and Caucasians). BH4 deficiency has been diagnosed in patients with hyperphenylalaninemia (HPA) by neonatal mass-screening based on BH4 oral loading tests, analysis of urinary or serum pteridines, and measurement of dihydropterindine reductase (DHPR) activity in blood from a Guthrie card. BH4 deficiency without treatment causes combined symptoms of HPA and neurotransmitter (dopamine, norepinephrine, epinephrine, and serotonin) deficiency, such as red hair, psychomotor retardation, and progressive neurological deterioration. Treatment of BH4 deficiencies consists of BH4 supplementation (2-20 mg/kg per day) or diet to control blood phenylalanine concentration and replacement therapy with neurotransmitters precausers (L-dopa/CarbiDOPA and 5-hydroxytryptophan), and supplements of folinic acid in DHPR deficiency.
Sil'kis, I. G. (2002). "A possible mechanism for the dopamine-evoked synergistic disinhibition of thalamic neurons via the "direct" and "indirect" pathways in the basal ganglia." Neurosci Behav Physiol 32(3): 205-12.
The mechanism of synaptic plasticity which we have previously proposed for striatal spiny neurons, along with published data on the predominance of dopamine-sensitive D1/D2 receptors on strionigral/striopallidal neurons, was used as the basis to propose the hypothesis that the induction of long-term potentiation/depression of the efficiency of the cortical inputs to these cells may result from the excitatory/inhibitory actions of dopamine on the activity of the neurons originating the "direct" and "indirect" pathways through the basal ganglia. Thus, the action of dopamine increases disinhibition of thalamic neurons via the "direct" pathway and decreases their inhibition via the "indirect" pathway. Both effects lead to increases in the activity of thalamic cells and in the activity of the efferent neocortical neurons which they excite. The actions of dopamine on striosomal neurons, which mainly have D1 receptors, may also be to induce long-term potentiation of cortical inputs. This effect should lead to increased inhibition of dopaminergic cells and decreases in their dopamine release, which may promote the maintenance of a stable dopamine concentration in the cortex-basal ganglia-thalamus-cortex neural network.
Sil'kis, I. G. (2002). "[Possible mechanism of cannabinoid-mediated modulation of signal transduction through the basal ganglia]." Ross Fiziol Zh Im I M Sechenova 88(2): 144-57.
A possible mechanism of cannabinoid-mediated akinesia is suggested. This effect is proposed to be the consequence of a decrease in LTD/LTP in cortical inputs to striatopallidal/striatonigral cells in the matrix due to CB1 receptor activation. In addition, cannabinoids can attenuate locomotor activity due to a reducing of glutamate/GABA release from axon terminals of subthalamic nucleus/striatonigral cells of matrix and subsequent decrease/increase in the activity of neurons of globus pallidus/substantia nigra pars reticulata. Cannabinoid-mediated rise of dopamine release might be a result of a decrease of dopamine neuron inhibition by striatonigral cells of striosomes. It follows from the suggested mechanism that an inactivation (activation) of CB1 receptors leading to rise (lowering) of the motor activity can be useful for treatment of Parkinson (Huntington) disease.
Sil'kis, I. G. (2002). "[A unified postsynaptic mechanism for the effect of various neuromodulators on modification of potentiated and depressed inputs to hippocampal cells (hypothesis)]." Usp Fiziol Nauk 33(1): 40-57.
The unitary postsynaptic mechanism underlying the influence of diverse neuromodulators on modification of excitatory and inhibitory inputs to granule, pyramidal and inhibitory hippocampal cells is suggested. According to this mechanism, the effect of dopamine, adenosine, acetylcholine, noradrenaline, serotonin, somatostatin, galanin, opioids, cannabinoids, neuropeptide Y on postsynaptic receptors, bound to Gi/0 proteins, should promote LTD of excitatory inputs and LTP of inhibitory inputs. The effect of dopamine, adenosine, acetylcholine, noradrenaline, serotonin, vasopressin, tachykinin, histamine on postsynaptic receptors, bound to Gs and Gq/11 proteins, should oppositively modulate the same inputs. Only synaptically activated excitatory and inhibitory inputs can by influenced by neuromodulators. The character of neuromodulatory influence on modification of hippocampal synaptic efficacy, implying from the suggested mechanism is in accordance with known experimental data.
Sindo, I. and J. I. Jorgensen (2002). "[Treatment of tics in Tourette syndrome with atypical antipsychotic drugs]." Ugeskr Laeger 164(32): 3755-9.
We reviewed articles in English dealing with research into the effect of atypical antipsychotic drugs on tic reduction in Tourette's syndrome. In Denmark, there are four registered atypical antipsychotic drugs; clozapine, sulpiride, olanzapine, and risperidone. The topic of interest is the effectiveness and side effects of these drugs as compared to the conventional antipsychotic, pimozide, which is today the preferred pharmacological treatment of Tourette's syndrome among the antipsychotics. The conclusion is that risperidone would be a good first-line antipsychotic drug for the treatment of Tourette's syndrome. It is as effective as pimozide, its side effect profile is overall much more favourable, and unlike pimozide it does not contain the risk of causing heart arrhythmia.
Slagle, M. (2002). "Medication update." South Med J 95(4): 400-3.
Solanto, M. V. (2002). "Dopamine dysfunction in AD/HD: integrating clinical and basic neuroscience research." Behav Brain Res 130(1-2): 65-71.
There is strong evidence that the catecholamines dopamine and norepinephrine are both important in the pathophysiology of ADHD, as well as in the mechanism of therapeutic action of stimulant drugs. Due to the known effects of stimulants in blocking reuptake of catecholamines and (in the case of D-amphetamine) facilitating their release, it has traditionally been believed that the stimulants compensate for catecholamine deficiency in ADHD. More recently, however, alternate hypotheses of a hyperdopaminergic and/or hyper-noradrenergic state in ADHD have been suggested. This paper will be limited to a review of the evidence for involvement of dopamine in mediating behavioral and cognitive symptoms and response to stimulants in ADHD, with implications for possible mechanisms.
Song, F., J. Raftery, et al. (2002). "Cost-effectiveness of pharmacological interventions for smoking cessation: a literature review and a decision analytic analysis." Med Decis Making 22(5 Suppl): S26-37.
To evaluate the relative cost-effectiveness of nicotine replacement therapy (NRT) and bupropion SR for smoking cessation, the authors reviewed published studies and developed a decision analytic model from the UK National Health Services perspective. Irrespective of the methods or assumptions involved, the results of published studies consistently indicated that NRT for smoking cessation is cost-effective. No published studies have evaluated the relative cost-effectiveness of bupropion SR for smoking cessation. The results of the decision analyses indicated that, as compared with advice or counseling alone, the incremental cost per life-years saved is about $1,441-$3,455 for NRT, $920-$2,150 for bupropion SR, and $1,282-$2,836 for NRT plus bupropion SR. The cost-effectiveness of adding NRT and bupropion SR to advice or counseling for smoking cessation is better than many other accepted health care interventions.
Sonuga-Barke, E. J. (2002). "Psychological heterogeneity in AD/HD--a dual pathway model of behaviour and cognition." Behav Brain Res 130(1-2): 29-36.
Psychological accounts have characterised attention-deficit/hyperactivity disorder (AD/HD) as either a neuro-cognitive disorder of regulation or a motivational style. Poor inhibitory control is thought to underpin AD/HD children's dysregulation while delay aversion is a dominant characteristic of their motivational style. A recent 'head to head' study of these two accounts suggest that delay aversion and poor inhibitory control are independent co-existing characteristics of AD/HD (combined type). In the present paper we build on these findings to propose a dual pathway model of AD/HD that recognises two quite distinct sub-types of the disorder. In one AD/HD is the result of the dysregulation of action and thought resulting from poor inhibitory control associated with the meso-cortical branch of the dopamine system projecting in the cortical control centres (e.g. pre-frontal cortex). In the other AD/HD is a motivational style characterised by an altered delay of reward gradient linked to the meso-limbic dopamine branch associated with the reward circuits (e.g. nucleus accumbens). The two pathways are further distinguished at the levels of symptoms, cognitive and motivation profiles and genetic and non-genetic origins.
Spear, L. P. (2002). "The adolescent brain and the college drinker: biological basis of propensity to use and misuse alcohol." J Stud Alcohol Suppl(14): 71-81.
OBJECTIVE: This article reviews the literature on adolescent brain development and considers the impact of these neural alterations on the propensity to use and misuse alcohol. METHOD: Neural, behavioral and hormonal characteristics of adolescents across a variety of species were examined, along with a review of the ontogeny of ethanol responsiveness, tolerance development and stress/alcohol interactions. RESULTS: The adolescent brain is a brain in transition. Prominent among the brain regions undergoing developmental change during adolescence in a variety of species are the prefrontal cortex and other forebrain dopamine projection regions, stressor-sensitive areas that form part of the neural circuitry modulating the motivational value of alcohol and other reinforcing stimuli. Along with these characteristic brain features, adolescents also exhibit increased stressor responsivity and an altered sensitivity to a variety of ethanol effects. Findings are mixed to date as to whether exposure to ethanol during this time of rapid brain development alters neurocognitive function and later propensity for problematic ethanol use. CONCLUSIONS: Developmental transformations of the adolescent brain may have been evolutionarily advantageous in promoting behavioral adaptations to avoid inbreeding and to facilitate the transition to independence. These brain transformations may also alter sensitivity of adolescents to a number of alcohol effects, leading perhaps in some cases to higher intakes to attain reinforcing effects. These features of the adolescent brain may also increase the sensitivity of adolescents to stressors, further escalating their propensity to initiate alcohol use. Additional investigations are needed to resolve whether ethanol use during adolescence disrupts maturational processes in ethanol-sensitive brain regions.
Speciale, S. G. (2002). "MPTP: insights into parkinsonian neurodegeneration." Neurotoxicol Teratol 24(5): 607-20.
MPTP burst upon the medical landscape two decades ago, first as a mysterious parkinsonian epidemic, triggering an unparalleled quest for the toxin's identity, and closely followed by an intense pursuit of its cellular mechanisms of action. MPTP treatment created an animal model of many features of Parkinson's disease (PD), used primarily in primates and later in mice. The critical role of oxidative stress damage to vulnerable dopamine neurons, as well as for neurodegenerative diseases in general, emerged from MPTP neurotoxicity. A remarkable cross-fertilization of basic and clinical findings, including genetic and epidemiologic studies, has greatly advanced our understanding of PD and revealed multiple factors contributing to the parkinsonian phenotypes. Brain imaging localizes sites of action and provides potential presymptomatic diagnostic testing. Epidemiologic reports linking PD with pesticide exposure were complimented by supportive evidence from biochemical studies of MPTP and structurally related compounds, especially after low-level, long-term exposure. Genetic studies on the role of risk genes, such as alpha-synuclein or parkin, have been validated by biochemical, anatomical and neurochemical investigations showing factors interacting to produce pathophysiology in the animal model. Focusing on the pivotal role of mitochondria, subcellular pathways participating in cell death have been clarified by unraveling similar sites of action of MPTP. Along the way, compounds antagonizing or potentiating MPTP effects indicated new PD therapies, some of the former achieving clinical trials. The future is encouraging for combating PD and will continue to benefit from the MPTP neurotoxicity model.
Steece-Collier, K., E. Maries, et al. (2002). "Etiology of Parkinson's disease: Genetics and environment revisited." Proc Natl Acad Sci U S A 99(22): 13972-4.
Stein, D. J., H. G. Westenberg, et al. (2002). "Social anxiety disorder and generalized anxiety disorder: serotonergic and dopaminergic neurocircuitry." J Clin Psychiatry 63 Suppl 6: 12-9.
Awareness that an amygdala-based fear circuit plays a crucial role in mediating fear conditioning as well as anxiety symptoms is growing. The efficacy of selective serotonin reuptake inhibitors in certain anxiety disorders has been argued to reflect their ability to modulate this circuit. Whether additional neurocircuits play a differentiating role in specific anxiety disorders, such as social anxiety disorder and generalized anxiety disorder (GAD), is an ongoing subject of investigation. A review of the literature suggests that in social anxiety disorder, dopaminergically mediated striatal circuits may also be important, while in GAD, there may be abnormalities of prefrontal areas. Future work will undoubtedly clarify how genetic and environmental factors interact to fashion the neurocircuitry that mediates anxiety symptoms.
Stevens, J. R. (2002). "Schizophrenia: reproductive hormones and the brain." Am J Psychiatry 159(5): 713-9.
OBJECTIVE: Onset of schizophrenia occurs during the reproductive period in more than 80% of those affected. The author reviews neuroendocrine and physiologic events that occur in the basal forebrain at the initiation of and throughout the reproductive period and proposes their possible relationship to the onset of schizophrenia. METHOD: The neuroendocrine changes that occur in specific areas of the anterior basal forebrain during the reproductive period are reviewed and analyzed in relation to reported anatomic, molecular, and biochemical pathologies of schizophrenia. RESULTS: The reproductive period is associated with development of regular pulsatile release in the brain and bloodstream of gonadotropic releasing hormones from the hypothalamus, luteinizing and follicle stimulating hormones from the pituitary, and gonadal hormones from the ovaries and testes. In addition to being concentrated in the hypothalamus, brain receptors for gonadotropic and gonadal hormones are concentrated in specific subcortical forebrain nuclei of the limbic system that project to the thalamus and to cortical and subcortical structures that subserve perception, cognition, and behavior. CONCLUSIONS: There is a flood of estrogen and testosterone to the brain and body during puberty and throughout the reproductive period. To avoid hyperexcitability and seizures, the surge of these excitatory hormones must be counterbalanced by appropriate inhibitory factors. Excessive focal inhibition may be induced by increased release of or increased receptors for one or more inhibitory transmitters, e.g., dopamine, serotonin, and gamma-aminobutyric acid in the anterior basal forebrain. Further investigation of the physiology and pathology of this brain region, where abnormal electrical activity was recorded from individuals with schizophrenia many years ago and where dopamine D(2) and dopamine D(3) receptors targeted by the most effective antipsychotic agents are maximally expressed, could lead to greater understanding of the critical pathophysiology for development of schizophrenia.
Suchowersky, O. (2002). "Parkinson's disease: medical treatment of moderate to advanced disease." Curr Neurol Neurosci Rep 2(4): 310-6.
Parkinson's disease, a common neurodegenerative disorder, results in significant morbidity 10 to 15 years after disease onset and increased mortality. Levodopa is the mainstay of therapy and provides benefit for the duration of the illness. However, within 5 years, up to 50% of individuals develop fluctuations, including dyskinesias, wearing off, and "on/off" effects. Optimal management of Parkinson's disease patients requires careful titration of medications, with use of polypharmacy, including levodopa, dopamine agonists, catechol-O-methyltransferase inhibitors, amantadine, and anticholinergics in order to maintain good motor function and quality of life. With advancing disease, problems such as dysphagia, dysarthria, and gait and balance abnormalities occur, which are not responsive to dopaminergic medication. Due to extradopaminergic neuronal system degeneration, autonomic dysfunction can also be prominent. Recognition and management of these problems is helpful in improving quality of life in late-stage disease. In very late stages, dementia may complicate treatment, requiring discontinuation of combination therapy and use of low-dose levodopa with atypical neuroleptics.
Suhara, T. and T. Ichimiya (2002). "[Pathophysiology of mood disorders and the therapy]." Seishin Shinkeigaku Zasshi 104(6): 464-71.
Sullivan, M. A. and L. S. Covey (2002). "Nicotine dependence: the role for antidepressants and anxiolytics." Curr Opin Investig Drugs 3(2): 262-71.
The addictive nature of cigarette smoking has been appreciated only in the past two decades. Prior to the publication of DSM-III in 1980, excessive tobacco use had not been considered as a psychiatric problem requiring treatment [1]. Smoking has been recognized as a serious medical problem since thefirst Surgeon General's Report on Smoking and Health in 1964. An important development during the 10 to 20 years following this report was the growth of knowledge regarding the physiological effects of regular tobacco use and the importance of nicotine as the main pharmacological ingredient in tobacco. This body of information culminated in the 1988 Surgeon General's Report, which recognized chronic tobacco use as a form of addictive behavior [2]. Nicotine, like other drugs of abuse, has reinforcing psychoactive effects that lead to its repeated self-administration. Nicotine stimulates the release of several neurotransmitters including dopamine, norepinephrine, acetylcholine, 5-hydroxytryptamine, gamma-aminobutyric acid (GABA) and endorphins [3]. Through its effects on the dopaminergic, or 'reward', system, nicotine exerts psychoactive effects such as an increased sense of enjoyment. The norepinephrinergic effects of nicotine may account for increased attentiveness and improved performance in repetitive tasks, while its anxiolytic effects are likely mediated through GABA and the endorphins.
Svartberg, J., S. M. Carlsen, et al. (2002). "[Hyperprolactinemia and prolactinemia--investigation and treatment]." Tidsskr Nor Laegeforen 122(5): 494-8.
BACKGROUND: Prolactinoma represents the most commonly occurring hormone-secreting pituitary adenoma. The majority of prolactinomas are small, only rarely do we find larger prolactinomas, so-called macroadenomas. They are almost exclusively benign. The symptoms are mainly caused by elevated prolactin levels and result in changes to the reproductive and sexual function. In cases of macroprolactinomas, symptoms caused by local mass effects can be seen. A variety of other conditions may also cause hyperprolactinaemia; the goal of the examination is to identify the cause. MATERIAL AND METHODS: We have reviewed recent literature and compared findings with current management of hyperprolactinaemia and prolactinoma in Norwegian university hospitals. RESULTS AND INTERPRETATION: The primary treatment is medical, intended to normalize prolactin levels, restore gonadal function, and reduce tumour size. With the new selective dopamine agonists, the treatment is often simple and efficient, but not all patients are in need of treatment.
Swanson, J. M. and N. D. Volkow (2002). "Pharmacokinetic and pharmacodynamic properties of stimulants: implications for the design of new treatments for ADHD." Behav Brain Res 130(1-2): 73-8.
In the USA, the stimulant drug methylphenidate (MPH) is used to treat a large number (2 million or more per year) of children with Attention Deficit Hyperactivity Disorder (ADHD). Although the US FDA approved MPH in the 1960s, the pharmacokinetic (PK) properties of serum concentrations of MPH in children with ADHD were not described until the 1980s, and then in only a few cases. Recently, information from drug development programs have increased our knowledge about the serum PK and some pharmacodynamic (PD) characteristics of MPH in ADHD children, and studies based on positron emission tomograpy (PET) in adult volunteers have provided new knowledge about the PK properties of MPH at the primary site of action in the brain. We will review these two topics and use this new information to evaluate the mechanisms of action of MPH.
Szekeres, G. and Z. Janka (2002). "[Receptor polymorphism and response to treatment in schizophrenia]." Orv Hetil 143(35): 2027-33.
The new molecular genetic methods have generated dynamic changes in the field of schizophrenia research in the last decade. There is increasing knowledge about potential genetic variants affecting the phenotype in terms of response to antipsychotic therapy. It is known that polymorphisms of genes encoding proteins that participate in the metabolism of neuroleptics, alter the pharmacokinetics of drugs. In addition, experience has been emerging about receptor polymorphisms that may play substantial role in the etiology and pharmacotherapy of schizophrenia. These data throw new light upon issue of therapy resistance in schizophrenia. Authors review the literature about polymorphisms of neurotransmitter systems relevant to schizophrenia, and its associations with the response to typical and atypical antipsychotic treatments. They outline the trends of pharmacogenomics and its perspectives in the research of new treatment possibilities in schizophrenia.
Szekeres, G., L. Pavics, et al. (2002). "[Investigation of the dopamine dysregulation hypothesis of schizophrenia with neuroimaging techniques]." Ideggyogy Sz 55(7-8): 226-32.
The most elaborated biochemical concept of schizophrenia is the dopamine hypothesis. However, this classical theory is based on indirect observations. It has recently become possible to study this theory directly by means of advanced functional neuroimaging techniques, the development of specific radioligands and study protocols that are eligible to monitor dynamic changes in the neurotransmitter systems. According to the early concept, the essence of schizophrenia is the hyperactivity of the dopamine system. Nevertheless, this idea has gone through many modifications. In accordance with the modified dopamine hypothesis, the cognitive deficit and negative symptoms are related to the hypoactivity of the dorsolateral prefrontal cortex while the acute phases of the disease associates with hyperactivity of the ventral striatal elements of the dopaminergic system. Between these dysfunctions there is causality via their exuberant connections. Beyond that, the interactions between the prefrontal and striatal anomalies implicate the involvement of other neurotransmitters than dopamine. Observations from model psychosis induced by N-methyl-D-aspartate antagonists and in vivo neuroimaging investigations in humans support primarily the role of glutamatergic system. Our developing knowledge about the neurochemical mechanism of schizophrenia can significantly affect therapeutic strategies as well.
Szirmai, I. and T. Kovacs (2002). "[Parkinson syndrome and cognitive disorders]." Ideggyogy Sz 55(7-8): 220-5.
The cognitive (executive) ability of patients with Parkinson's-disease (PD) deteriorates gradually during the progression of the disease. Fluency of speech, word finding, working memory, ability to plan the future and flexibility decline. Cognitive disturbance was found to be proportional with the speech, posture, gait and balance problems and can not be influenced by L-dopa substitution. Apart the dorsal and ventral mesolimbic dopaminergic systems the coerulo-cortical noradrenergic, serotoninergic and cholinergic systems are also impaired in PD. Subcortical dementia in PD can also be explained by the functional disability of dorsolateral and anterior cingular circuits. Attention deficit can be explained by the dopamine depletion of cingular cortex. Cortical Lewy bodies, neurofibrillary tangles, neurit plaques and additional vascular pathology should also play a role in cognitive impairment of PD. In several systemic degenerative diseases associating with Parkinson's syndrome (PS) i.e. progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), multiple system atrophy (MSA) dementia can be detected with various severity, therefore the question arises concerning the correlation between cognitive disability and PS. Parkinson syndrome can also develop in frontotemporal dementias (FTD), Alzheimer's disease and cortical Lewy body disease (CLBD) but no correlation exists between motor disability and severity of dementia. In CLBD dementia can be the initial symptom in 18% of cases but PS can also preceeds the dementia. In PSP profound depletion of other monoaminergic neurotransmitter system was also reported. In FTDs associated with PS degeneration of substantia nigra, locus coeruleus and basal nucleus of Meynert has been reported with increased number of neurofibrillary tangles. In patients with vascular PS (VP) there is generally no tremor and rigidity, but pseudobulbar palsy, dementia, gate disturbance, incontinency appears; L-dopa treatment is generally ineffective. In VP no cellular loss can be found within the substantia nigra, but leukoaraiosis, lacunae in the white matter and basal ganglia are commonly demonstrated.
Tamminga, C. A. (2002). "Partial dopamine agonists in the treatment of psychosis." J Neural Transm 109(3): 411-20.
The discovery and characterization of dopamine in the mammalian brain earned Dr. Arvid Carlsson the Nobel Prize in 2000. Along with his many insights about dopamine pharmacology, came his proposal of the existence and critical role of dopamine autoreceptors in the overall regulation of dopamine-mediated neurotransmission. In this paper, the rationale, the putative mechanisms, and pertinent clinical data are reviewed to support the idea of the clinical relevance of dopamine agonists, especially partial agonists, in the treatment of psychosis. Evidence was gathered for the usefulness of this strategy in schizophrenia in early trials with apomorphine and N-propylnoraporphine (NPA). But clinical relevance was not a reality before the application of (-)-3PPP. These clinical results are presented. Moreover, now a partial dopamine agonist, aripiprazole, has been developed and will likely be marketed by BMS and Otsuka for the treatment of psychosis and will be the first drug in this class to be commercially available. Partial dopamine agonists represent the next new class of antipsychotic drugs, effective in treating schizophrenia.
Tanigawara, Y., O. Iketani, et al. (2002). "[Variability in drug response caused by the genetic polymorphisms of receptors]." Nippon Rinsho 60(1): 51-7.
A greater deal of attention has been given to the genetic polymorphism of receptors and related variability in drug response. In recent years, studies on pharmacogenomics accomplished remarkable progress in this issue. These studies include, the relationships between beta 2-adrenegic receptor polymorphism and the pharmacological effect of blonchodilator, dopamine D2 or 5-HT2 receptor polymorphism and response to antipsychotic medication, vitamin D receptor variants and the active vitamin D therapy, PPAR gamma and the insulin resistance treatment and so on. However, some of them are still controversial, and it requires further investigation to apply these studies to the actual therapy.
Tarsy, D., R. J. Baldessarini, et al. (2002). "Effects of newer antipsychotics on extrapyramidal function." CNS Drugs 16(1): 23-45.
Following acceptance of clozapine as a superior antipsychotic agent with low risk of adverse extrapyramidal syndromes (EPS), such as dystonia, parkinsonism, akathisia or tardive dyskinesia, several novel antipsychotic drugs have been developed with properties modelled on those of clozapine. Though generally considered 'atypical' in their relatively low risk of inducing EPS, these agents vary considerably in their pharmacology and impact on neurological functioning. Although few comparative data are available, the atypical antipsychotics can be tentatively ranked by EPS risk (excluding akathisia and neuroleptic malignant syndrome) in the following order: clozapine < quetiapine < olanzapine = ziprasidone. At higher doses, risperidone is ranked with a higher EPS risk than olanzapine and ziprasidone, but its risk of EPS is lower with lower doses. In general, this ranking is inversely related to antidopaminergic (D2 receptor) potency. The high antiserotonergic (5-HT2A receptor) potency of risperidone, clozapine, ziprasidone and olanzapine, but not quetiapine, as well as the antimuscarinic activity of olanzapine and clozapine may also limit EPS. For the treatment of psychotic reactions to dopamine agonist therapy in Parkinson's disease, clozapine is both effective and relatively well tolerated; quetiapine may be tolerated, olanzapine is not well tolerated, risperidone is poorly tolerated, and amisulpride and ziprasidone have not been well evaluated. Clozapine, perhaps because of its anticholinergic activity, can reduce parkinsonian tremor. It is useful for ongoing psychosis with tardive dyskinesia, especially for dystonic features. No atypical antipsychotic is clearly effective for motor abnormalities in Huntington's disease or Tourette's syndrome, and the effect of these drugs on other neurological disorders have been well evaluated in only small numbers of patients. In summary, with the exception of clozapine, and perhaps quetiapine, atypical antipsychotics have brought only relative avoidance of EPS, strongly encouraging continued searches for novel antipsychotic agents.
Thase, M. E. (2002). "What role do atypical antipsychotic drugs have in treatment-resistant depression?" J Clin Psychiatry 63(2): 95-103.
Despite significant advances in the treatment of depression, many patients fail to respond to treatment with adequate dose and duration. Multiple therapeutic approaches are available for the treatment of patients not responding to standard antidepressant medication. These include switching medication or combination and augmentation strategies. A substantial number of patients do not respond to multiple treatment trials. These patients suffer from treatment-resistant depression (TRD) and represent a challenge to the treating physician. There have been a growing number of reports on the use of atypical antipsychotics as augmenting agents in nonpsychotic TRD. Second-generation antipsychotics are less likely to provoke parkinsonian side effects. It has also been reported that these agents produce lower rates of tardive movement disorders than traditional neuroleptics. Furthermore, second-generation antipsychotics are serotonin-2A/2C antagonists, possibly allowing them to improve the efficacy and some aspects of the side effect profile of selective serotonin reuptake inhibitors (SSRIs). Weight gain and sedation are likely to be the most common adverse events of such combined therapy. In a recent controlled clinical trial, the atypical antipsychotic olanzapine was combined with fluoxetine therapy in an 8-week, double-blind clinical trial in patients with TRD. This combination drug therapy demonstrated clinical efficacy on several rating scales and showed rapid onset of action. Although more studies will be required to confirm and extend these findings, the results suggest that there may be a clinical benefit to combining atypical antipsychotics with SSRIs in nonpsychotic TRD.
Thaxton, L. and M. A. Myers (2002). "Sleep disturbances and their management in patients with brain injury." J Head Trauma Rehabil 17(4): 335-48.
OBJECTIVES: Sleep disturbances in people with brain injuries, although quite common, remain a problematic management issue for caregivers. This article will review the architecture of sleep, the assessment of insomnia, and discussion of common medications that may exacerbate the problem. Nonpharmacological management techniques, including stimulus control, sleep restriction, and relaxation therapy, will also be discussed. MAIN OUTCOME MEASURES: An intensive analysis of pharmacological agents used in treatment, including descriptions of the positive and negative effects of the various classes of drugs (e.g., sedative/hypnotics, antihistamines, dopamine agonists, and stimulants) will be provided. CONCLUSIONS: These discussions will hopefully assist in the decision-making processes of caregivers managing this unique group of persons with sleep difficulties.
Thiery, J. C., P. Chemineau, et al. (2002). "Neuroendocrine interactions and seasonality." Domest Anim Endocrinol 23(1-2): 87-100.
Sheep in temperate latitudes are seasonal breeders. Of the different seasonal cues, photoperiod is the most reliable parameter and is used by animals as an indication of the time of the year to synchronize endogenous annual rhythms of reproduction and physiology. The photoperiodic information is transduced into neuroendocrine changes through variations in melatonin secretion from the pineal gland. Melatonin triggers variations in the secretion of luteinizing hormone-releasing hormone, luteinizing hormone and follicle stimulating hormone (LHRH/LH/FSH) responsible for seasonal changes in reproductive activity. In female sheep, the seasonal changes in the hormonal LH pattern mainly reflect an increase in the negative feedback exerted by estradiol under long days on the frequency of pulsatile LH secretion. The resulting seasonal inhibition of LH secretion involves the activation of monoaminergic and especially dopaminergic systems by estradiol. Other types of physiological regulation subject to seasonal changes such as voluntary food intake (VFI), fat metabolism, body mass and pelage growth also occur in sheep, goats or related wild species. Several neuroendocrine intermediates seem to be shared by these different systems and may participate in their synchronization, providing the advantage that this helps mammalian species to adapt to their environment.
Tintner, R. and J. Jankovic (2002). "Treatment options for Parkinson's disease." Curr Opin Neurol 15(4): 467-76.
PURPOSE OF REVIEW: Parkinson's disease is a common neurodegenerative disorder. Clinical trials designed to assess the safety and efficacy of novel neuroprotective as well as symptomatic medical and surgical strategies are being performed to increase and enhance treatment options. The purpose of this review is to summarize these therapeutic options, emphasizing reports published in the last year. RECENT FINDINGS: Experimental therapeutics in Parkinson's disease has focused on prevention of levodopa complications, treatment of dyskinesias associated with levodopa therapy, surgical intervention and neuroprotection. SUMMARY: There are at least four important implications of the recent therapeutic trials: (1) the incidence of levodopa-related dyskinesias decreases as a result of initial use of dopamine agonists; (2) surgery, primarily in the form of the bilateral, high-frequency stimulation of the subthalamic nucleus, is highly effective in patients who are responsive to levodopa but experience marked motor fluctuation or other complications; (3) while neuroprotection has not yet been demonstrated with any currently used therapeutic agent, improved understanding of mechanisms of cell death will undoubtedly result in the discovery of new drugs with potential disease-modifying effects; and (4) implantation of fetal mesencephalon tissue and other grafts may be effective in younger patients with Parkinson's disease, but is associated with significant complications and remains experimental.
Toledo-Aral, J. J., S. Mendez-Ferrer, et al. (2002). "Dopaminergic cells of the carotid body: physiological significance and possible therapeutic applications in Parkinson's disease." Brain Res Bull 57(6): 847-53.
Parkinson's disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra projecting to the striatum. One therapeutic approach to this disease has been the intrastriatal transplantation of dopamine-secreting cells. We have investigated the suitability of glomus cells of the carotid body for dopamine-cell replacement in animal models of Parkinson's disease. Carotid body glomus cells are physiologic arterial oxygen sensors that release large amounts of dopamine in response to hypoxia. We have used hemi-Parkinsonian rats, induced by injection of 6-hydroxydopamine into the substantia nigra, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated monkeys with chronic Parkinsonism. In both cases we made transplants of carotid body cell aggregates into the putamen. Functional recovery of the grafted animals was observed after the surgery and was stable for several months. Although the study was more detailed in the rat, in the two animal models the amelioration of the motor deficits was paralleled by striatal dopaminergic reinnervation and survival of grafted glomus cells. Our results suggest that intrastriatal autotransplants of carotid body tissue could be a feasible technique to treat some cases of Parkinson's disease in humans.
Tonstad, S. (2002). "Use of sustained-release bupropion in specific patient populations for smoking cessation." Drugs 62 Suppl 2: 37-43.
Smoking cessation trials of sustained-release bupropion (bupropion SR) were initially conducted in a general population of smokers who were motivated to quit smoking. Bupropion SR has also been found to be a useful treatment of tobacco dependence in various special populations of smokers who often experience difficulty in overcoming tobacco addiction. Point-prevalence quit rates at 6 months were higher in those treated with bupropion SR than in those receiving placebo in studies on smokers with chronic obstructive pulmonary disease (23% vs 16%) and in those with cardiovascular disease (34% vs 12%). Abstinence from smoking after treatment with bupropion SR was not affected by a history of major depression or alcoholism. Women treated with bupropion SR were just as likely as men to abstain from smoking. Approximately one-third of a study population who were initially unwilling or unable to quit smoking were able to reduce their smoking by 50% or more during therapy with bupropion SR; 14% of these went on to achieve abstinence. Bupropion SR was well tolerated in these trials; importantly, it had no clinically significant effect on mean blood pressure in smokers, including those with hypertension, and attenuated the weight gain associated with smoking cessation, particularly in women.
Tonzi, M. K. and J. A. Fain (2002). "Understanding diabetic gastroparesis: a case study." Gastroenterol Nurs 25(4): 154-60; quiz 161-2.
The purpose of this article is to present an overview of diabetic gastroparesis, defined as delayed gastric emptying in the absence of mechanical obstruction. Diabetic gastroparesis is a substantial and unrecognized problem. Failure to treat may result in a decreased quality of life and a potential increase for morbidity. The treatment protocol for diabetic gastroparesis combines dietary and pharmacologic measures. This article will discuss normal physiology of gastric emptying along with the pathogenesis of delayed emptying in patients with diabetes. Nursing implications for the care of the patient with diabetic gastroparesis is also presented along with commonly used pharmacologic agents.
Torta, R. and F. Monaco (2002). "Atypical antipsychotics and serotoninergic antidepressants in patients with epilepsy: pharmacodynamic considerations." Epilepsia 43 Suppl 2: 8-13.
PURPOSE: To discuss the pharmacodynamic aspects of the administration of atypical antipsychotics (APs) and serotoninergic antidepressants (SSRIs) to patients with epilepsy. METHODS: This article represents an overview of all studies concerning the administration of APs and SSRIs to people with epilepsy. In particular, it deals with the relationship between neuroleptics (NLTs), APs, SSRIs, serotonin, and dopamine, with special focus on the possible epileptogenic role of psychoactive drugs. RESULTS: NLTs may induce seizures by blocking D2, H1, and.1 receptors, or by sexual hormone activation or a pharmacologic kindling mechanism. The difference among APs in their ability to induce seizures is related mainly to the percentage of D2-receptor occupancy and possibly also to their action on neurosteroids. Seizures occur at SSRIs therapeutic doses, with a 0.1-4% incidence. Coversely, in animal studies fluoxetine was claimed to exert an anticonvulsant action. CONCLUSIONS: The study of the pharmacodynamic aspects of the administration of APs and SSRIs to patients with epilepsy can help to evaluate the importance of some mechanisms of action of several psychoactive drugs in relation to their pro- or anticonvulsant activity.
Toth, B. E., I. Bodnar, et al. (2002). "Physiological role of salsolinol: its hypophysiotrophic function in the regulation of pituitary prolactin secretion." Neurotoxicol Teratol 24(5): 655-66.
We have recently observed that 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) produced by hypothalamic neurons can selectively release prolactin from the anterior lobe (AL) of the pituitary gland. Moreover, high affinity binding sites for SAL have been detected in areas, like median eminence (ME) and the neuro-intermediate lobe (NIL) that are known terminal fields of the tuberoinfundibular DAergic (TIDA) and tuberohypophysial (THDA)/periventricular (PHDA) DAergic systems of the hypothalamus, respectively. However, the in situ biosynthesis and the mechanism of action of SAL are still enigmatic, these observations clearly suggest that sites other than the AL might be targets of SAL action. Based on our recent observations it may be relevant to postulate that an "autosynaptocrine" regulatory mechanism functioning at the level of the DAergic terminals localized in both the ME and NIL, may play a role in the hypophyseotrophic regulation of PRL secretion. Furthermore, SAL may be a key player in these processes. The complete and precise mapping of these intra-terminal mechanisms should help us to understand the tonic DAerg regulation of PRL secretion. Moreover, it may also give insight into the role of pre-synaptic processes that most likely have distinct and significant functional as well as pathological roles in other brain areas using DAergic neurotransmission, like striatonigral and mesolimbic systems.
Trabace, L., T. Cassano, et al. (2002). "CHF2819: pharmacological profile of a novel acetylcholinesterase inhibitor." CNS Drug Rev 8(1): 53-69.
CHF2819 is a novel orally active acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD). CHF2819 is a selective inhibitor of AChE, it is 115 times more potent against this enzyme than against butyrylcholinesterase (BuChE). Moreover, CHF2819 is more selective for inhibition of central (brain) AChE than peripheral (heart) AChE. In vivo CHF2819, 0.5, 1.5, and 4.5 mg/kg p.o., significantly and in dose-dependent manner increased acetylcholine (ACh) levels in hippocampus of young adult rats. Moreover, aging animals, with lower basal ACh levels than young adult rats, also exhibit a marked increase in hippocampal levels of this neurotransmitter after administration of CHF2819. At 1.5 mg/kg p.o. CHF2819 attenuated scopolamine-induced amnesia in a passive avoidance task. Furthermore, it decreased dopamine (DA) levels and increased extracellular levels of 5-hydroxytryptamine (5-HT) in the hippocampus, without modifying norepinephrine (NE) levels. By oral administration to young adult rats CHF2819 did not affect extracellular hippocampal levels of glutamate (Glu), aspartate (Asp), gamma-aminobutyric acid (GABA), taurine (Tau), arginine (Arg) or citrulline (Cit). Functional observational battery (FOB) screening demonstrated that CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological endpoints (body weight and temperature). CHF2819 induced, however, involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose-dependent manner. The neurochemical and behavioral profiles of CHF2819 suggest that this orally active novel AChEI could be of clinical interest for the treatment of Alzheimer-type dementia associated with multiple neurotransmitter abnormalities in the brain. In particular, CHF2819 might be a useful therapeutic drug for AD patients with cognitive impairment accompanied by depression.
Trifaro, J. M. (2002). "Molecular biology of the chromaffin cell." Ann N Y Acad Sci 971: 11-8.
A large number of molecular biology studies have been performed on chromaffin cells, and many genes involved in catecholamine synthesis, storage, and release have been cloned and their function determined. Catecholamine synthesis takes place in different cellular compartments, and enzymes involved in this process are subject to a fine regulation, as demonstrated by recent studies on their gene promoters. Genes coding for such intravesicular proteins as chromogranin A, B, and secretogranin II (chromogranin C) are also regulated in response to a variety of stimuli. Chromogranin gene promoters and transcription factors involved in their regulation have been elucidated. This review serves as an introduction to the studies described in the chapters to follow.
Tsai, G. and J. T. Coyle (2002). "Glutamatergic mechanisms in schizophrenia." Annu Rev Pharmacol Toxicol 42: 165-79.
Schizophrenia is a chronic, severely disabling brain disorder with symptomatic onset in early adulthood. Typical antipsychotic medications that block dopamine D2 receptors are most effective in treating the psychosis but have limited effects on the negative symptoms and cognitive impairments. Considerable research has demonstrated that noncompetitive NMDA receptor antagonists, the dissociative anaesthetic like phencyclidine and ketamine, reproduce the cardinal symptomatic features of schizophrenia. Postmortem studies reveal variable alterations in glutamate receptors and their modulators in schizophrenia. Several clinical trials indicate agents that enhance NMDA receptor function via the glycine modulatory site reduce negative and variably improve cognitive function in schizophrenics receiving typical antipsychotics. Thus, hypofunction of a subpopulation of cortico-limbic NMDA receptors may participate in the pathophysiology of schizophrenia.
Tsuru, H., N. Tanimitsu, et al. (2002). "Role of perivascular sympathetic nerves and regional differences in the features of sympathetic innervation of the vascular system." Jpn J Pharmacol 88(1): 9-13.
Maintenance of blood pressure is mostly dependent on sympathetic "tone", and the sympathetic nerve innervates the entire vascular bed, excepting the capillaries. Although norepinephrine (NE) is the principal neurotransmitter released upon sympathetic nerve stimulation, neuropeptide Y and ATP are cotransmitters in various vascular tissues. In addition, dopamine and epinephrine, as well as acetylcholine, have been shown to be sympathetic neurotransmitters in specific vasculatures. Transmitter NE release is modified by a number of endogenous substances including the transmitter itself. Chronic denervation of the preganglionic fiber induces an increase in NE release per pulse, indicating postganglionic neuronal supersensitivity. So far, three main adrenoceptor types have been shown, alpha1, alpha2 and beta, each of which is further divided into at least three subtypes, as well as the alpha1L-adrenoceptor, a phenotype of the cloned alpha1a-adrenoceptor, in the blood vessel. Thus, the response of vessels with different receptor types to a transmitter varies quantitatively and even qualitatively from one vessel to another. The remarkable diversity in the sympathetic innervation mechanism in the vascular system may play an important role in regional variations in the regulation of blood flow. The sympathetic nerve also exerts long-term trophic action on the blood vessel. In conclusion, the sympathetic nervous system plays an important role not only in the regulation of cardiovascular dynamics but in the maintenance of the vessel structure, as well.
Turrone, P., G. Remington, et al. (2002). "The vacuous chewing movement (VCM) model of tardive dyskinesia revisited: is there a relationship to dopamine D(2) receptor occupancy?" Neurosci Biobehav Rev 26(3): 361-80.
Tardive dyskinesia (TD) is a late side effect of long-term antipsychotic use in humans, and the vacuous chewing movement (VCM) model has been used routinely to study this movement disorder in rats. Recent receptor occupancy studies in humans and rats have found that antipsychotics given in doses which lead to moderate levels of D(2) receptor blockade can achieve optimal clinical response while minimizing the emergence of acute motor side effects. This suggests that clinicians may have been using inappropriately high doses of antipsychotics. A review of the existing VCM literature indicates that most animal studies have similarly employed antipsychotic doses that are high, i.e. doses that lead to near complete D(2) receptor saturation. To verify whether the incidence or severity of VCMs would decrease with lower antipsychotic doses, we conducted initial experiments with different doses of haloperidol (HAL) given either as repeated daily injections or as depot injections over the course of several weeks. Our results demonstrate that (1) the incidence of VCMs is significantly related to HAL dose, and (2) significant levels of VCMs only emerge when haloperidol is continually present. These findings are consistent with the possibility that total D(2) occupancy, as well as 'transience' of receptor occupation, may be important in the development of late-onset antipsychotic-induced dyskinetic syndromes.
Ueda, S., S. Sakakibara, et al. (2002). "Vulnerability of monoaminergic neurons in the brainstem of the zitter rat in oxidative stress." Prog Brain Res 136: 293-302.
In the monograph of Santiago Ramon y Cajal, he provided a detailed description about the morphological changes in degeneration and regeneration of peripheral and central nervous systems following lesions. He discussed factors that may promote or inhibit axonal growth after peripheral and/or central nerve injury. Cajal with a brilliant insight anticipated the existence of several factors acting on degeneration and regeneration. Free radicals have been proposed to be one of such factors. These highly reactive oxygen species-derived free radicals play a pathogenetic role in neurological disorders, including ischemia, trauma, Alzheimer's disease and Parkinson's disease (PD). In this review we will discuss the similarities and differences between the morphological changes under oxidant stress and Cajal's drawings of degeneration and regeneration following the central injury. The monoaminergic neuron systems in the brainstem appear vulnerable to these free radicals, which have also been implicated in the selective degeneration of the nigrostriatal DA system. We analyzed the degeneration of fibers and the neuronal cell death of brainstem monoaminergic neuron systems in a mutant rat, which has abnormal metabolism of oxygen species in the brain. The degeneration of DA cell bodies and fibers was characterized by swollen varicosities and clustered fibers.
Uhl, G. R., F. S. Hall, et al. (2002). "Cocaine, reward, movement and monoamine transporters." Mol Psychiatry 7(1): 21-6.
Recent evidence enriches our understanding of the molecular sites of action of cocaine reward and locomotor stimulation. Dopamine transporter blockade by cocaine appears a sufficient explanation for cocaine-induced locomotion. Variation in DAT appears to cause differences in locomotion without drug stimulation. However, previously-held views that DAT blockade was the sole site for cocaine reward have been replaced by a richer picture of multitransporter involvement with the rewarding and aversive actions of cocaine. These new insights, derived from studies of knockout mice with simultaneous deletions and/or blockade of multiple transporters, provide a novel model for the rewarding action of this heavily-abused substance and implicate multiple monoamine systems in cocaine's hedonic activities.
Ujike, H. (2002). "Stimulant-induced psychosis and schizophrenia: the role of sensitization." Curr Psychiatry Rep 4(3): 177-84.
Three different conditions, psychostimulant-induced behavioral sensitization in rodents, psychostimulant-induced psychoses in human, and chronic schizophrenia show similar longitudinal alternations, progressively enhanced susceptibility to abnormal behaviors, psychotic state, and relapse. Sensitization phenomena to the drugs or endogenous dopamine should be involved in the mechanisms underlying the development of such susceptibility. Recently, an enhanced dopamine release in vivo by amphetamine administration in the striatum has been shown in schizophrenics, which is a replication of that previously proven in the behavioral sensitization in rats. Accordingly, common molecular mechanisms of sensitization phenomena must develop in these three conditions, and are overviewed in this review
van Harten, P. N. (2002). "[Drug-induced akathisia]." Ned Tijdschr Geneeskd 146(3): 110-4.
Akathisia (restlessness and characteristic movements of the legs) is one of the most disagreeable extrapyramidal side effects and often causes non-compliance. Dopamine blocking agents such as antipsychotics and antiemetics, may induce akathisia. Particular care must be taken to distinguish akathisia from psychotic agitation and restless legs. The prevalence of akathisia in patients using classical antipsychotics is 20-30% and for users of clozapine, olanzapine and quetiapine (atypical antipsychotics) it is lower. Risk factors are a high dosage of antipsychotics, akathisia in a previous treatment, and diabetes mellitus. The treatment of akathisia starts, if possible, with the antipsychotic being withdrawn or the dose administered being lowered. Another treatment possibility is switching to clozapine, olanzapine or quetiapine, or adding a beta-blocking agent, an anticholinergic or mianserin.
Vanitallie, T. B. (2002). "Stress: a risk factor for serious illness." Metabolism 51(6 Suppl 1): 40-5.
The body's principal adaptive responses to stress stimuli are mediated by an intricate stress system, which includes the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathoadrenal system (SAS). Dysregulation of the system, caused by the cumulative burden of repetitive or chronic environmental stress challenges (allostatic load) contributes to the development of a variety of illnesses including hypertension, atherosclerosis, and the insulin-resistance-dyslipidemia syndrome, as well as certain disorders of immune function. The brain's limbic system, particularly the hippocampus and amygdala, is also intimately involved in the stress response. Chronically elevated corticosteroid levels induced by persisting stress may adversely affect hippocampal structure and function, producing deficits of both memory and cognition. The ability of stress to cause illness in humans is most clearly exemplified by post-traumatic stress disorder (PTSD), which consists of a predictable constellation of distressing behavioral symptoms and physiological features. An appreciable proportion of the observed variance in vulnerability to PTSD is attributable to genetic factors. The relationship of this disorder to its precipitating cause-a recent, severely traumatic event-is unambiguous. The neuroendocrinology of PTSD is noteworthy, being characterized in many adult victims by enhanced negative feedback sensitivity of glucocorticoid receptors in the stress response system, and lower than normal urinary and plasma cortisol levels. Adult patients with PTSD also have been shown to exhibit exaggerated catecholamine responses to trauma-related stimuli. On the other hand, severely maltreated prepubertal children with PTSD continue to excrete greater than normal urinary cortisol, catecholamines, and dopamine years after disclosure of the causative abuse.
Velasco, M., F. Contreras, et al. (2002). "Dopaminergic receptors: a new antihypertensive mechanism." J Hypertens 20 Suppl 3: S55-8.
The neutrotransmitter dopamine, precursor of noradrenaline, induces a variety of cardiovascular and renal physiological responses, including an increase in myocardial contractility and cardiac output without changes in heart rate, passive and active vasodilatation, diuresis and natriuresis. These responses result from its interaction with the dopamine receptors D1, D2, D3, D4 and D5. In addition, recent findings suggest the existence of D6 and D7 receptors. In some types of hypertension dopamine is known to influence the control of arterial pressure by influencing the central and peripheral nervous system and target organs such as the kidneys and adrenal glands. Since dopamine and its derivatives have been shown to have antihypertensive effects, it is important to review the physiological and pharmacological aspects of dopamine and its receptors, and the clinical uses that they could have in the therapy of arterial hypertension.
Vermetten, E. and J. D. Bremner (2002). "Circuits and systems in stress. I. Preclinical studies." Depress Anxiety 15(3): 126-47.
This paper reviews the preclinical literature related to the effects of stress on neurobiological and neuroendocrine systems. Preclinical studies of stress provide a comprehensive model for understanding neurobiological alterations in post-traumatic stress disorder (PTSD). The pathophysiology of stress reflects long-standing changes in biological stress response systems and in systems involved in stress responsivity, learning, and memory. The neural circuitry involved includes systems mediating hypothalamic-pituitary-adrenal (HPA) axis, norepinephrine (locus coeruleus), and benzodiazepine, serotonergic, dopaminergic, neuropeptide, and central amino acid systems. These systems interact with brain structures involved in memory, including hippocampus, amygdala, and prefrontal cortex. Stress responses are of vital importance in living organisms; however excessive and/or repeated stress can lead to long-lasting alterations in these circuits and systems involved in stress responsiveness. Intensity and duration of the stressor, and timing of the stressor in life, have strong impact in this respect.
Verney, C., C. Lebrand, et al. (2002). "Changing distribution of monoaminergic markers in the developing human cerebral cortex with special emphasis on the serotonin transporter." Anat Rec 267(2): 87-93.
This article reviews the current knowledge of the early onset of the monoaminergic innervation in the developing cerebral cortex in humans and of changes in the distribution of tyrosine hydroxylase (TH) immunoreactivity in different neuronal populations of the developing telencephalon. The early genesis of the central monoaminergic neurons in mammals has led to postulations of a trophic role of monoamines in brain morphogenesis--especially in the cerebral cortex. The developmental effects of amines can be linked to the transient expression of different molecules linked to dopamine or serotonin neurotransmission. We present novel data on the immunocytochemistry of the vesicular monoamine transporter (VMAT2) and of the high-affinity serotonin transporter (SERT) in human fetuses. SERT is a marker of the serotoninergic axons and allows visualization of the serotonin afferents of the raphe in the human telencephalon. In addition, during a restricted time period corresponding to 12-14 postovulatory weeks, we found SERT-immunolabeled fibers in the rostral and caudal limbs of the internal capsule that do not correspond to serotoninergic fibers, but do coincide with the calbindin D28k-labeled thalamocortical fiber tracts. The present observations are correlated with findings in rodents, in which a transient expression of SERT is visible in the thalamocortical axons during early postnatal life. The function of this transporter has been shown to be important for the fine-tuning of cortical sensory maps during the critical period of development of these maps. Although the present observation does not allow ascertainment of which neurons transiently express SERT, it lends support to the notion that serotonin and serotonin uptake could have important developmental roles, during the formation of brain connections in humans, as they have in rodents.
Vizi, E. S. and I. J. Elenkov (2002). "Nonsynaptic noradrenaline release in neuro-immune responses." Acta Biol Hung 53(1-2): 229-44.
Evidence has recently been obtained that the branches of the autonomic nervous system, mainly, the sympathetic [25], regulate cytokine production. Not only the primary (thymus, bone marrow) and secondary (spleen, tonsils, and lymph nodes) lymphoid organs, but also many other tissues are involved in immune responses and are heavily influenced by noradrenaline (NA) derived from varicose axon terminals of the sympathetic nervous system [25, 100]. Besides NA released from nonsynaptic varicosities of noradrenergic terminals [92], circulating catecholamines (adrenaline, dopamine, NA) are also able to influence immune responses, the production of pro- and anti-inflammatory cytokines by different immune cells. The sympathetic nervous system (catecholamines) and the hypothalamic-pituitary-adrenal (HPA) axis (cortisol) are the major integrative and regulatory components of different immune responses. In our laboratory convincing evidence has been obtained that NA released non-synaptically [90, 92] from sympathetic axon terminals and enhanced in concentration in the close proximity of immune cells is able to inhibit production of proinflammatory (TNF-alpha, IFN-gamma, IL-12, IL-1) and increase antiinflammatory cytokines (IL-10) in response to LPS [25, 91], indicating a fine-tuning control of the production of TNF-alpha and other cytokines by sympathetic innervation under stressful conditions. This effects are mediated via beta2-adrenoceptors expressed on immune cells and coupled to cAMP levels.
Vleeming, W., B. Rambali, et al. (2002). "The role of nitric oxide in cigarette smoking and nicotine addiction." Nicotine Tob Res 4(3): 341-8.
The purpose of this study is to describe the interrelationship between nitric oxide (NO) and nicotine in cigarette smoking addiction, in view of the underlying hypothesis that NO contributes to smoking (nicotine) addiction, and to suggest the ways to improve prevention as well as cessation strategies. A literature search of Medline using the keywords nicotine and nitric oxide covering 1995 to May 2001 was made. Further information not obtained from the Medline search was derived from the references cited in these publications. Smokers are exposed first to high concentrations of inhaled NO from smoke and, second, to endogenously released NO after uptake of nicotine into the brain. As a result, the basal endogenous NO synthesis in airways and blood vessels of smokers is reduced. Subsequently, because NO is involved in maintaining airway dilatation, smokers may have constricted airways. During smoking, however, NO from smoke may dilate the constricted airways, allowing the smoke an easier passage into the lungs, and exposing the body and the brain to more nicotine. NO can endogenously be released by nicotine from nervous tissue, and may decrease the sympathetic output of the brain, which is associated with stress reduction. This second form of exposure to NO also inhibits the re-uptake of dopamine, which may contribute to dopaminergic receptor stimulation and thus to the acute rewarding effects of nicotine. The important role of NO in nicotine addiction is further supported by the finding that in animals NO synthase (NOS) inhibitors attenuate symptoms of the nicotine abstinence syndrome. NO may contribute to the development of cigarette smoking and nicotine addiction since: (1) inhaled NO from smoke may be able to increase nicotine absorption, (2) NO released through nicotine reduces symptoms of stress, (3) NO endogenously released by nicotine increases post-synaptic dopamine levels, and (4) NOS inhibitors attenuate symptoms of the nicotine abstinence syndrome. It remains to be determined whether reducing the NO content in cigarette smoke may reduce nicotine absorption. It also needs to be clarified whether NOS inhibitors or a low L-arginine diet might be useful in the treatment of nicotine addiction.
Volkow, N. D., J. S. Fowler, et al. (2002). "Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies." Behav Pharmacol 13(5-6): 355-66.
The involvement of dopamine (DA) in drug reinforcement is well established, but much less in known about its contribution to addiction. We have used positron emission tomography to investigate in humans the role of DA in drug reinforcement, addiction and drug vulnerability. We have shown that during drug intoxication increases in striatal DA are associated with the drug's reinforcing effects only if the DA changes occur rapidly. These results corroborate the relevance of drug-induced DA increases and of pharmacokinetics in the rewarding effects of drugs in humans. During withdrawal, we have shown significant reductions in DA D(2) receptors and in DA release in drug abusers, which is likely to result in decreased sensitivity to non-drug-related reinforcing stimuli. The DA D(2) reductions were associated with decreased activity in the orbitofrontal cortex, which we postulate is one of the mechanisms underlying compulsive drug administration in the addict. In fact, during craving the orbitofrontal cortex becomes hyperactive in proportion to the desire for the drug. In non-drug-abusing subjects striatal DA D(2) receptors levels predicted the reinforcing responses to stimulant drugs, providing evidence that striatal DA D(2) receptors modulate reinforcing responses to stimulants in humans and may contribute to the predisposition for drug self-administration.
Wainwright, P. E. (2002). "Dietary essential fatty acids and brain function: a developmental perspective on mechanisms." Proc Nutr Soc 61(1): 61-9.
Brain development is a complex interactive process in which early disruptive events can have long-lasting effects on later functional adaptation. It is a process that is dependent on the timely orchestration of external and internal inputs through sophisticated intra- and intercellular signalling pathways. Long-chain polyunsaturated fatty acids (LCPUFA), specifically arachidonic acid and docosahexaenoic acid (DHA), accrue rapidly in the grey matter of the brain during development, and brain fatty acid (FA) composition reflects dietary availability. Membrane lipid components can influence signal transduction cascades in various ways, which in the case of LCPUFA include the important regulatory functions mediated by the eicosanoids, and extend to long-term regulation through effects on gene transcription. Our work indicates that FA imbalance as well as specific FA deficiencies can affect development adversely, including the ability to respond to environmental stimulation. For example, although the impaired water-maze performance of mice fed a saturated-fat diet improved in response to early environmental enrichment, the brains of these animals showed less complex patterns of dendritic branching. Dietary n-3 FA deficiency influences specific neurotransmitter systems, particularly the dopamine systems of the frontal cortex. We showed that dietary deficiency of n-3 FA impaired the performance of rats on delayed matching-to-place in the water maze, a task of the type associated with prefrontal dopamine function. We did not, however, find an association over a wider range of brain DHA levels and performance on this task. Some, but not all, studies of human infants suggest that dietary DHA may play a role in cognitive development as well as in some neurodevelopmental disorders; this possibility has important implications for population health.
Wakamatsu, K. and S. Ito (2002). "Advanced chemical methods in melanin determination." Pigment Cell Res 15(3): 174-83.
Among the biopolymers, melanins are unique in many respects. The other essential biopolymers - proteins, nucleic acids, and carbohydrates - are chemically well characterized; their precursors (monomer units) and modes of connection between the monomer units are known, and sequences of their connection can be determined with well-established methodologies. In contrast, we still do not have a method to determine accurately the ratio of various units present in melanins. This is largely because of the chemical properties of melanins, such as their insolubility over a broad range of pH, the heterogeneity in their structural features, and also because of the lack of methods that can split melanin polymers into their monomer units (all other biopolymers can be hydrolysed to the corresponding monomer units). To overcome this difficulty, we developed a rapid and sensitive method for quantitatively analysing eumelanin and pheomelanin in biological samples by chemical degradation methods followed by HPLC determination. This HPLC microanalytical method for characterizing eumelanin and pheomelanin has become a useful tool for the study of melanogenesis. This review will summarize the usefulness and limitations of the various chemical and spectrophotometric methods used to analyse melanins at the biochemical, cellular, and tissue levels. Emphasis is given on the usefulness of 4-amino-3-hydroxyphenylalanine as a specific marker of pheomelanin.
Walther, B. W. (2002). "Treating restless legs syndrome: current pathophysiological concepts and clinical trials." Expert Opin Investig Drugs 11(4): 501-14.
Restless legs syndrome is a distinctive clinical syndrome with a prevalence of about 5% in the general population. One of the outstanding characteristics of restless legs syndrome is its extreme responsiveness to dopaminergic agents. Together with the latest pathophysiological and genetic findings, recent epidemiological and clinical data give a new insight into the classification of restless legs syndrome, thus building the theoretical foundation for the development of new pharmacological methods in its treatment. Current efforts within this area focus on establishing dopaminergic substances for therapy. The hypothesis of a disturbed iron metabolism in restless legs syndrome has been revived by recent theoretical considerations. The present review attempts to explain current strategies of treatment for restless legs syndrome in relation to aetiological, genetic and pathophysiological findings.
Wang, Z. Y. and G. E. Bisgard (2002). "Chronic hypoxia-induced morphological and neurochemical changes in the carotid body." Microsc Res Tech 59(3): 168-77.
The carotid body (CB) plays an important role in the control of ventilation. Type I cells in CB are considered to be the chemoreceptive element which detects the levels of PO(2), PCO(2), and [H(+)] in the arterial blood. These cells originate from the neural crest and appear to retain some neuronal properties. They are excitable and produce a number of neurochemicals. Some of these neurochemicals, such as dopamine and norepinephrine, are considered to be primarily inhibitory to CB function and others, such as adenosine triphosphate, acetylcholine, and endothelin, are thought to be primarily excitatory. Chronic hypoxia (CH) induces profound morphological as well as neurochemical changes in the CB. CH enlarges the size of CB and causes hypertrophy and mitosis of type I cells. Also, CH changes the vascular structure of CB, including inducing marked vasodilation and the growth of new blood vessels. Moreover, CH upregulates certain neurochemical systems within the CB, e.g., tyrosine hydroxylase and dopaminergic activity in type I cells. There is also evidence that CH induces neurochemical changes within the innervation of the CB, e.g., nitric oxide synthase. During CH the sensitivity of the CB chemoreceptors to hypoxia is increased but the mechanisms by which the many CH-induced structural and neurochemical changes affect the sensitivity of CB to hypoxia remains to be established.
Waterwort, D. M., A. S. Bassett, et al. (2002). "Recent advances in the genetics of schizophrenia." Cell Mol Life Sci 59(2): 331-48.
The genetic etiology of schizophrenia, a common and debilitating psychiatric disorder, is supported by a wealth of data. Review of the current findings suggests that considerable progress has been made in recent years, with a number of chromosomal regions consistently implicated by linkage analysis. Three groups have shown linkage to 1q21-22 using similar models, with HLOD scores of 6.5, 3.2, and 2.4. Other replicated loci include 13q32 that has been implicated by two independent groups with significant HLOD scores (4.42) or NPL values (4.18), and 5pl4.1-13.1, 5q21-33, 8p2l-22, and 10p11-15, each of which have been reported as suggestive by at least three separate groups. Different studies have also replicated evidence for a modest number of candidate genes that were not ascertained through linkage. Of these, the greatest support exists for the DRD3 (3q13.3), HTR2A (13q14.2), and CHRNA7 (15q13-q14) genes. The refinement of phenotypes, the use of endophenotypes, reduction of heterogeneity, and extensive genetic mapping have all contributed to this progress. The rapid expansion of information from the human genome project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia. A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in therapeutic interventions.
Weinshenker, D. and P. Szot (2002). "The role of catecholamines in seizure susceptibility: new results using genetically engineered mice." Pharmacol Ther 94(3): 213-33.
The catecholamines norepinephrine and dopamine are abundant in the CNS, and modulate neuronal excitability via G-protein-coupled receptor signaling. This review covers the history of research concerning the role of catecholamines in modulating seizure susceptibility in animal models of epilepsy. Traditionally, most work on this topic has been anatomical, pharmacological, or physiological in nature. However, the recent advances in transgenic and knockout mouse technology provide new tools to study catecholamines and their roles in seizure susceptibility. New results from genetically engineered mice with altered catecholamine signaling, as well as possibilities for future experiments, are discussed.
Weiss, F. and L. J. Porrino (2002). "Behavioral neurobiology of alcohol addiction: recent advances and challenges." J Neurosci 22(9): 3332-7.
Addictive behavior associated with alcoholism is characterized by compulsive preoccupation with obtaining alcohol, loss of control over consumption, and development of tolerance and dependence, as well as impaired social and occupational functioning. Like other addictive disorders, alcoholism is characterized by chronic vulnerability to relapse after cessation of drinking. To understand the factors that compel some individuals to drink excessively, alcohol research has focused on the identification of brain mechanisms that support the reinforcing actions of alcohol and the progression of changes in neural function induced by chronic ethanol consumption that lead to the development of dependence. More recently, increasing attention has been directed toward the understanding of neurobiological and environmental factors in susceptibility to relapse.
Westerink, B. H. (2002). "Can antipsychotic drugs be classified by their effects on a particular group of dopamine neurons in the brain?" Eur J Pharmacol 455(1): 1-18.
During the four decades that research has been carried out on antipsychotic drugs, a variety of methods have been used to study the effects of these compounds on dopamine neurotransmission. An important issue in this research was to find an explanation for the difference between "typical" and "atypical" antipsychotic drugs. The hypothesis that the beneficial properties and the motor side effects of antipsychotic drugs result from their effects on different groups of dopamine neurons has received considerable attention. Numerous researchers have tried to discover regiospecific actions of antipsychotic drugs in mesolimbic and in mesocortical dopamine neurons. An overview of these research attempts is presented here. Electrophysiological studies showed a selective action of atypical antipsychotic drugs on A10 dopamine neurons. It was found that chronic treatment with these compounds induced a preferential depolarisation block of the A10 neurons that project to the mesolimbic areas. The model represents certain clinical features of antipsychotic drug use and offers a possible explanation for the lack of extrapyramidal side effects of atypical antipsychotic drugs. Dopamine neurons projecting from A10 to the frontal cortex are also considered as a possible site of action of atypical antipsychotic drugs. Microdialysis studies have shown that certain atypical antipsychotic drugs selectively enhance the release of dopamine in the prefrontal cortex when compared with typical antipsychotic drugs. The finding that repeated treatment with antipsychotic drugs increased dopamine D(2) receptor binding in the frontal cortex confirms the significance of this brain area. These properties might indeed explain certain beneficial effects of atypical antipsychotic drugs such as improvement of cognitive dysfunction. However the effects of typical and atypical antipsychotic drugs in the frontal cortex could not be fully differentiated, which illustrates the difficulty of localising clinical effects of antipsychotic drugs in terms of regional dopamine neurons. Recently new insights into the mechanism of action of typical and atypical antipsychotic drugs have been published. Clinical positron emission tomography (PET) studies have indicated that a moderate dopamine D(2) receptor occupancy, probably combined with a high dissociation rate, might provide the optimal clinical conditions for an antipsychotic drug, without inducing extrapyramidal side effects. Moreover the efficacy of benzamides as atypical antipsychotic drugs suggests that low to moderate dopamine D(2) blockade is probably the most important-if not the only-criterion that determines "atypicality". Interestingly these new insights are based on PET studies of the human basal ganglia and not on the comparison of different brain areas. Apparently, according to this concept an ideal antipsychotic drug need not to act on a particular type of dopamine neurons, as it is the moderate dopamine D(2) receptor occupancy that determines the desirable clinical effects. It is concluded that both beneficial actions and side effects, of antipsychotic drugs might be dose dependently localised in A9 as well as A10 dopamine neurons.
Westkaemper, R. B. and R. A. Glennon (2002). "Application of ligand SAR, receptor modeling and receptor mutagenesis to the discovery and development of a new class of 5-HT(2A) ligands." Curr Top Med Chem 2(6): 575-98.
The present review describes our approach to the development of a structurally unique class of 5-HT(2A) ligands. On the basis of an abbreviated graphics model of a 5-HT(2A) serotonin receptor, it was hypothesized that introduction of an additional aromatic ring might enhance the affinity of phenylethylamine (an agent that lacks significant affinity for the 5-HT(2A) receptors). Continued work with such structures, and the continual refinement of graphics receptor models, ultimately led to the identification of AMDA (27, 5-HT(2A) K(i) = 20 nM). AMDA is a 5-HT(2A) antagonist that, unlike certain other tricyclic 5-HT(2A) antagonists, binds with very low affinity at dopamine D(2) receptors, the serotonin transporter, and the norepinephrine transporter. Comparative structure-affinity studies indicate that AMDA binds in a manner distinct from the tricyclic antagonists Graphics models were employed to identify possible modes of binding. This investigation illustrates the impact of a combination of classical medicinal chemistry, receptor modeling, and molecular biology on novel drug design.
Wheatley, K., R. L. Stowe, et al. (2002). "Evaluating drug treatments for Parkinson's disease: how good are the trials?" Bmj 324(7352): 1508-11.
Whitehorn, D. and L. C. Kopala (2002). "Neuromotor dysfunction in early psychosis." Ann Clin Psychiatry 14(2): 113-21.
Neuromotor dysfunction, particularly extrapyramidal signs and symptoms (EPSS), plays an important role in the assessment and treatment of patients in the early stages of psychotic disorders such as schizophrenia. By blocking dopamine D2 receptors, antipsychotic medications can produce EPSS, including tardive dyskinesia. EPSS is also observed in a third or more of patients first presenting with a psychotic disorder, prior to initiation of antipsychotic pharmacotherapy. This suggests that abnormalities in neuromotor control may be an integral component of the brain mechanisms associated with psychosis. Atypical antipsychotic agents can alleviate psychosis without inducing EPSS. Preexisting EPSS may be corrected.
Wightman, R. M. and D. L. Robinson (2002). "Transient changes in mesolimbic dopamine and their association with 'reward'." J Neurochem 82(4): 721-35.
Mesolimbic dopaminergic neurons modulate complex circuitry in the ventral forebrain involved in reward processing, although the precise function of the dopaminergic input is debated. Electrophysiological measurements have revealed that mesolimbic dopaminergic neurons can fire in either tonic or phasic modes, and that phasic firing accompanies the alerting or anticipatory phases of reward. However, the neurochemical relevance of this rapid neuronal discharge within the reward processing circuitry is not yet clear, in part because of difficulty in interpretation of extracellular dopamine measurements. Herein, the nature of the information provided by different neurochemical techniques is critically discussed. Classical methods of monitoring dopamine reveal changes in extracellular dopamine resulting from tonic neuronal activity, but do not have the temporal resolution to distinguish concentration transients. However, recent advances in dopamine sensors now enable transient dopamine concentrations resulting from phasic firing to be positively identified and followed on a physiologically relevant timescale. This has enabled demonstrations of discrete, phasic dopamine signals accompanying rewarding or alerting stimuli. Thus, enhanced dopamine release at terminals appears to be coincident with phasic electrical activity at cell bodies. These accumulating data promise to help unravel the precise role of phasic dopamine transmission in reward processing.
Wise, R. A. (2002). "Brain reward circuitry: insights from unsensed incentives." Neuron 36(2): 229-40.
The natural incentives that shape behavior reach the central circuitry of motivation trans-synaptically, via the five senses, whereas the laboratory rewards of intracranial stimulation or drug injections activate reward circuitry directly, bypassing peripheral sensory pathways. The unsensed incentives of brain stimulation and intracranial drug injections thus give us tools to identify reward circuit elements within the associational portions of the CNS. Such studies have implicated the mesolimbic dopamine system and several of its afferents and efferents in motivational function. Comparisons of natural and laboratory incentives suggest hypotheses as to why some habits become compulsive and give insights into the roles of reinforcement and of prediction of reinforcement in habit formation.
Wong, M. G., B. G. Tehan, et al. (2002). "Molecular mapping in the CNS." Curr Pharm Des 8(17): 1547-70.
Since ancient times the operation of the brain has elicited more than usual interest. Data mining of the human genome is revealing that many CNS abnormalities have a genetic component. As yet this information can not be used directly to cure or ameliorate specific CNS disorders although this is regarded as having great potential for future therapies. Current CNS drug design and 3D QSAR is based on knowing either the structures of key proteins and how smaller molecules interact with them to obtain a pharmacological response, or on hypothesising about key structural features and interactions by a variety of molecular modelling and computational techniques. Methods used include conformational analyses, pharmacophore development and QSAR which are now being actively applied to increase our understanding of how molecules interact with specific sites within the CNS as a basis for the design of new pharmacologically active compounds. In this review we give an overview of the latest strategies used in 3D-QSAR based drug design and survey the most recent applications of these strategies to the CNS. By way of example, accounts are given of computer-based research aimed at drugs targeting GABA, glutamate, dopamine and opioid receptors.
Woolacott, N. F., L. Jones, et al. (2002). "The clinical effectiveness and cost-effectiveness of bupropion and nicotine replacement therapy for smoking cessation: a systematic review and economic evaluation." Health Technol Assess 6(16): 1-245.
Wullimann, M. F. and E. Rink (2002). "The teleostean forebrain: a comparative and developmental view based on early proliferation, Pax6 activity and catecholaminergic organization." Brain Res Bull 57(3-4): 363-70.
An improved comparative interpretation of the teleostean forebrain suggests that the dorsal tier (Vd,Vc) and ventral tier (Vv,Vl) nuclei of the ventral telencephalic area (subpallium) represent the striatum and septum, respectively. Among other arguments, a dopaminergic innervation originating in the diencephalic posterior tubercle reaches Vd and dense efferents of Vv project to the midline hypothalamus in the adult zebrafish subpallium. The adult area dorsalis telencephali represents the teleostean pallium. Regulatory genes typically expressed in the early amniote subpallium (e.g., Dlx-1) are also restricted to the presumptive zebrafish ventral telencephalic area. Further, early Pax6 protein distribution in the zebrafish telencephalon corresponds to the migrating stream noted at the pallial-subpallial boundary in amniotes, but a ventricular, radial glia-based expression in the pallium is absent. The peripherally migrated, adult diencephalic preglomerular complex of the basal plate posterior tubercle (early: M2) provides sensory inputs to the pallium. Early Pax6 protein distribution indicates that at least part of M2 may directly originate from alar plate ventral thalamic Pax6-expressing cells. Dopaminergic cells of the basal plate posterior zebrafish forebrain (P1-P3) are restricted to the ventral thalamic prosomere (P3), including those forming the adult ascending dopaminergic system. Moreover, the latter likely depend developmentally on the dorsally adjacent alar plate Pax6-expressing cells.
Xi, Z. X. and E. A. Stein (2002). "GABAergic mechanisms of opiate reinforcement." Alcohol Alcohol 37(5): 485-94.
The neurobiological mechanisms of opiate-induced reinforcement are still not completely understood. Over the past two decades, the vast majority of studies have focused on the role of the mesolimbic dopamine (DA) system. However, current studies strongly suggest that opiate actions on gamma-aminobutyric acid (GABA)-ergic cells in both the ventral tegmental area (VTA) and the nucleus accumbens (NAcc) appear to play critical roles. In this review, we focus on the neurochemical substrates of opiate reinforcement and review the role of DA and non-DA substrates, including opioid, GABA, glutamate and serotonin on opiate-reinforced behaviour and the activity of dopaminergic and GABAergic neurons in the VTA and the NAcc.
Yager, J. Y. and D. S. Hartfield (2002). "Neurologic manifestations of iron deficiency in childhood." Pediatr Neurol 27(2): 85-92.
Iron deficiency is a common disorder in pediatric patients. Although the most common manifestation is that of anemia, iron deficiency is frequently the source of a host of neurologic disorders presenting to general pediatric neurologic practices. These disorders include developmental delay, stroke, breath-holding episodes, pseudotumor cerebri, and cranial nerve palsies. Although frequent, the identification of iron deficiency as part of the differential diagnosis in these disorders is uncommon and frequently goes untreated. The purpose of the current review is to highlight what is understood regarding iron deficiency and it's underlying pathophysiology as it relates to the brain, and the association of iron deficiency with common neurologic pediatric disease.
Yarlagadda, A. (2002). "Role of calcium regulation in pathophysiology model of schizophrenia and possible interventions." Med Hypotheses 58(2): 182-6.
Recent advances into the neuroscience research related to pathophysiology of schizophrenia have been impressive. While some are based on pre-existing theories and models, others have explored on a molecular level attempting to integrate the concepts of the past and present. However, given the complex multifactorial etiology of schizophrenia attempts to improve the current treatment modalities raise more questions than answers. In the cascade model of the hypotheses, the focus will be on a common factor/marker for the disease, to address the possible stepwise correlation between the various theories. Homeostasis of calcium, its relation to the release of glutamate, dopamine and nitric oxide will be discussed in detail with the potential for interventions aimed at every stage. Although this hypothesis emphasizes the role of calcium as a common factor, other potential causes such as autoantibodies to the receptors, such as NMDA (and GABA) cannot be ruled out.
Yelnik, J. (2002). "Functional anatomy of the basal ganglia." Mov Disord 17 Suppl 3: S15-21.
Four organizational levels of the basal ganglia that could be particularly determinant in terms of functional properties are reviewed: (1) macroscopic anatomy, which is characterized by a dramatic decrease of cerebral tissue volume from the cerebral cortex to the deepest portions of the basal ganglia; (2) connectivity, which consists of both complex loops and a partition into three territories, sensorimotor, associative, and limbic (which process motor, cognitive, and emotional information, respectively); (3) neuronal morphology, characterized by a dramatic numeric and geometric convergence of striatal neurons onto pallidonigral neurons; and (4) dopaminergic innervation of the basal ganglia, which is organized as a dual system that is supposed to have opposite effects on the activity of the system. Current models of the basal ganglia are discussed.
Zhou, F. M., C. J. Wilson, et al. (2002). "Cholinergic interneuron characteristics and nicotinic properties in the striatum." J Neurobiol 53(4): 590-605.
The neostriatum (dorsal striatum) is composed of the caudate and putamen. The ventral striatum is the ventral conjunction of the caudate and putamen that merges into and includes the nucleus accumbens and striatal portions of the olfactory tubercle. About 2% of the striatal neurons are cholinergic. Most cholinergic neurons in the central nervous system make diffuse projections that sparsely innervate relatively broad areas. In the striatum, however, the cholinergic neurons are interneurons that provide very dense local innervation. The cholinergic interneurons provide an ongoing acetylcholine (ACh) signal by firing action potentials tonically at about 5 Hz. A high concentration of acetylcholinesterase in the striatum rapidly terminates the ACh signal, and thereby minimizes desensitization of nicotinic acetylcholine receptors. Among the many muscarinic and nicotinic striatal mechanisms, the ongoing nicotinic activity potently enhances dopamine release. This process is among those in the striatum that link the two extensive and dense local arbors of the cholinergic interneurons and dopaminergic afferent fibers. During a conditioned motor task, cholinergic interneurons respond with a pause in their tonic firing. It is reasonable to hypothesize that this pause in the cholinergic activity alters action potential dependent dopamine release. The correlated response of these two broad and dense neurotransmitter systems helps to coordinate the output of the striatum, and is likely to be an important process in sensorimotor planning and learning.
Zhu, B. T. (2002). "Catechol-O-Methyltransferase (COMT)-mediated methylation metabolism of endogenous bioactive catechols and modulation by endobiotics and xenobiotics: importance in pathophysiology and pathogenesis." Curr Drug Metab 3(3): 321-49.
The metabolic O-methylation of endogenous catecholamines and other catechols catalyzed by catechol-O-methyltransferase (COMT; EC 2.1.1.6) was first described by Dr. Julix Axelrod and his colleagues almost half a century ago. In the past several years, research interest in this catechol-metabolizing system has been renewed because of its potential pathophysiological and pathogenic significance in estrogen-induced hormonal cancers, in the development of degenerative brain disorders, as well as in the development of cardiovascular diseases. In this review paper, I provide a brief overview of the COMT metabolic system, with particular attentions being paid to the following three areas: (i) the regulation of this catechol-metabolizing system by endogenous regulatory factors (mainly S-adenosyl-L-homocysteine and homocysteine) as well as by exogenous factors such as dietary phytochemicals; (ii) decreased metabolic O-methylation of endogenous catecholamines as an important risk factor for the development of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases in the elderly and also as a risk factor for the development of a variety of cardiovascular diseases; and (iii) the relative importance of the COMT-catalyzed O-methylation metabolism of endogenous catechol estrogens in the causation and prevention of estrogen-induced hormonal cancers. Some unifying hypotheses are also discussed in this paper with the hope that they may provide useful mechanistic insights into our understanding of the biological functions that are associated with this important metabolic system.
Zullino, D., P. Delacrausaz, et al. (2002). "[The place of SSRIs in the treatment of schizophrenia]." Encephale 28(5 Pt 1): 433-8.
One of the major clinical challenges in the treatment of schizophrenia is the treatment of negative symptoms, which are particularly associated with poor long-term outcome. Clozapine is often effective in the treatment of a great proportion of previously neuroleptic refractory patients. Its utility is, however, limited by the high risk of agranulocytosis. Depressive and negative symptoms such as anhedonia, lack of interest, motor retardation and social withdrawal show some overlap. Because of the similarities between negative and depressive symptoms in schizophrenic patients and the success of antidepressants in the treatment of depressive symptoms in schizophrenic disorders, the augmentation of antipsychotics by SSRI antidepressants has repeatedly been suggested as a promising strategy in schizophrenic patients with negative symptoms. Besides several open studies, five controlled trials of the effect of SSRI addition to current treatment with classic neuroleptic agents, have been published. They reveal some evidence for increased efficacy of conventional antipsychotics after addition of SSRIs. Neither placebo-controlled studies nor open trials have revealed additional efficacy of antipsychotic/SSRI combination on the positive symptoms or depressive symptoms in comparison with antipsychotic treatment alone, but the patients in the reviewed studies had been generally selected for their prominent negative symptoms, their neuroleptic resistance or their chronicity. There seems to be, however, clear evidence supporting the efficacy of SSRI augmentation of conventional antipsychotics in the treatment of negative schizophrenic symptoms. The data on clozapine reveal no additional therapeutic potential if pharmacokinetic interactions are controlled for. Path analysis allows an estimate whether, and to which degree, the effect of a treatment on a symptom is mediated by effects on other symptoms. Path analysis has, though, not been reported for antipsychotic/SSRI combinations until now. Nevertheless, SSRI augmentation in the treatment of schizophrenia seems to act directly, has only limited efficacy in treating depressive symptoms, and does not seem to have an effect on positive symptoms or EPS. Furthermore, there is no evidence for an increased efficacy due to increased plasma levels of typical neuroleptics. A paradox exists, as both the serotonin-agonists and antagonists produce similar effects in combination with dopamine-blocking drugs. As reasons for this paradox have been proposed: the complexity of multiple 5HT receptor types, their differing distribution, their different serotonin-affinity and their partly divergent postsynaptic effects. In conclusion, some inferences can be made despite the limitations of the data. There is some evidence for increased efficacy of conventional antipsychotics in negative symptoms after addition of SSRIs, and, whereas path analyses are still lacking, this seems to be a direct effect. SSRIs may be an alternative to clozapine, especially in patients for whom there are contraindications for a clozapine treatment. As yet, there is no convincing rationalization for the paradox that both serotonergic and antiserotonergic substances, e.g. atypical antipsychotics, may improve negative symptoms.
Zwar, N. and R. Richmond (2002). "Bupropion sustained release. A therapeutic review of Zyban." Aust Fam Physician 31(5): 443-7.
BACKGROUND: Originally developed as an antidepressant, bupropion hydrochloride is a selective re-uptake inhibitor of dopamine and noradrenalin which was found to reduce nicotine withdrawal symptoms and the urge to smoke. Bupropion came onto the Australian market in November 2000 as a 150 mg sustained release preparation to be used as an aid to smoking cessation in combination with counselling. Following the PBS listing in February 2001, there was a dramatic increase in prescribing, and considerable public and professional attention focused on this drug. OBJECTIVE: This review summarises the evidence on how bupropion sustained release (SR) works, its contraindications and risks, adverse effects, studies on efficacy and place in smoking cessation pharmacotherapy. DISCUSSION: Bupropion SR is a useful oral and non-nicotine form of pharmacotherapy for smoking cessation. Efficacy has been demonstrated in two key published trials. In one of these trials efficacy was superior to nicotine patch. There is also evidence of efficacy in patients with mild to moderate chronic obstructive pulmonary disease. Bupropion SR is contraindicated in a number of conditions where there is an increased risk of seizures. This includes patients with a current seizure disorder or any history of seizures. It must not be used concurrently with monoamine oxidase inhibitors and interacts with medications which can lower the seizure threshold. Minor adverse effects such as insomnia, headache, dry mouth and nausea are common. Serious adverse effects are rare but include seizures (risk of 1/1000) and hypersensitivity reactions. The latter can manifest as skin rash and a serum sickness-like reaction.