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Dopamine Reviews: 2003

(230 References)

(2003). "Alzheimer's disease: emerging noncholinergic treatments." Geriatrics 58 Suppl: 3-14, inside back cover.
With population trends skewing toward a larger percentage of elderly, Alzheimer's disease is projected to afflict many millions in the United States and around the world in the next 50 years. In terms of cost and psychological burden, the anticipated burden of this disease on caregivers and society at large is staggering. It is hoped that, with the development of new insights into the processes of this devastating illness and the development of new medications that may interrupt those processes, the projected incidence and impact of AD may be modified in the near future.

Adir, Y. and J. I. Sznajder (2003). "Regulation of lung edema clearance by dopamine." Isr Med Assoc J 5(1): 47-50.
In the kidney, dopamine inhibits Na,K-ATPase, which results in natriuresis because less Na+ is reabsorbed by the proximal and distal tubules. In contrast, dopamine stimulates Na,K-ATPase activity in the alveolar epithelium, leading to increased alveolar fluid reabsorption. Importantly, dopamine increases alveolar fluid reabsorption not only in normal alveolar epithelium but also in models of lung injury. Dopamine short-term regulation of alveolar epithelial Na,K-ATPase occurs via D1 receptor activation, protein kinase C and protein phosphatase 2A pathways, leading to increased Na,K-ATPase activity by recruiting sodium pumps from the intracellular compartment to the basolateral membranes. Conversely, D2 receptor activation by long-term dopamine regulates (approximately 24 hours) alveolar epithelial Na,K-ATPase via the MAPK pathway, [figure: see text] which results in de novo synthesis of Na,K-ATPase proteins. Conceivably, by increasing Na,K-ATPase activity and promoting alveolar fluid reabsorption, dopamine can be of clinical relevance for the treatment of patients with acute hypoxemic respiratory failure due to pulmonary edema.

Agid, Y., I. Arnulf, et al. (2003). "Parkinson's disease is a neuropsychiatric disorder." Adv Neurol 91: 365-70.

Ahlskog, J. E. (2003). "Slowing Parkinson's disease progression: recent dopamine agonist trials." Neurology 60(3): 381-9.
In recent clinical trials, chronic treatment of patients with PD with pramipexole or ropinirole was associated with a slower decline of imaged striatal dopaminergic signal, compared to levodopa monotherapy. Although this could reflect slowed progression of PD, equally plausible is a pharmacologic effect on proteins that interact with the imaging radioligands. To date, there is no compelling evidence favoring dopamine agonists over levodopa; either is an appropriate choice for initial treatment of PD.

Albin, R. L. and K. A. Frey (2003). "Initial agonist treatment of Parkinson disease: a critique." Neurology 60(3): 390-4.
The evidence supporting initial dopamine agonist treatment of PD is reviewed. The two rationales for initial agonist treatment are reduced frequency of motor complications and possible relative neuroprotection by dopamine agonists. The basic science supporting these rationales is equivocal. The clinical evidence for advantages of initial agonist treatment is incomplete. More data are required to determine the optimal initial treatment for PD.

Areosa, S. A. and F. Sherriff (2003). "Memantine for dementia." Cochrane Database Syst Rev(1): CD003154.
BACKGROUND: Alzheimer's disease, vascular and mixed dementia are the commonest forms of dementia in older people. There is evidence that the excitatory activity of L-glutamate plays a role in the pathogenesis of Alzheimer's disease and in the damage from an ischaemic stroke. A low affinity antagonist to N-Methyl-D-aspartate (NMDA) type receptors, such as memantine, may prevent excitatory amino acid neurotoxicity without interfering with the physiological actions of glutamate required for memory and learning. OBJECTIVES: To determine the clinical efficacy and safety of memantine for people with Alzheimer's disease, vascular, or mixed dementia. SEARCH STRATEGY: Trials were identified from a search of the Trial-based Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 9 October 2002 using the terms: memantin*, D-145, DMAA, DRG-0267. All major health care databases and trial databases within the scope of the group are searched regularly to keep this Register up to date. SELECTION CRITERIA: Double-blind, parallel group, placebo-controlled, randomized and unconfounded trials in which memantine was administered to people with dementia. DATA COLLECTION AND ANALYSIS: Data were extracted, pooled where possible, and weighted mean differences, standardized mean differences or odds ratios were estimated. Intention-to-treat (ITT) and observed cases (OC) analyses are reported, where data were available. MAIN RESULTS: There were a total of seven trials that met inclusion criteria, of which five had sufficient data for analysis. The analysis of change from baseline for cognition gave statistically significant results in favour of memantine (20 mg/day) (MD: -2,83 95% CI -4.37 to -1.29, P=0.0003) at 28 weeks and for memantine (30mg/day) at 6 weeks (MD: -3.04. 95% CI -5.68 to -0.40, P=0.02). Effects on Activities of Daily living (ADL) were difficult to interpret. One study provided data using a non-validated scale for measuring five simple instrumental tasks under the guidance of an investigator. When pooled with another study the analysis gave statistically significant results in favour of memantine for 30 mg/day at 6 weeks (SMD: -1.36 95% CI -1.77 to -0.96, P=0.0003). Mood and behaviour: One trial provided data on memantine 30 mg/day at 6 weeks using the NOSIE scale. The OC analysis found statistically significant differences in favour of treatment (MD: 23.30 95% CI 17.83 to 28.77, P<0.00001). Global scales: The analysis revealed a statistically significant difference in favour of memantine (20mg/day ) at 6 weeks (MD: -12.30 95% CI -16.90 to -7.70, P<0.00001). Similar results were found for larger doses (memantine 30 mg/day) at 6 weeks in a pooled meta-analysis of two other studies (WMD: -10.77 95% CI -13.46 to -8.09, P<0.00001). With regard to the Global Impression of Change three studies found statistically significant results in favour of 10, 20 and 30 mg/day of memantine compared with placebo at 6 or 12 weeks. There was a benefit in favour of memantine (20 mg/day) compared with placebo at 6 weeks, for the numbers improved ( 24/41 compared with 11/41)(OR, 3.85, 95% CI 1.52 to 9.75, P=0.004), in favour of memantine (30 mg/day) compared with placebo at 6 weeks, for the numbers improved ( 20/30 compared with 8/29)(OR, 5.25, 95% CI 1.72 to 15.98, P=0.004) and in favour of memantine (10 mg/day) compared with placebo at 12 weeks, for the numbers improved ( 60/82 compared with 38/84)(OR, 3.30, 95% CI 1.72 to 6.33, P=0.0003). In general memantine seemed to be well tolerated. There was no statistically significant difference between memantine and placebo for the three studies that reported adverse events.There were some data on specific adverse events. In one study the incidence of restlessness by the end of the treatment at 6 weeks was statistically significantly lower in the placebo group than in the group taking memantine 30 mg/day (15/30 compared with 2/29) (OR 13.50, 95% CI 2.71 to 67.19, P=0.001). The number of dropouts was similar in treatment and placebo groups at 6 or 28 weeks time for memantine 20 mg/day and at 6 weeks for memantine 30 mg/day. REVIEWER'S CONCLUSIONS: Memantine is a safe drug and may be useful for treating Alzheimer's, vascular,and mixed dementia of all severities. Most of the trials so far reported have been small and not long enough to detect clinically important benefits. However there is a possible benefit on cognition and global measures, and an early improvement in behaviour in people with dementia. More studies are needed.

Asif, A., R. A. Preston, et al. (2003). "Radiocontrast-induced nephropathy." Am J Ther 10(2): 137-47.
Radiocontrast administration remains the third leading cause of hospital-acquired acute renal failure. Clinically, radiocontrast-induced nephropathy (RIN) is defined as a sudden decline in renal function after radiocontrast administration. Typically, the serum creatinine level begins to increase at 24 to 72 hours after the administration of contrast, peaks at 3 to 5 days, and requires another 3 to 5 days to return to baseline. RIN increases the incidence of life-threatening complications such as sepsis, bleeding, and respiratory failure and increases the cost of medical care by extending the hospital stay. The increased mortality associated with acute renal failure encountered in this scenario calls for a heightened awareness of the diagnosis and prevention of RIN. Whereas individuals with healthy renal function are not generally considered to be at particular risk for RIN, patients with preexisting renal insufficiency and diabetes mellitus are much more likely to experience acute renal failure after contrast administration. In the past, a variety of therapeutic interventions have been used to prevent or attenuate RIN, including saline hydration, diuretics, mannitol, calcium channel antagonists, theophylline, endothelin receptor antagonists, hemodialysis, and dopamine. More recently, studies demonstrate a positive impact of fenoldopam (dopamine-1 receptor, dopamine-1 agonist) and the antioxidant N-acetylcysteine in ameliorating RIN. This article discusses the pathophysiology, risk factors, and prevention of RIN.

Azorin, J. M. (2003). "[Criteria defining antimanic drugs (psychopharmacological specificity and/or nonspecificity?)]." Encephale 29(Pt 1): 59-67.
The question as to whether specific antimanic drugs differ in their action profile from nonspecific drugs is addressed in regard to symptomatic, nosographic, regulatory and physiopathological issues. Results from clinical studies have shown that mood stabilizers and typical neuroleptics differ as regards improvement of manic symptoms: the former appear to act more evenly on all symptoms of mania, showing a more total normalization of affect, ideation and behaviour whereas the latter tend to sedate patients or to cause a psychomotor retardation, leaving the core manic symptoms unaffected. This has been many times underlined, in particular for lithium, notwithstanding the fact that rating scales employed in clinical trials have often been charged to fall far short of being sensitive enough to pick up the qualitative changes in manic psychopathology. Antimanic drugs may also be more or less specific in their capacities to treat all facets of the manic episode (psychotic, depressive, irritable) whatever the bipolar subtype (bipolar I, II, rapid and non-rapid cycling, secondary bipolar disorder) or the disease stage (early and late episodes). In this respect divalproate seems to have a broader spectrum of efficacy than other available agents. Newer antipsychotics such as olanzapine are promising too. From a regulatory point of view, the current European requirements for a specific antimanic drug are more stringent than the US requirements of the Food and Drug Administration (FDA). Efficacy must be demonstrated in short-term studies showing an effect in acute mania; moreover it has to be shown that efficacy is to be maintained during the episode. So far, three armed randomized controlled trials are required, in which the test product is compared both with placebo and with a standard treatment. A possible design is a comparison of test product, placebo and active control for 3 weeks followed by a two-arm phase for the remaining 9 weeks, comparing only test product and active control. In addition, a specific antimanic has to demonstrate that it does not cause switching to depression. As regards physiopathology, integrative models of bipolar disorder, ie kindling and behavioural sensitization, offer an exciting perspective on the specificity issue; agents active in these models initialize a cascade of intracellular signaling that leads to changes in the expression of immediate early genes as well as late effector genes in corticolimbic structures: the former may contribute to acute symptomatology whereas the latter give rise to neuroanatomical reorganization which could underlie more stable changes in mood and cognition. Due to their action on intracellular messaging systems, dopamine D(1) receptors, serotonin 5HT(1a) or 5HT(2a) receptors, especially in orbitofrontal circuit, antimanic agents may exhibit a more specific activity than other drugs. This specificity could concern a whole spectrum of bipolarity which might be characterized by impulsivity.

Babel, B. T., A. Nemeth, et al. (2003). "[Multidisciplinary therapy of Tourette syndrome]." Orv Hetil 144(5): 211-6.
The marked fluctuation in symptoms with a spectrum of behavioral problems contribute to misdiagnosis of Tourette syndrome. The authors review the recent progress in diagnosis and management with an emphasis on multidisciplinary approach. Possible associations with various genes have been found in etiology of Tourette syndrome. Development of the disease comes of dopaminerg neurotransmission disorder resulting in cortico-striato-thalamic system dysfunction. Tics are brief movements or sounds that occur intermittently and unpredictably mimicking fragments of normal behavior. Diagnostic criteria are based on the motor and vocal phenomena and their dynamics. The key concept in management are the tic severity scaling correlating with quality of life measurements. Therapeutic interventions indicated at severe alteration in patient's quality of life. Treatment plan combines various drug protocols, psychotherapy and behavioral therapy which should be optimalized for most disabling symptom. Social isolation and self injurious behavior complicates the treatment resistant, severe cases. In these subgroup of patient, an adequate selection of stereotactic intervention could provide an effective control of tic severity or behavioral disorder. Tourette syndrome, as a typical neuropsychiatric disorder, is a striking example for improved efficacy of multidisciplinary approach.

Bailer, U. F. and W. H. Kaye (2003). "A review of neuropeptide and neuroendocrine dysregulation in anorexia and bulimia nervosa." Curr Drug Target CNS Neurol Disord 2(1): 53-9.
Neuropeptides play an important role in the regulation of feeding behavior and obesity. The mechanisms for controlling food intake involve a complicated interplay between peripheral systems (including gustatory stimulation, gastrointestinal peptide secretion, and vagal afferent nerve responses) and central nervous system (CNS) neuropeptides and/or monoamines. These neuronal systems include neuropeptides (CRH, opioids, neuropeptide-Y (NPY) and peptide YY (PYY), vasopressin and oxytocin, CCK, and leptin) and monamines (serotonin, dopamine, norepinephrine). In addition to regulating eating behavior, a number of CNS neuropeptides participate in the regulation of neuroendocrine pathways. Thus, clinical studies have evaluated the possibility that CNS neuropeptide alterations may contribute to dysregulated secretion of the gonadal hormones, cortisol, thyroid hormones and growth hormone in the eating disorders. Most of the neuroendocrine and neuropeptide alterations apparent during symptomatic episodes of AN and BN tend to normalize after recovery. This observation suggests that most of the disturbances are consequences rather than causes of malnutrition, weight loss and/or altered meal patterns. Still, an understanding of these neuropeptide disturbances may shed light on why many people with AN or BN cannot easily "reverse" their illness and even after weight gain and normalized eating patterns, many individuals who have recovered from AN or BN have physiological, behavioral and psychological symptoms that persist for extended periods of time.

Bailey, R. K. (2003). "Atypical psychotropic medications and their adverse effects: a review for the African-American primary care physician." J Natl Med Assoc 95(2): 137-44.
There are now five new-generation atypical psychiatric medications currently available. As these new treatments have become more common, they have grown to account for a significant percentage of all psychiatric medications prescribed. This is because of their efficacy in the treatment of several psychiatric disorders, ease of administration, and absence of the well-known extrapyramidal adverse effects long-attributed to the standard dopamine blocking anti-psychotic medications. As these medications have become treatments of choice, we have discovered additional information about their respective side effects. Issues such as bone marrow suppression, endocrine abnormalities, and most recently cardiac arrhythmia have produced concern. This paper will address all in an attempt to inform the primary care physician of the most prominent and clinically relevant adverse effects of these agents. A particular focus will address the increasing concern that these new medications can produce hyperglycemia and diabetes mellitus.

Barbarich, N. C., W. H. Kaye, et al. (2003). "Neurotransmitter and imaging studies in anorexia nervosa: new targets for treatment." Curr Drug Target CNS Neurol Disord 2(1): 61-72.
Anorexia and Bulimia Nervosa are disorders of unknown etiology that invariably begin during adolescence and near in time to puberty in young women. These disorders are associated with aberrant eating behaviors, body image distortions, impulse and mood disturbances, as well as characteristic temperament and personality traits. It is well known that malnutrition produces changes in neuroendocrine function. More recently, disturbances in neuronal systems have been found to play a role in the modulation of feeding, mood, and impulse control. These neuronal systems include neuropeptides (CRH, opioids, neuropeptide-Y (NPY) and peptide YY (PYY), vasopressin and oxytocin, CCK, and leptin) and monoamines (serotonin, dopamine, norepinephrine). Disturbances of most of these neuronal systems have been found when people are ill with an eating disorder, but it was not certain whether they were a cause or consequence of symptoms. In order to address these questions, a growing number of studies have investigated whether neuromodulatory disturbances persist after recovery. Studies from several centers tend to show altered serotonin activity persists after prolonged normalization of weight, nutrition, and menstrual function, as do anxiety, obsessionality, and perfectionism. While there are fewer data, there may be persistent alterations of dopamine or some neuropeptides in some subjects in a recovered state. The inaccessibility of the central nervous system has made it difficult to understand brain and behavior. In the past decade, new tools, such as brain imaging, have offered the possibility of better characterization of complex neuronal function and behavior. Such studies have tended to consistently find that alterations of brain regions, such as the temporal lobe, occur in people who are ill with anorexia nervosa and appear to persist after some degree of weight gain and recovery. New imaging technology, that marries Positron Emission Tomography (PET) imaging with selective neurotransmitter radioligands, confirms that altered serotonin neuronal pathway activity persists after recovery from an eating disorder and supports the possibility that these psychobiological alterations might contribute to traits, such as increased anxiety or extremes of impulse control, that, in turn, may contribute to a vulnerability to the development of an eating disorder. In summary, studies of pathophysiology are starting to nominate new candidates for treatment leading to the possibility of finding effective treatments for this often chronic or fatal disorder.

Barros, D. M., L. A. Izquierdo, et al. (2003). "Pharmacological findings contribute to the understanding of the main physiological mechanisms of memory retrieval." Curr Drug Target CNS Neurol Disord 2(2): 81-94.
Recent pharmacological findings have shown that retrieval of one-trial avoidance learning requires glutamate receptors, cAMP-dependent protein kinase and mitogen-activated protein kinases in the hippocampus, entorhinal, posterior parietal and anterior cingulate cortex. It requires AMPA but not other type of glutamate receptors or the protein kinases in the amygdala. Retrieval is modulated by dopamine D1, beta-noradrenergic, serotonin 1A and cholinergic receptors in the four cortical structures mentioned, and by beta-noradrenergic receptors in the basolateral amygdala. Further, retrieval is also modulated by peripheral ACTH, glucocorticoids, vasopressin, beta-endorphin and catecholamines; these hormones probably act through beta-noradrenergic receptor systems in the basolateral amygdala. Exposure to novelty or the systemic administration of antidepressant drugs prior to retention tests enhances retrieval, even for very remote memories. The effect of novelty is mediated by molecular mechanisms similar to those of retrieval itself.

Barzilai, A., D. Daily, et al. (2003). "The molecular mechanisms of dopamine toxicity." Adv Neurol 91: 73-82.

Bastia, E. and M. A. Schwarzschild (2003). "DARPP chocolate: a caffeinated morsel of striatal signaling." Sci STKE 2003(165): PE2.
The psychomotor stimulant effects of caffeine, the most widely consumed psychoactive substance, are mediated through its antagonism of extracellular adenosine receptors in the basal ganglia. In the absence of caffeine, adenosine stimulates inhibitory striatopallidal neurons that suppress motor activity by binding to A2A receptors, thereby activating a cyclic adenosine 3',5'-monophosphate (cAMP) and protein kinase A signaling pathway. Bastia and Schwarzschild discuss recent research implicating DARRP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kilodaltons) as an attractive mediator of the sustained psychomotor stimulant effect seen with low doses of caffeine. They highlight the role of postsynaptic A2A receptor blockade, but leave open the possibility that antagonism of presynaptic or postsynaptic A1 receptors also contributes to DARPP-32-dependent psychomotor stimulation by caffeine.

Batra, V., A. A. Patkar, et al. (2003). "The genetic determinants of smoking." Chest 123(5): 1730-9.
Dependence on tobacco, like many other drug dependencies, is a complex behavior with both genetic and environmental factors contributing to the variance. The heritability estimates for smoking in twin studies have ranged from 46 to 84%, indicating a substantial genetic component to smoking. Candidate gene studies have detected functional polymorphisms in genes coding for the cytochrome P450 enzymes, and variations in these genes that lead to more rapid nicotine metabolism have been implicated in smoking. Similarly, smoking has been associated with polymorphisms in dopaminergic genes that may influence the dopamine receptor number and/or function. Animal experiments have localized specific subunits of the nicotinic receptors that may mediate the reinforcing properties of nicotine and have investigated their role in nicotine dependence. However, environmental factors have also been found to contribute to the risk of initiation and persistence of smoking. We review the scientific evidence that supports a role for genetic influences on smoking, discuss the specific genetic and neurobiological mechanisms that may mediate susceptibility to nicotine dependence, identify possible gene/environmental interactions that may be important in understanding smoking behavior, and suggest directions for future research. Insights into the genetic contributions to smoking can potentially lead to more effective strategies to reduce smoking.

Beard, J. (2003). "Iron deficiency alters brain development and functioning." J Nutr 133(5 Suppl 1): 1468S-72S.
Iron deficiency anemia in early life is related to altered behavioral and neural development. Studies in human infants suggest that this is an irreversible effect that may be related to changes in chemistry of neurotransmitters, organization and morphology of neuronal networks, and neurobiology of myelination. The acquisition of iron by the brain is an age-related and brain-region-dependent process with tightly controlled rates of movement of iron across the blood-brain barrier. Dopamine receptors and transporters are altered as are behaviors related to this neurotransmitter. The growing body of evidence suggests that brain iron deficiency in early life has multiple consequences in neurochemistry and neurobiology.

Beinfeld, M. C. (2003). "What we know and what we need to know about the role of endogenous CCK in psychostimulant sensitization." Life Sci 73(6): 643-54.
The unique distribution of CCK and its receptors and its co-localization with dopamine makes it ideally situated to pay a role in dopamine-mediated reward and psychostimulant sensitization. A number of studies support the hypothesis that CCK acting through the CCK 1 and CCK 2 receptors is an endogenous modulator of dopamine neurotransmission. Behavioral studies with CCK antagonists and CCK 1 receptor mutant rats support a role for endogenous CCK in behavioral sensitization to psychostimulants. CCK microdialysis studies in the nucleus accumbens (NAC) have demonstrated that extracellular CCK is increased in the NAC by psychostimulants, providing neurochemical evidence that CCK could be involved in the behavioral response to psychostimulants. A model for how CCK may be acting in multiple brain regions to foster sensitization is presented and the gaps in our knowledge about the role of CCK in psychostimulant sensitization are described.

Berridge, C. W. and B. D. Waterhouse (2003). "The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes." Brain Res Brain Res Rev 42(1): 33-84.
Through a widespread efferent projection system, the locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. Initial studies provided critical insight into the basic organization and properties of this system. More recent work identifies a complicated array of behavioral and electrophysiological actions that have in common the facilitation of processing of relevant, or salient, information. This involves two basic levels of action. First, the system contributes to the initiation and maintenance of behavioral and forebrain neuronal activity states appropriate for the collection of sensory information (e.g. waking). Second, within the waking state, this system modulates the collection and processing of salient sensory information through a diversity of concentration-dependent actions within cortical and subcortical sensory, attention, and memory circuits. Norepinephrine-dependent modulation of long-term alterations in synaptic strength, gene transcription and other processes suggest a potentially critical role of this neurotransmitter system in experience-dependent alterations in neural function and behavior. The ability of a given stimulus to increase locus coeruleus discharge activity appears independent of affective valence (appetitive vs. aversive). Combined, these observations suggest that the locus coeruleus-noradrenergic system is a critical component of the neural architecture supporting interaction with, and navigation through, a complex world. These observations further suggest that dysregulation of locus coeruleus-noradrenergic neurotransmission may contribute to cognitive and/or arousal dysfunction associated with a variety of psychiatric disorders, including attention-deficit hyperactivity disorder, sleep and arousal disorders, as well as certain affective disorders, including post-traumatic stress disorder. Independent of an etiological role in these disorders, the locus coeruleus-noradrenergic system represents an appropriate target for pharmacological treatment of specific attention, memory and/or arousal dysfunction associated with a variety of behavioral/cognitive disorders.

Bertoldi, M. and C. Borri Voltattorni (2003). "Reaction and substrate specificity of recombinant pig kidney Dopa decarboxylase under aerobic and anaerobic conditions." Biochim Biophys Acta 1647(1-2): 42-7.
Dopa decarboxylase (DDC) catalyzes as main reaction the stereospecific CO(2) abstraction from L-Dopa and L-5-hydroxytryptophan (5-HTP), generating the corresponding aromatic amines, dopamine and serotonin, respectively. Side reactions with turnover time of minutes are also catalyzed by the enzyme. In particular, DDC exhibits half-transaminase activity toward D-aromatic amino acids and oxidative deaminase activity toward aromatic amines. The latter reaction could represent a new activity for this class of enzymes. Studies on the effect exerted by O(2) on reaction specificity of DDC revealed that under anaerobic conditions decarboxylation of L-aromatic amino acids takes place with a k(cat) approximately half of that measured in the presence of O(2), and is accompanied by a decarboxylation-dependent transamination, whereas oxidative deamination of aromatic amines is replaced by half-transamination. Half-transamination of D-aromatic amino acids is unaffected by the presence or absence of O(2). Some structural elements relevant for the control of reaction and substrate specificity of DDC have been identified by means of limited tryptic digestion and site-directed mutagenesis studies. All together, the data indicate that the chemical nature of the substrate, the presence of O(2), the integrity of a mobile loop, the absence of perturbation in the coenzyme-binding cleft and pH are important requirements for the achievement of a closed conformational state where the highest level of reaction specificity is reached.

Bezard, E., C. E. Gross, et al. (2003). "Presymptomatic compensation in Parkinson's disease is not dopamine-mediated." Trends Neurosci 26(4): 215-21.
The symptoms of Parkinson's disease (PD) appear only after substantial degeneration of the dopaminergic neuron system (e.g. an 80% depletion of striatal dopamine)--that is, there is a substantive presymptomatic period of the disease. It is widely believed that dopamine-related compensatory mechanisms are responsible for delaying the appearance of symptoms. Recent advances in understanding the presymptomatic phase of PD have increased our understanding of these dopamine-related compensatory mechanisms and have highlighted the role of non-dopamine-mediated mechanisms both within and outside the basal ganglia. This increased knowledge of plasticity within cortical-basal-ganglia-thalamocortical circuitry as dopaminergic neuron degeneration progresses has implications for understanding plasticity in neural circuits generally and, more specifically, for developing novel therapeutics or presymptomatic diagnostics for PD.

Bigal, M. E. and S. J. Tepper (2003). "Ergotamine and dihydroergotamine: a review." Curr Pain Headache Rep 7(1): 55-62.
The ergot alkaloids were the first specific antimigraine therapy available. However, with the advent of the triptans, their use in the treatment of migraine has declined and their role has become less clear. This review discusses the pharmacology, efficacy, and safety of the ergots. In randomized clinical trials, oral ergotamine was found to be superior to placebo, but inferior to 100 mg of oral sumatriptan. In contrast, rectal ergotamine was found to have higher efficacy (73% headache relief) than rectal sumatriptan (63% headache relief). Intranasal dihydroergotamine was found to be superior to placebo, but less effective than subcutaneous and intranasal sumatriptan. Ergotamine is still widely used in some countries for the treatment of severe migraine attacks. It is generally regarded as a safe and useful drug if prescribed for infrequent use, in the correct dose, and in the absence of contraindications; however, safer and more effective options do exist in the triptans. In patients with status migrainous and patients with frequent headache recurrence, ergotamine is still probably useful.

Black, D. L. and P. J. Grabowski (2003). "Alternative pre-mRNA splicing and neuronal function." Prog Mol Subcell Biol 31: 187-216.

Blanchet, P. J. (2003). "Antipsychotic drug-induced movement disorders." Can J Neurol Sci 30 Suppl 1: S101-7.
Very early in the process of diagnosing abnormal involuntary movement (AIM) disorders, one can be rewarded by keeping a high index of suspicion for possible drug-induced causes, not only through a complete list of current medications, but also identification of the drugs the patient used to take and other possible offending medications that might be available from family members and other sources. Among drug-induced movement disorders, antipsychotic drugs and other dopamine receptor blocking agents occupy a central place. Their various acute and tardive motor complications provide the template of this short review. Movement disorders caused by antidepressants, lithium, antiemetics, antiparkinsonian agents, anticonvulsants, calcium channel blockers, sympathomimetics and others are only briefly covered in table form.

Blanchet, P. J. (2003). "The fluctuating Parkinsonian patient--clinical and pathophysiological aspects." Can J Neurol Sci 30 Suppl 1: S19-26.
Although levodopa-related motor response complications remain challenging from a pathophysiological and therapeutic standpoint, major advances have been made in the last decade, supporting the development of several promising drugs. Eventually, these drugs may help us to prevent, alleviate, or even "deprime" these frequent and disabling complications. Knowledge of the basic mechanisms and hypotheses underlying this fascinating conversion in the parkinsonian brain allows neurologists to understand the rationale behind emerging treatment strategies.

Blanchet, P. J., L. V. Metman, et al. (2003). "Renaissance of amantadine in the treatment of Parkinson's disease." Adv Neurol 91: 251-7.

Bodack, M. I. (2003). "Blurred vision during airline flight reveals prolactinoma." Optometry 74(3): 159-72.
BACKGROUND: Pituitary adenomas can manifest with a variety of endocrinologic signs and symptoms, including amenorrhea, galactorrhea, infertility, and acromegaly. Because of the anatomic location of the pituitary gland, and its proximity to the optic chiasm and cavernous sinuses, pituitary adenomas can also result in decreased visual acuity, diplopia, ophthalmoplegia, visual-field loss, and optic atrophy. In general, these tumors are slow-growing. However, there are reports in the medical literature of patients with previously undiagnosed brain tumors in whom neurological signs suddenly developed when in higher altitudes. CASE REPORT: A 47-year-old woman came in for an evaluation of a one-month history of blurry peripheral vision that occurred during-then persisted following--an international flight. Examination and automated visual-field testing revealed a decrease in her best-corrected visual acuity and a bi-temporal hemianopsia. Subsequent examinations by a neurologist and endocrinologist revealed a significant pituitary adenoma-specifically, a prolactinoma. The patient was treated with bromocriptine and has shown a rapid improvement in her visual field and a regression of the tumor, as evidenced by a repeat MRI. CONCLUSION: In this case, the sudden development of the patients symptoms during an airline flight, and the persistence of the symptoms after landing, resulted in the discovery of a prolactinoma.

Boksa, P. and B. F. El-Khodor (2003). "Birth insult interacts with stress at adulthood to alter dopaminergic function in animal models: possible implications for schizophrenia and other disorders." Neurosci Biobehav Rev 27(1-2): 91-101.
Altered subcortical dopaminergic activity is thought to be involved in the pathophysiology of several disorders including schizophrenia, substance abuse and attention deficit hyperactivity disorder. Epidemiological studies have implicated perinatal insults, particularly obstetric complications involving fetal or neonatal hypoxia, as etiological risk factors for schizophrenia. This suggests the possibility that perinatal hypoxia might have lasting effects on dopaminergic function. In animal models, dopaminergic systems appears to be particularly vulnerable to a wide range of perinatal insults, resulting in persistent alterations in function of mesolimbic and mesostriatal pathways. This review summarizes recent work characterizing long-term changes in dopaminergic function and biochemistry in models of Caesarean section (C-section) birth and of C-section birth with added global anoxia in the rat and guinea pig. C-section birth and C-section with anoxia appear to be two distinct hypoxic birth insults, with somewhat differing patterns of lasting effects on dopamine systems. In addition, birth insult alters the manner in which dopaminergic function is regulated by stress at adulthood. The possible relevance of these finding to effects of human birth procedures is discussed.

Bolos, J. (2003). "Current strategies for the development of novel antipsychotic drugs." Mini Rev Med Chem 3(3): 239-51.
While classical neuroleptics are characterized by dopamine D(2) antagonism, this is also considered to be the cause of their neurological side effects. In recent years, novel antipsychotic drugs with improved efficacy, devoid of extrapyramidal effects are being developed. The mechanisms of action of these new atypical antipsychotics can be classified into three general groups: a) binding to D(2) together with non-dopaminergic receptors, b) interaction with dopamine receptor subtypes other than D(2) and c) selective binding to non-dopaminergic systems, such as glutamatergic, sigma, neurotensin, and cannabinoid.

Bonci, A., G. Bernardi, et al. (2003). "The dopamine-containing neuron: maestro or simple musician in the orchestra of addiction?" Trends Pharmacol Sci 24(4): 172-7.
Dopamine-containing neurons originating in the ventral tegmental area project primarily to the nucleus accumbens and the prefrontal cortex, forming the mesolimbic and mesocortical systems, respectively. Virtually every drug of abuse influences dopamine-mediated neurotransmission by affecting directly or indirectly the activity of these cells. Amphetamine and cocaine, in addition to opioids and nicotine, induce short- and long-term modifications of firing in the dopamine-containing neurons of the ventral mesencephalon. Although exposure to psychostimulants mainly depresses neuronal activity, nicotine and morphine enhance neuronal activity. However, under particular conditions, these drugs could cause different changes of firing. In this article, we propose that changes in the activity of dopamine-containing neurons are related to the processes of addiction. Therefore, we suggest that both the modulation of dopamine release in the extracellular space and transient or enduring changes in the firing of dopamine-containing neurons could be associated with important features of drugs of abuse.

Bowles, T. M. and G. M. Levin (2003). "Aripiprazole: a new atypical antipsychotic drug." Ann Pharmacother 37(5): 687-94.
OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of aripiprazole for the treatment of schizophrenia. DATA SOURCES: Information was selected from MEDLINE (1995-August 2002). Abstracts, scientific posters, and presentations were also used. STUDY SELECTION/DATA EXTRACTION: All published information regarding the pharmacokinetic, pharmacodynamic, and clinical characteristics of aripiprazole was considered. Studies providing a comprehensive description of aripiprazole were selected. DATA SYNTHESIS: Aripiprazole is a dopamine partial agonist and a serotonin-2A antagonist; it is dosed 10-30 mg/d, with no initial titration necessary. Short-term clinical trials demonstrated efficacy in acute exacerbations, and long-term studies showed that aripiprazole can maintain remission of schizophrenia. Most adverse events were mild. The incidence of extrapyramidal symptoms was low, with akathisia being the most common. CONCLUSIONS: Aripiprazole currently demonstrates comparable efficacy and safety for use in schizophrenia.

Brandstadter, D. and W. H. Oertel (2003). "Depression in Parkinson's disease." Adv Neurol 91: 371-81.

Briguori, C., D. Tavano, et al. (2003). "Contrast agent--associated nephrotoxicity." Prog Cardiovasc Dis 45(6): 493-503.
Radiocontrast media can lead to a reversible form of acute renal failure that begins soon after the contrast dye administration and generally is benign. Contrast media accounts for 10% of all causes of hospital-acquired acute renal failure and represents the third leading cause of in-hospital renal function deterioration after decreased renal perfusion and postoperative renal insufficiency. The in-hospital mortality rate in patients developing renal insufficiency is related directly to the magnitude increase of serum creatinine concentration. The mortality rate ranges from 3.8% with an increase in serum creatinine level of 0.5 to 0.9 mg/dL to 64% with an increase of greater than 3.0 mg/dL. The mechanism by which contrast-induced renal failure occurs is not well understood. Contrast agent-associated nephrotoxicity appears to be a result of direct contrast-induced renal tubular epithelial cell toxicity and renal medullary ischemia. Furthermore, a key mechanism seems to be alteration in renal dynamics, probably caused by imbalances between vasodilator and vasoconstrictor factors, including the activities of nitric oxide, prostaglandins, endothelin, and reactive oxygen species. The optimal strategy to prevent contrast-associated nephrotoxicity remains uncertain. At present, recommendations are as follows: (1) periprocedural hydration, (2) use of a low-osmolality contrast, and (3) limiting the amount of contrast agent. Recently, considerable interest has resulted from the preliminary positive data on the effectiveness of prophylactic administration of acetylcysteine and fenoldopam. The former may prevent the direct oxidative tissue damage, whereas the latter is a selective intrarenal vasodilator.

Brooks, D. J. (2003). "Imaging end points for monitoring neuroprotection in Parkinson's disease." Ann Neurol 53 Suppl 3: S110-8; discussion S118-9.
In this review, the potential role of positron emission tomography and single-photon emission computed tomography as biological markers for following the progression of Parkinson's disease (PD) is discussed, and their value for assessing the efficacy of putative neuroprotective agents in PD is considered. It is concluded that functional imaging provides a valuable adjunct to clinical assessment when judging the efficacy of neuroprotective approaches to PD.

Bruno, A. (2003). "Cerebrovascular complications of alcohol and sympathomimetic drug abuse." Curr Neurol Neurosci Rep 3(1): 40-5.
Alcohol abuse has been linked to intracranial hemorrhage, both intracerebral and subarachnoid. Some studies have found a dose-response relationship, so that increasing levels of abuse are associated with greater risk of hemorrhage. However, alcohol abuse has not been clearly linked to cerebral infarction, and some studies find that mild-to-moderate drinking appears to be associated with a decreased risk of cerebral infarction. Intravenous administration of drugs of abuse predisposes to endocarditis, which may lead to embolic stroke. Associations have been reported between various sympathomimetic drugs and cerebral infarction. A possible mechanism for cerebral infarction is focal arterial vasoconstriction and occasionally cerebral vasculitis. Associations have also been reported between various sympathomimetic drugs and intracranial hemorrhage. A likely mechanism for intracranial hemorrhage is acute arterial hypertension. With the exception of endocarditis, management of stroke related to drug abuse is largely supportive, with emphasis on supportive care to prevent stroke complications, physical and occupational therapy, and aggressive addiction rehabilitation.

Burke, W. J. (2003). "3,4-dihydroxyphenylacetaldehyde: a potential target for neuroprotective therapy in Parkinson's disease." Curr Drug Target CNS Neurol Disord 2(2): 143-8.
The simplest explanation for the selective loss of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD) is that DA or a metabolite is neurotoxic. Recently, a series of investigations implicate the MAO metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as the critical endogenous toxin which triggers DA neuron loss in PD: 1. Hereditary PD contains mutations in the gene for alpha-synuclein (alpha-syn). Investigations implicate a DA metabolite as mediator of alpha-syn neurotoxicity, and DOPAL is 1000-fold more toxic than DA in vivo. 2. A deficit in mitochondrial complex I is found in PD SN. Inhibition of complex I causes increases in DOPAL levels and death of DA neurons in vitro and in vivo. 3. L-DOPA, the precursor of DA, which is used to treat PD, is toxic and contributes to the progression of PD. L-DOPA-treated rats have an 18-fold increase in striatal DOPAL. 4. Free hydroxyl radicals (.OH) trigger aggregation of alpha-syn to its toxic form. DOPAL with H(2)O(2) generates.OH radicals. These investigations provide several therapeutic strategies to limit DOPAL toxicity and progression of PD: 1. Delaying the start of L-DOPA therapy by early use of DA receptor agonists, which may also be free radical scavengers, limits the amount of DOPAL formed from L-DOPA. 2. Nonspecific MAO inhibitors may more effectively decrease production of DOPAL from DA than MAO-B inhibitors. 3. Newer more potent and targeted free radical scavengers could block DOPAL toxicity. 4. Coenzyme Q(10) increases complex I activity and nicotine adenine dinucleotide (NAD) synthesis, and thereby could enhance DOPAL catabolism by aldehyde dehydrogenase, which uses NAD as a cofactor. 5. DA uptake blockers could be used to limit intraneuronal DOPAL production. 6. Tauroursodeoxycholic acid, an inhibitor of apoptosis shown to be effective in models of Huntington's disease, may also prove effective in blocking DOPAL toxicity in PD. 7. Agents which block aggregation of alpha-syn should limit DOPAL toxicity.

Bymaster, F. P., D. L. McKinzie, et al. (2003). "Use of M1-M5 muscarinic receptor knockout mice as novel tools to delineate the physiological roles of the muscarinic cholinergic system." Neurochem Res 28(3-4): 437-42.
In this review we report recent findings on the physiological role of the five known muscarinic acetylcholine receptors (mAChRs) as shown by gene targeting technology. Using knockout mice for each mAChRs subtype, the role of mAChRs subtypes in a number of physiological functions was confirmed and new activities were discovered. The M1 mAChRs modulate neurotransmitter signaling in cortex and hippocampus. The M3 mAChRs are involved in exocrine gland secretion, smooth muscle contractility, pupil dilation, food intake, and weight gain. The role of the M5 mAChRs involves modulation of central dopamine function and the tone of cerebral blood vessels. mAChRs of the M2 subtype mediate muscarinic agonist-induced bradycardia, tremor, hypothermia, and autoinhibition of release in several brain regions. M4 mAChRs modulate dopamine activity in motor tracts and act as inhibitory autoreceptors in striatum. Thus, as elucidated by gene targeting technology, mAChRs have widespread and manifold functions in the periphery and brain.

Bymaster, F. P., R. K. McNamara, et al. (2003). "New approaches to developing antidepressants by enhancing monoaminergic neurotransmission." Expert Opin Investig Drugs 12(4): 531-43.
Major depressive disorder (MDD) is a serious illness with far reaching societal and economic ramifications. The monoamine-deficiency hypothesis that depressive symptoms are associated with reductions in monoamine neurotransmission, particularly serotonin and noradrenaline, is supported by both neurochemical findings and the successful treatment of MDD with compounds that enhance monoaminergic neurotransmission. This review focuses on novel compounds in different stages of development for the treatment of MDD that enhance monoaminergic neurotransmission via a number of different mechanisms, including re-uptake inhibition of one or more monoamines, monoamine oxidase inhibitors, the combination of monoamine antagonists with re-uptake inhibitors and monoamine receptor subtype agonists. Compounds that enhance individual monoamines have antidepressant properties and compounds that enhance multiple monoamines appear to have a synergistic antidepressant effect and potentially faster onset of action. The differing mechanisms of action possessed by these novel monoamine-enhancing compounds will offer greater treatment flexibility in the therapeutic management of MDD.

Cacciari, B., G. Pastorin, et al. (2003). "Medicinal chemistry of A2A adenosine receptor antagonists." Curr Top Med Chem 3(4): 403-11.
Due to the clearly demonstrated receptor-receptor interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, the discovery and development of potent and selective A(2A)adenosine receptor antagonists became, in the last ten years, an attractive field of research to discovery new drugs for the treatment of neurodegenerative disorders, such as Parkinsons disease. Different compounds have been deeply investigated as A(2A) adenosine receptor antagonists, which could be classified in two great families: xanthine derivatives and nitrogen poliheterocyclic systems. These studies led to the discovery of some highly potent and selective A(2A) adenosine receptor antagonists such as ZM241385, SCH58261 and some xanthine derivatives (KW6002), which have been used as pharmacological tools for studying this receptor subtype. However, those compounds showed some problems that do not permit their use in clinical studies, such as poor water solubility (SCH58261, and xanthine derivatives) or good affinity for A(2B) adenosine receptor subtype (ZM241385). In the last few years great efforts have been made to overcome these problems, trying to optimize not only the pharmacological profile but also the pharmacokinetic character of this class of compounds. The aim of this report is to briefly summarize the recent progress made in this attractive field of research.

Caceda, R., B. Kinkead, et al. (2003). "Do neurotensin receptor agonists represent a novel class of antipsychotic drugs?" Semin Clin Neuropsychiatry 8(2): 94-108.
Schizophrenia is one of the major psychiatric disorders for which effective pharmacotherapy has been available for approximately 50 years. Study of the mechanism of action of these antipsychotic drugs (APDs) has largely focused on the mesolimbic dopamine system and in the neurotransmitter systems that regulate it. Modulation of the neurotensin (NT) circuit in the mesolimbic system can underlie the mechanism of action of APDs. Several lines of evidence support this hypothesis, including: (1) association of NT with neural circuits relevant to the pathophysiology of schizophrenia and the therapeutic effects of APDs; (2) prediction of antipsychotic efficacy and side effect liability based on APD effects on the NT system; (3) low concentrations of NT in the cerebrospinal fluid of a subset of patients with schizophrenia and its normalization after associated clinical improvement with APDs; and (4) remarkable behavioral similarities between peripherally administered APDs and central NT administration. For these reasons, drugs that directly modify the activity of NT systems, particularly NT receptor agonists, could plausibly represent a novel class of APDs.

Carroll, F. I. (2003). "2002 Medicinal Chemistry Division Award address: monoamine transporters and opioid receptors. Targets for addiction therapy." J Med Chem 46(10): 1775-94.

Ceballos-Baumann, A. O. (2003). "Functional imaging in Parkinson's disease: activation studies with PET, fMRI and SPECT." J Neurol 250 Suppl 1: I15-23.
Activation studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) represent a powerful tool to study the functional anatomy of Parkinson's disease (PD). Activation studies offer the opportunity to study regional cerebral function in man in vivo under different conditions with the analysis of task specific changes in regional cerebral blood flow (rCBF) with PET or in the blood oxygenation level dependent (BOLD) effect with fMRI. The combination of PET and deep brain stimulation is particularly attractive to study the effects of discrete perturbations at different target structures throughout the basal ganglia-thalamocortical circuitries. The use of rCBF PET and fMRI to study the pathophysiology of PD in the motor and sensory system and mechanisms of dopaminergic therapy as well as surgical interventions will be reviewed.

Clarke, C. E. (2003). "Dopamine agonist monotherapy in early Parkinson's disease." Hosp Med 64(1): 8-11.
While levodopa therapy for Parkinson's disease is still considered the gold standard, motor complications are significant disadvantages of treatment. Monotherapy with dopamine agonists may present an alternative approach with a reduced likelihood of developing dyskinesias. Further studies are required before a definitive judgment can be made.

Couldwell, W. T., R. L. Rovit, et al. (2003). "Role of surgery in the treatment of microprolactinomas." Neurosurg Clin N Am 14(1): 89-92, vii.
Prolactinomas are a common cause of reproductive and sexual dysfunction and account for a large proportion of pituitary adenomas. The objectives for treatment of hyperprolactinemia due to microprolactinomas are to suppress excessive hormone secretion, preserve residual pituitary function, and prevent disease recurrence. These objectives may be achieved in most patients harboring microprolactinomas by medical treatment with effective dopamine agonists or microsurgical or endoscopic adenomectomy by an experienced surgeon. The choice of pituitary surgery should be made in consideration of the volume and location of the adenoma, age of the patient, the desire for restoration of fertility, and the efficacy and tolerability of dopamine agonists. The presence of a symptomatic microprolactinoma, especially in a young patient, should remain an indication for micro- or endoscopic tumor removal. This article reviews the emergence of radiosurgery as a treatment for microprolactinomas.

Cox, B., M. E. Durieux, et al. (2003). "Toxicity of local anaesthetics." Best Pract Res Clin Anaesthesiol 17(1): 111-36.
The complications of failure, neural injury and local anaesthetic toxicity are common to all regional anaesthetic techniques, and individual techniques are associated with specific complications. All potential candidates for regional anaesthesia should be thoroughly evaluated and informed of potential complications. Central neural blockades still account for more than 70% of regional anaesthesia procedures. Permanent neurological injury is 0.02-0.07%. Pain on injection and paraesthesias while performing regional anaesthesia are danger signals of potential injury and must not be ignored. The incidence of systemic toxicity to local anaesthetics has significantly decreased in the past 30 years, from 0.2 to 0.01%. Peripheral nerve blocks are associated with the highest incidence of systemic toxicity (7.5 per 10,000) and the lowest incidence of serious neural injury (1.9 per 10,000).

Crosby, N., K. H. Deane, et al. (2003). "Amantadine in Parkinson's disease." Cochrane Database Syst Rev(1): CD003468.
BACKGROUND: Although levodopa is the most common drug prescribed to relieve the symptoms of Parkinson's disease it is associated with motor and psychiatric side-effects. Consequently, interest has turned to alternative drugs with improved side-effect profiles to replace or augment levodopa. Amantadine, originally used as an antiviral drug, has been shown to improve the symptoms of Parkinson's disease. OBJECTIVES: To compare the efficacy and safety of amantadine therapy (monotherapy or adjuvant therapy) versus placebo in treating people with Parkinson's disease. SEARCH STRATEGY: Electronic searches of The Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2001), MEDLINE (1966-2001), EMBASE (1974-2001), SCISEARCH (1974-2001), BIOSIS (1993-2001), GEROLIT (1979-2001), OLDMEDLINE (1957-1965), LILACS (1982-2001), MedCarib (17th Century - 2001), PASCAL (1973-2001), JICST-EPLUS (1985-2001), RUSSMED (1973-2001), DISSERTATION ABSTRACTS (2000-2001), SIGLE (1980-2001), ISI-ISTP (1990-2001), Aslib Index to Theses (2001), Clinicaltrials.gov (2001), metaRegister of Controlled Trials (2001), NIDRR (2001) and NRR (2001) were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of amantadine were contacted. SELECTION CRITERIA: Randomised controlled trials comparing amantadine with placebo in the treatment of patients with a clinical diagnosis of idiopathic Parkinson's disease. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by NC and KD onto standardised forms and disagreements were resolved by discussion. MAIN RESULTS: Six randomised controlled trials were found comparing amantadine monotherapy or adjuvant therapy with placebo in the treatment of idiopathic Parkinson's disease. Five examined amantadine as adjuvant therapy with optimal levels of levodopa or anticholinergics and one examined amantadine as an adjuvant therapy with minimum tolerated levels of anticholinergics or as a monotherapy. Five were double-blind cross-over studies and one was a double-blind parallel group study. In total they examined 215 patients. The parallel group study allowed the randomisation codes to be broken and allowed patients in the placebo group to then receive amantadine. This could have led to bias. One study did not present the results of the placebo arm of the trial, hence we could not determine the difference between the two treatment groups. Two cross-over studies presented the results of the combined data from both treatment and placebo arms. The risk of carry-over effect into the second arm meant that these results could not be analysed. The final two studies presented at least some of their data from the end of the first arm of the trials. However only means were given, without standard deviations, so we could not determine the statistical significance of any difference between the amantadine and placebo groups. Although the authors did report on the side-effects from amantadine (such as livido recticularis, dry mouth and blurred vision), they state that none of them were severe. REVIEWER'S CONCLUSIONS: A considerable amount of evidence on the effectiveness of amantadine has accrued from non-controlled trials, often in patients with Parkinsonian conditions other than idiopathic Parkinson's disease. However, rigorous analysis of the six randomised controlled trials of amantadine reveals insufficient evidence of its efficacy and safety in the treatment of idiopathic Parkinson's disease.

Dada, L. A. and J. I. Sznajder (2003). "Mechanisms of pulmonary edema clearance during acute hypoxemic respiratory failure: role of the Na,K-ATPase." Crit Care Med 31(4 Suppl): S248-52.
Pulmonary edema is the hallmark of acute respiratory distress syndrome. It occurs when the permeability of the alveolar-capillary barrier is increased, causing alveolar flooding and impaired gas exchange. The mechanisms of alveolar fluid resorption are different from those of alveolar edema formation. Alveolar fluid resorption into the vessels is brought about mainly by active transport of sodium ions (Na+) out of the alveolar spaces with water following the osmotic gradient. Na+ transport across the alveolar epithelium, and thus alveolar fluid resorption, is regulated by apical Na+ channels, the basolateral sodium potassium-adenosine triphosphatase (Na,K-ATPase), and possibly chloride channels. The Na,K-ATPase has been localized to the alveolar epithelium and the importance of its role in contributing to lung edema clearance has been demonstrated. In models of lung injury, several reports have shown that catecholamines such as isoproterenol and dopamine up-regulate Na+ channels and the Na,K-ATPase giving rise to increased alveolar fluid resorption. Although recombinant gene technology is not yet a therapeutic option for the treatment of pulmonary edema, several experimental studies have reported that overexpression of Na,K-ATPase genes causes increased fluid resorption during hyperoxic lung injury. There is significant evidence that fluid clearance is impaired in patients with lung injury. Therapeutic strategies aimed at increasing the ability of alveolar epithelium to resorb the edema should lead to benefits for patients with acute respiratory distress syndrome.

Dantzler, T. E. and E. J. Lawitz (2003). "Treatment of chronic hepatitis C in nonresponders to previous therapy." Curr Gastroenterol Rep 5(1): 78-85.
About 55% to 60% of treatment-naive patients fail to achieve a sustained virologic response after therapy with standard interferon and ribavirin. The use of polyethylene glycol-enhanced interferon (PEG-IFN) plus ribavirin for retreatment of this challenging group is currently being evaluated by several investigators. Although no sustained virologic response rates have been reported yet from these trials, reported on-treatment response rates for previous nonresponders range from 25% to 30%, and an early estimate of the sustained virologic response rate is about 11%. Outcomes for treatment of relapsers and interferon monotherapy nonresponders have been significantly better than those for combination nonresponders. On-treatment responses of 40% to 43% in previous combination therapy nonresponders are now being seen with the addition of amantadine (triple therapy), and sustained response rates with this regimen are awaited. Large trials are underway to evaluate the role of maintenance therapy for virologic nonresponders with advanced liver disease.

Das, D. and B. Ali (2003). "Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Conservative management [correction of mangement] of asymptomatic cocaine body packers." Emerg Med J 20(2): 172-4.
A short cut review was carried out to establish whether asymptomatic cocaine body packers can be managed conservatively. Altogether 171 papers were found using the reported search, of which four presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. A clinical bottom line is stated.

Davids, E., K. Zhang, et al. (2003). "Animal models of attention-deficit hyperactivity disorder." Brain Res Brain Res Rev 42(1): 1-21.
Attention-deficit hyperactivity disorder (ADHD) involves clinically heterogeneous dysfunctions of sustained attention, with behavioral overactivity and impulsivity, of juvenile onset. Experimental models, in addition to mimicking syndromal features, should resemble the clinical condition in pathophysiology, and predict potential new treatments. One of the most extensively evaluated animal models of ADHD is the spontaneously hypertensive rat. Other models include additional genetic variants (dopamine transporter gene knock-out mouse, coloboma mouse, Naples hyperexcitable rat, acallosal mouse, hyposexual rat, and population-extreme rodents), neonatal lesioning of dopamine neurons with 6-hydroxydopamine, and exposure to other neurotoxins or hippocampal irradiation. None is fully comparable to clinical ADHD. The pathophysiology involved varies, including both deficient and excessive dopaminergic functioning, and probable involvement of other monoamine neurotransmitters. Improved models as well as further testing of their ability to predict treatment responses are required.

de Erausquin, G. A. (2003). "[Mechanism of molecular action of neuroleptics]." Vertex 14(51): 36-44.
The discovery of the neurotransmitter function of dopamine in the central nervous system opened the most successful chapter in the pharmacological treatment of psychosis. It is a generally accepted fact that the antipyschotic action of neuroleptics depends upon blockade of D2 receptors, in part because all of currently used neuroleptics share that action, and in part because for all typical neuroleptics there is a tight correlation between D2 receptor affinity and clinical potency. The differencial effect of atypical neuroleptics has been correlated with the ratio of affinities of for the D2 and the 5HT2A receptors. Alternatively, it has been proposed that the lack of motor side effects is due to fast dissociation of the ligand from the D2 receptor. Regardless of the receptor interaction involved, it is evident that ligand-receptor interactions, occuring over miliseconds, cannot fully account for clinical effects observed over weeks or months. Chronic neuroleptic treatment causes structural and morpholog ical changes in striatum, accumbens and prefrontal and limbic cortex that distinguish between typical and atypical drugs, and thar are correlated with sustained changes in the expression of transcription factors, immediate early genes, second messengers and neuropeptides.

De Lima, M. S. and M. Hotopf (2003). "Benefits and risks of pharmacotherapy for dysthymia: a systematic appraisal of the evidence." Drug Saf 26(1): 55-64.
BACKGROUND: Dysthymia is a prevalent form of subthreshold depressive disorder, associated with considerable disability and high co-morbidity. This paper systematically appraises the evidence for the efficacy and acceptability of the pharmacological treatment for this condition. METHODS: Randomised, controlled trials evaluating the efficacy of drug therapies for dysthymia were included. A comprehensive search of the literature was performed, aiming to avoid publication bias. Pooled relative risks (RR) and 95% CIs were calculated with the Random Effect Model method. The number needed to treat (NNT) and number needed to harm (NNH) were estimated for statistically significant results. RESULTS: Twenty-five trials were included for the main comparisons. Regarding placebo-controlled trials (n = 16), similar results were obtained in terms of efficacy for different groups of drugs, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and other drugs (sulpiride, amineptine, and ritanserin). The pooled RR for treatment response was 0.68 (95% CI 0.57-0.81) for TCA and the NNT was 4.3 (95% CI 3.2-6.5); 0.68 (95% CI 0.56-0.82) for SSRIs (NNT 5.1; 95% CI 3.9-7.7); 0.59 (95% CI 0.48-0.71) for MAOIs (NNT 2.9; 95% CI 2.2-4.3). Other drugs (amisulpride, amineptine and ritanserin) showed similar results. The equivalent efficacy between antidepressants as found in trials where active medications were compared confirmed the efficacy findings from placebo trials. In general, patients treated with a TCA were more likely to report adverse events, compared with placebo and SSRIs. CONCLUSIONS: Pharmacotherapy for dysthymia appears to be an effective short-term treatment for dysthymic disorder. Newer antidepressants are equally effective and have better acceptability than TCAs, although their higher cost must be balanced against this assumed advantage.

Del Arco, A., G. Segovia, et al. (2003). "Changes in dialysate concentrations of glutamate and GABA in the brain: an index of volume transmission mediated actions?" J Neurochem 85(1): 23-33.
Brain microdialysis has become a frequently used method to study the extracellular concentrations of neurotransmitters in specific areas of the brain. For years, and this is still the case today, dialysate concentrations and hence extracellular concentrations of neurotransmitters have been interpreted as a direct index of the neuronal release of these specific neurotransmitter systems. Although this seems to be the case for neurotransmitters such as dopamine, serotonin and acetylcholine, the extracellular concentrations of glutamate and GABA do not provide a reliable index of their synaptic exocytotic release. However, many microdialysis studies show changes in extracellular concentrations of glutamate and GABA under specific pharmacological and behavioural stimuli that could be interpreted as a consequence of the activation of specific neurochemical circuits. Despite this, we still do not know the origin and physiological significance of these changes of glutamate and GABA in the extracellular space. Here we propose that the changes in dialysate concentrations of these two neurotransmitters found under specific treatments could be an expression of the activity of the neurone-astrocyte unit in specific circuits of the brain. It is further proposed that dialysate changes of glutamate and GABA could be used as an index of volume transmission mediated actions of these two neurotransmitters in the brain. This hypothesis is based firstly on the assumption that the activity of neurones is functionally linked to the activity of astrocytes, which can release glutamate and GABA to the extracellular space; secondly, on the existence of extrasynaptic glutamate and GABA receptors with functional properties different from those of GABA receptors located at the synapse; and thirdly, on the experimental evidence reporting specific electrophysiological and neurochemical effects of glutamate and GABA when their levels are increased in the extracellular space. According to this concept, glutamate and GABA, once released into the extracellular compartment, could diffuse and have long-lasting effects modulating glutamatergic and/or GABAergic neurone-astrocytic networks and their interactions with other neurotransmitter neurone networks in the same areas of the brain.

Delmas, C. (2003). "[Hyperactivity in children]." Soins Psychiatr(224): 42-4.

DiMaio, S., N. Grizenko, et al. (2003). "Dopamine genes and attention-deficit hyperactivity disorder: a review." J Psychiatry Neurosci 28(1): 27-38.
OBJECTIVE: To review the results of genetic studies investigating dopamine-related genes in attention-deficit hyperactivity disorder (ADHD). DATA SOURCES: Papers (association/linkage, meta-analyses and animal model studies) were identified through searches of the PubMed database and systematically reviewed. DATA SYNTHESIS: Consistent results from molecular genetic studies are pointing strongly to the possible link between 2 specific genes, the dopamine transporter (SLC3A6) and the dopamine receptor 4 (DRD4), and ADHD. CONCLUSIONS: The implication of SLC6A3 and DRD4 genes in ADHD appears to be one of the most replicated in psychiatric genetics and strongly suggests the involvement of the brain dopamine systems in the pathogenesis of ADHD. However, more work is required to further these findings by genotype-to-phenotype correlations and identify the functional allelic variants/mutations that are responsible for these associations. The role of other dopamine genes, which may have smaller effects than SLC6A3 and DRD4, needs also to be determined.

Dobner, P. R., A. Y. Deutch, et al. (2003). "Neurotensin: dual roles in psychostimulant and antipsychotic drug responses." Life Sci 73(6): 801-11.
Central administration of neurotensin (NT) results in a variety of neurobehavioral effects which, depending upon the administration site, resemble the effects of antipsychotic drugs (APDs) and psychostimulants. All clinically effective APDs exhibit significant affinities for dopamine D(2) receptors, supporting the hypothesis that an increase in dopaminergic tone contributes to schizophrenic symptoms. Psychostimulants increase extracellular dopamine (DA) levels and chronics administration can produce psychotic symptoms over time. APDs and psychostimulants induce Fos and NT expression in distinct striatal subregions, suggesting that changes in gene expression underlie some of their effects. To gain insight into the functions of NT, we analyzed APD and psychostimulant induction of Fos in NT knockout mice and rats pretreated with the NT antagonist SR 48692. In both NT knockout mice and rats pretreated with SR 48692, haloperidol-induced Fos expression was markedly attenuated in the dorsolateral striatum; amphetamine-induced Fos expression was reduced in the medial striatum. These results indicate that NT is required for the activation of specific subpopulations of striatal neurons in distinct striatal subregions in response to both APDs and psychostimulants. This review integrates these new findings with previous evidence implicating NT in both APD and psychostimulant responses.

Doi, N. (2003). "[Anti-tuberculosis drugs]." Nippon Rinsho 61 Suppl 2: 762-7.

Donnelly, C. L. (2003). "Pharmacologic treatment approaches for children and adolescents with posttraumatic stress disorder." Child Adolesc Psychiatr Clin N Am 12(2): 251-69.
Posttraumatic stress disorder is a common cause of morbidity in children and adolescents. The disorder in youth is similar to that in adults, with high rates of psychiatric comorbidity. Children seem to be more sensitive to the effects of trauma, and early life trauma exposure may induce a complex sequence of events that leads to the development of multiple psychiatric disorders in adulthood. The state of knowledge regarding medication treatments for children and adolescents is in the earliest stages of development. There are no well-conducted, randomized clinical trials to guide practitioners. Medication may play an important role in reducing debilitating symptoms of PTSD and providing a buffer for children while they confront difficult material in therapy and may help to improve their general functioning in day-to-day life. Given the various medications with potential usefulness in PTSD, it is helpful to use a stepwise approach to treatment. As a general principal, broad-spectrum agents, such as the SSRIs, are a good first choice. The SSRIs have efficacy in treating the core symptoms of PTSD and conditions such as the anxiety disorders and depression that commonly co-occur with PTSD. These agents also improve social and occupational functioning and an individual's perception of improved quality of life [41, 45, 46]. Although the SSRIs are generally effective for a broad spectrum of problems, clinicians should systematically monitor for the persistence of symptoms that do not respond to these agents. For example, despite significant improvements in core PTSD symptoms in one study that used sertraline, little improvement was seen in patients' comorbid anxiety and depressive symptoms [41]. This finding demonstrates the value of continuous symptom monitoring and shows that residual or comorbid symptoms may require a different medication to augment effective SSRI treatment for PTSD. A reasonable approach is to begin with a broad-spectrum agent, such as an SSRI, which should target anxiety, mood, and reexperiencing symptoms. Adrenergic agents, such as clonidine, used either alone or in combination with an SSRI may be useful when symptoms of hyperarousal and impulsivity are problematic. Supplementing with a mood stabilizer may be necessary in severe affective dyscontrol. Similarly, introduction of an atypical neuroleptic agent may be necessary in cases of severe self-injurious behavior, dissociation, psychosis, or aggression. Comorbid conditions such as ADHD should be targeted with pharmacotherapy known to be effective, such as psychostimulants or newer agents such as atomoxetine. Pharmacologic treatment of PTSD in childhood is one approach to alleviating the acute and chronic symptoms of the disorder. Despite the lack of well-designed, randomized, controlled trials that support efficacy, medication can be used in a rational and safe manner. Reduction in even one disabling symptom, such as insomnia or hyperarousal, may have a positive ripple effect on a child's overall functioning. Pharmacotherapy is typically used as one component of a more comprehensive multiple modality treatment package, including psychoeducation of the parent and child, focused exposure-based psychotherapy with adjunctive family therapy when indicated, and long-term booster interventions that use an admixture of psychodynamic, cognitive-behavioral, and pharmacologic interventions.

Douglass, A. B. (2003). "Narcolepsy: differential diagnosis or etiology in some cases of bipolar disorder and schizophrenia?" CNS Spectr 8(2): 120-6.
Does narcolepsy, a neurological disease, need to be considered when diagnosing major mental illness? Clinicians have reported cases of narcolepsy with prominent hypnagogic hallucinations that were mistakenly diagnosed as schizophrenia. In some bipolar disorder patients with narcolepsy, the HH resulted in their receiving a more severe diagnosis (ie, bipolar disorder with psychotic features or schizoaffective disorder). The role of narcolepsy in psychiatric patients has remained obscure and problematic, and it may be more prevalent than commonly believed. Classical narcolepsy patients display the clinical "tetrad"--cataplexy, hypnagogic hallucinations, daytime sleep attacks, and sleep paralysis. Over 85% also display the human leukocyte antigen marker DQB1*0602 (subset of DQ6). Since 1998, discoveries in neuroanatomy and neurophysiology have greatly advanced the understanding of narcolepsy, which involves a nearly total loss of the recently discovered orexin/hypocretin (hypocretin) neurons of the hypothalamus, likely by an autoimmune mechanism. Hypocretin neurons normally supply excitatory signals to brainstem nuclei producing norepinephrine, serotonin, histamine, and dopamine, with resultant suppression of sleep. They also project to basal forebrain areas and cortex. A literature review regarding the differential diagnosis of narcolepsy, affective disorder, and schizophrenia is presented. Furthermore, it is now possible to rule out classical narcolepsy in difficult psychiatric cases. Surprisingly, psychotic patients with narcolepsy will likely require stimulants to fully recover. Many conventional antipsychotic drugs would worsen their symptoms and make them appear to become a "chronic psychotic," while in fact they can now be properly diagnosed and treated.

Earley, C. J. (2003). "Clinical practice. Restless legs syndrome." N Engl J Med 348(21): 2103-9.

Ebbert, J. O., L. C. Rowland, et al. (2003). "Treatments for spit tobacco use: a quantitative systematic review." Addiction 98(5): 569-83.
AIMS: Spit tobacco use is prevalent in the United States and is associated with adverse health consequences. Health-care providers have neither evidence summaries nor evidence-based guidelines to assist them in treating patients who use spit tobacco. DESIGN: We completed a systematic review of the literature to determine the efficacy and safety of pharmacological and behavioral interventions for the treatment of spit tobacco use. FINDINGS: We found six randomized controlled trials testing pharmacological interventions and eight testing behavioral interventions. Using random-effects meta-analyses,bupropion sustained-release (SR) increased point prevalence tobacco abstinence at 12 weeks [odds ratio (OR) 2.1; 95% confidence interval (CI), 1.0-4.2]. Nicotine replacement therapy with patch or gum increased point prevalence tobacco abstinence at 6 months (OR 1.3; 95% CI, 1.0-1.6).Behavioral interventions increased long-term (6 month)point prevalence tobacco abstinence (OR 1.7; 95% CI, 1.1-2.9).Studies including an oral examination followed by feedback to the patient had the highest treatment effect. CONCLUSIONS: Behavioral interventions for ST users are effective for increasing ST abstinence rates. Bupropion SR is probably effective and nicotine replacement therapy may be effective. This evidence from randomized controlled trials provides health-care professionals with information necessary to effectively treat spit tobacco use.

Eberhardt, O. and J. B. Schulz (2003). "Apoptotic mechanisms and antiapoptotic therapy in the MPTP model of Parkinson's disease." Toxicol Lett 139(2-3): 135-51.
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model constitutes the best-characterized toxin paradigm for Parkinson's disease, faithfully replicating most of its clinical and pathological hallmarks. Many lines of evidence point to a significant contribution of apoptosis to cell death after application of 1-methyl-4-phenylpyridinium (MPP(+)) in cell culture or MPTP in vivo. This holds true for apoptotic DNA strand breaks, activation of the JNK pathway and caspases, induction of Par-4 protein and the protection conferred by interference with p53, Apaf-1 or Bax signalling. In MPTP models, intervention in upstream events of apoptosis, e.g. by inhibition of the JNK pathway, provides morphological and functional rescue. In contrast, inhibition of the propagation and execution phase of apoptosis, e.g. by inhibition of caspases, blocks or delays cell death but may not recover neuronal function. At this stage, the combination of an anti-apoptotic together with a neurorestorative therapy may be promising.

Ellenbroek, B. A. and J. F. Liegeois (2003). "JL 13, an atypical antipsychotic: a preclinical review." CNS Drug Rev 9(1): 41-56.
The extensive pharmacological evaluation of JL 13 as an atypical antipsychotic drug has revealed a close similarity to clozapine, however with some major advantages. JL 13 was characterized as a weak D(2) antagonist, both in vitro and in vivo, with a strong affinity for the D(4) and the 5-HT(2A) receptors. It has no affinity for the 5-HT(2C) receptor. In vivo microdialysis experiments in rat showed that JL 13, like clozapine, preferentially increased extracellular dopamine concentrations in the prefrontal cortex compared to nucleus accumbens or striatum. Behavioral studies showed that JL 13, like clozapine, has the profile of an atypical antipsychotic. Thus, JL 13 did not antagonize apomorphine-induced stereotypy nor did it produce catalepsy, but it antagonized apomorphine-induced climbing in rodents. It was inactive against d-amphetamine-induced stereotypy but antagonized d-amphetamine-induced hyperactivity in the mouse. Likewise, in the paw test, it was more effective in prolonging hindlimb retraction time than prolonging forelimb retraction time. Like other antipsychotic drugs, JL 13 reversed the apomorphine- and amphetamine-induced disruption of prepulse inhibition. In a complex temporal regulation schedule in the dog, JL 13 showed a high resemblance with clozapine without inducing sialorrhea, palpebral ptosis or any significant motor side effects. In rats and squirrel monkeys JL 13 induced a high degree of generalization (70%) to clozapine. Regarding behavioral toxicology, JL 13 did not produce dystonia or Parkinsonian symptoms in haloperidol-sensitized monkeys. After acute administration, again like clozapine, JL 13 induced only a transient increase in circulating prolactin. Last but not the least, regarding a possible hematological toxicity, unlike clozapine, JL 13 did not present sensitivity to peroxidase-induced oxidation. Moreover, its electrooxidation potential was close to that of loxapine and far from that of clozapine. Taking all these preclinical data into account, it appears that JL 13 is a promising atypical antipsychotic drug.

Escalante, C. P. (2003). "Treatment of cancer-related fatigue: an update." Support Care Cancer 11(2): 79-83.
Fatigue, a common complaint of cancer patients, requires a multidisciplinary evaluation and treatment approach because of the multiple etiologies and contributing factors. Current treatments for fatigue include educating patients and caregivers about fatigue, applying etiology-specific treatments, utilizing nonpharmacologic interventions, and prescribing pharmacologic therapies. Often, an individualized treatment plan that includes several modalities may be developed. Presently, there is a lack of well-designed clinical trials to evaluate pharmacologic agents for the treatment of cancer-related fatigue.

Esler, M., G. Lambert, et al. (2003). "Sympathetic nerve activity and neurotransmitter release in humans: translation from pathophysiology into clinical practice." Acta Physiol Scand 177(3): 275-84.
AIM: There has been a revolution in cardiovascular neuroscience in recent years with, in some cases, translation into clinical practice of the knowledge of pathophysiology gained through application of sympathetic nerve recording and catecholamine isotope dilution methodology. OBESITY-RELATED HYPERTENSION: An earlier hypothesis, based on findings in most models, was that weight gain in obesity is due in part to sympathetic nervous underactivity reducing thermogenesis. Microneurography and regional noradrenaline spillover measurements in human obesity have disproven this hypothesis, weakening the case for the use of beta3-adrenergic agonists to stimulate thermogenesis. Sympathetic nerve firing rates in post-ganglionic fibres directed to the skeletal muscle vasculature are increased, as is renal sympathetic tone, with a doubling of the spillover rate of noradrenaline from the kidneys. Given these findings, antiadrenergic antihypertensive drugs may be the preferred agents for obesity-related hypertension, but this has not been adequately tested. ESSENTIAL HYPERTENSION: Whether stress causes high blood pressure, previously hotly debated, has been under recent review by an Australian Government body, the Specialist Medical Review Council. Despite medicolegal implications, the ruling was that stress is one proven cause of hypertension. The judgment was reached after consideration of the epidemiological evidence, but in particular the described neural pathophysiology of essential hypertension: (a) persistent sympathetic nervous stimulation is commonly present, (b) suprabulbar projections of noradrenergic brainstem neurones are activated and (c) adrenaline is released as a cotransmitter in sympathetic nerves. These were taken to be biological markers of stress. CARDIAC FAILURE: At one time, the failing heart was thought to be sympathetically denervated. Longterm administration of inotropic adrenergic agonists, to provide the cardiac catecholamine stimulation thought to be lacking, increased mortality. Noradrenaline isotope dilution methodology subsequently demonstrated that the sympathetic outflow to the heart was preferentially activated, cardiac noradrenaline spillover being increased as much as 50-fold. The level of stimulation of the cardiac sympathetic nerves was the most powerful predictor of death. These observations provide the theoretical foundation for the very successful introduction of beta-adrenergic blockers for treatment of heart failure.

Ferguson, S. S. (2003). "Receptor tyrosine kinase transactivation: fine-tuning synaptic transmission." Trends Neurosci 26(3): 119-22.
G-protein-coupled receptors generate signals that promote gene transcription through the 'transactivation' of receptor tyrosine kinases (RTKs) and activation of the mitogen-activated protein kinase (MAPK) cascade -- a process that involves RTK autophosphorylation and endocytosis. Pioneering work now suggests that D4-dopamine-receptor-mediated transactivation of the platelet-derived growth factor beta receptor has immediate effects on synaptic neurotransmission via Ca(2+)-dependent inactivation of NMDA receptors. The demonstration of a physiological role for RTK transactivation in the CNS provides novel opportunities for understanding how aberrant dopamine signalling might contribute to cognitive and attention deficits associated with schizophrenia and attention-deficit hyperactivity disorder.

Ferry, L. and J. A. Johnston (2003). "Efficacy and safety of bupropion SR for smoking cessation: data from clinical trials and five years of postmarketing experience." Int J Clin Pract 57(3): 224-30.
Bupropion SR was introduced for smoking cessation in the US in 1997. This review assesses the efficacy and safety of bupropion SR for treatment of tobacco dependence based on data from clinical trials and five years of postmarketing experience. Through June 2001, there were approximately 32 million patient exposures to bupropion (9 million for smoking cessation) in clinical practice, and more than 8000 patients have been studied in clinical trials for tobacco dependence. In clinical trials, bupropion SR was more effective than placebo at improving initial and long-term abstinence rates and preventing relapse. Bupropion SR is generally well tolerated. The most common adverse event in clinical trials or clinical practice is insomnia, which can also be a symptom of nicotine withdrawal. The two main risks of treatment with bupropion SR are major motor seizure and hypersensitivity reaction. Clinical trials data suggest that the incidence of seizure is approximately 0.1%, and that of serious cases of hypersensitivity approximately 0.12%. Benefit-risk assessment, assuming a 30% one-year quit rate demonstrates that for every 10,000 smokers treated with bupropion SR, 19 lives are saved and 86 cases of smoking-attributed morbidity are averted in a five-year period while the risk of experiencing one of the two potentially serious adverse events during treatment is 0.22%. These data further establish both the efficacy and safety of bupropion SR and its use in preventing the adverse health effects of chronic tobacco use.

Fleminger, S., R. J. Greenwood, et al. (2003). "Pharmacological management for agitation and aggression in people with acquired brain injury." Cochrane Database Syst Rev(1): CD003299.
BACKGROUND: Of the many psychiatric symptoms that may result from brain injury, agitation and/or aggression are often the most troublesome. It is therefore important to evaluate the efficacy of psychotropic medication used in its management. OBJECTIVES: To evaluate the effects of drugs for agitation and/or aggression following acquired brain injury (ABI). SEARCH STRATEGY: We searched MEDLINE (1966-2002), EMBASE (1980-2002) and the Cochrane Controlled Trials Register (1996-2002), Web of Science Citation Index, reference lists of papers meeting the inclusion criteria and recent reviews. We handsearched Brain Injury and the Journal of Head Trauma Rehabilitation. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) that evaluated the efficacy of drugs acting on the central nervous system for agitation and/or aggression, secondary to ABI, in participants over 10 years of age. Studies using lower levels of evidence (i.e. case series studies, single case studies and controlled group comparison studies), were collated in an appendix. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Authors were contacted where necessary for additional information. Studies of patients within six months after brain injury and/or in a confusional state, were distinguished from those of patients more than six months post-injury, or who were not confused. MAIN RESULTS: Six randomised controlled trials were identified. Four RCTs evaluated the beta-blockers, propranolol and pindolol, one RCT evaluated the central nervous system stimulant, methylphenidate and one RCT evaluated amantadine, a drug normally used in parkinsonism and related disorders. The best evidence of effectiveness in the management of agitation and/or aggression following ABI was for beta-blockers. Two RCTs found propranolol to be effective (one study early and one late after injury). However, these studies used relatively small numbers, have not been replicated, used large doses, and did not use a global outcome measure or long-term follow-up. Comparing early agitation to late aggression, there was no evidence for a differential drug response. Firm evidence that carbamazepine or valproate is effective in the management of agitation and/or aggression following ABI is lacking. REVIEWER'S CONCLUSIONS: Numerous drugs have been tried in the management of aggression in ABI but without firm evidence of their efficacy. It is therefore important to choose drugs with few side effects and to monitor their effect. Beta-blockers have the best evidence for efficacy and deserve more attention. The lack of evidence highlights the need for better evaluations of drugs for this important problem.

Fraser, M. O. and M. B. Chancellor (2003). "Neural control of the urethra and development of pharmacotherapy for stress urinary incontinence." BJU Int 91(8): 743-8.
This review discusses the control of the urethra by the central nervous system, emphasizing the importance of nervous system control and the role of serotonin and noradrenaline in storage, micturition and sphincter reflexes. The concept of pharmacological neuromodulation and the use of pharmacological therapy as first-line therapy for stress urinary incontinence (SUI) is presented. Coordination between the urinary bladder and urethra is mediated by many reflex pathways organized in the brain and spinal cord. During bladder filling, activation of mechanoreceptor afferent nerves in the bladder wall triggers firing in the cholinergic efferent pathways to the external urethral sphincter and in sympathetic adrenergic pathways to the urethral smooth muscle. These storage reflexes depend on interneuronal circuitry in the spinal cord and are modulated by descending pathways. It would therefore seem that neurotransmission in the central nervous system and periphery may be important in SUI, and moreover that pharmacological agents affecting these neurotransmitter pathways may be used to treat SUI. The central and peripheral mechanisms of action of duloxetine affect serotonin and noradrenaline neurotransmission in ways that may ameliorate the symptoms of SUI.

Friedman, H., C. Newton, et al. (2003). "Microbial infections, immunomodulation, and drugs of abuse." Clin Microbiol Rev 16(2): 209-19.
The use of recreational drugs of abuse has generated serious health concerns. There is a long-recognized relationship between addictive drugs and increased levels of infections. Studies of the mechanisms of actions of these drugs became more urgent with the advent of AIDS and its correlation with abused substances. The nature and mechanisms of immunomodulation by marijuana, opiates, cocaine, nicotine, and alcohol are described in this review. Recent studies of the effects of opiates or marijuana on the immune system have demonstrated that they are receptor mediated, occurring both directly via specific receptors on immune cells and indirectly through similar receptors on cells of the nervous system. Findings are also discussed that demonstrate that cocaine and nicotine have similar immunomodulatory effects, which are also apparently receptor mediated. Finally, the nature and mechanisms of immunomodulation by alcohol are described. Although no specific alcohol receptors have been identified, it is widely recognized that alcohol enhances susceptibility to opportunistic microbes. The review covers recent studies of the effects of these drugs on immunity and on increased susceptibility to infectious diseases, including AIDS.

Garcia-Borreguero, D., O. Larrosa, et al. (2003). "Parkinson's disease and sleep." Sleep Med Rev 7(2): 115-29.
Sleep disorders are common in Parkinson's disease (PD), as almost two thirds of PD patients report them. From a clinical point of view, they can be classified into disorders of initiation and maintenance of sleep (DIMS), parasomnias, and excessive daytime sleepiness (EDS). Among the causes of DIMS are degenerative changes in the CNS affecting centers for sleep regulation, persistence into the night of daytime PD-related symptoms, concomitant medical or psychiatric disease, disruption of circadian rhythms, and effects of dopaminergic (and other) medication on sleep regulation. Parasomnias might further contribute to sleep disturbance, as they can be accompanied by motor desinhibition during REM sleep. Parasomnias can precede by several years the presence of daytime PD symptoms. EDS has been over the last years the focus of attention for both sleep and movement disorders specialists, due to the fact that it might predispose to traffic accidents. However, the so-called "sleep attacks" never occur without preexisting somnolence. Thus, a careful sleep history can be helpful to determine which patients are exposed to suffer them. Although EDS was initially attributed to the effects of dopaminergic medication, it seems likely that several disease-related factors might also play an important role. An adequate education of the PD patients in sleep hygiene measures and a skilled use of the medication seem necessary to prevent sleep disturbance.

Gerdeman, G. L., J. G. Partridge, et al. (2003). "It could be habit forming: drugs of abuse and striatal synaptic plasticity." Trends Neurosci 26(4): 184-92.
Drug addiction can take control of the brain and behavior, activating behavioral patterns that are directed excessively and compulsively toward drug usage. Such patterns often involve the development of repetitive and nearly automatic behaviors that we call habits. The striatum, a subcortical brain region important for proper motor function as well as for the formation of behavioral habits, is a major target for drugs of abuse. Here, we review recent studies of long-term synaptic plasticity in the striatum, emphasizing that drugs of abuse can exert pronounced influences on these processes, both in the striatum and in the dopaminergic midbrain. Synaptic plasticity in the ventral striatum appears to play a prominent role in early stages of drug use, whereas dopamine- and endocannabinoid-dependent synaptic plasticity in the dorsal striatum could contribute to the formation of persistent drug-related habits when casual drug use progresses towards compulsive drug use and addiction.

Gerlach, M., P. Foley, et al. (2003). "The relevance of preclinical studies for the treatment of Parkinson's disease." J Neurol 250 Suppl 1: I31-4.
An essential element of pharmaceutical development, defined as the period between the discovery of a new agent and its market release, is provided by the "preclinical studies". They consist of the in vitro and in vivo studies performed before examination of the agent in human subjects. Regulatory authorities prescribe specific requirements regarding the nature and number of preclinical studies. In the present paper, we discuss the relevance of these studies for the treatment of Parkinson's disease (PD) on the basis of three examples: the L-DOPA ( L-3,4-dihydroxyphenylalanine, levodopa) story; the development of selegiline as a palliative and neuroprotective drug; and the safety concerns regarding tolcapone, an inhibitor of central and peripheral catechol-O-methyltransferase (COMT).

Gleason, O. C. (2003). "Delirium." Am Fam Physician 67(5): 1027-34.
Delirium is characterized by an acute change in cognition and a disturbance of consciousness, usually resulting from an underlying medical condition or from medication or drug withdrawal. Delirium affects 10 to 30 percent of hospitalized patients with medical illness; more than 50 percent of persons in certain high-risk populations are affected. The associated morbidity and mortality make diagnosis of this condition extremely important. Patients with delirium can present with agitation, somnolence, withdrawal, and psychosis. This variation in presentation can lead to diagnostic confusion and, in some cases, incorrect attribution of symptoms to a primary psychiatric disorder. To make the distinction, it is important to obtain the history of the onset and course of the condition from family members or caregivers. Primary care physicians must be able to recognize delirium so that the underlying etiology can be ascertained and addressed. The management of delirium involves identifying and correcting the underlying problem, and symptomatically managing any behavioral or psychiatric symptoms. Low doses of antipsychotic drugs can help to control agitation. The use of benzodiazepines should be avoided except in cases of alcohol or sedative-hypnotic withdrawal. Environmental interventions, including frequent reorientation of patients by nursing staff and education of patients and families, should be employed in all cases.

Goldstein, L. B. (2003). "Pharmacotherapy in stroke rehabilitation." Adv Neurol 92: 447-50.

Goldstein, D. S., G. Eisenhofer, et al. (2003). "Sources and significance of plasma levels of catechols and their metabolites in humans." J Pharmacol Exp Ther 305(3): 800-11.
Human plasma contains several catechols, including the catecholamines norepinephrine, epinephrine, and dopamine, their precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), and their deaminated metabolites, dihydroxyphenylglycol, the main neuronal metabolite of norepinephrine, and dihydroxyphenylacetic acid, a deaminated metabolite of dopamine. Products of metabolism of catechols include 3-methoxytyrosine (from L-DOPA), homovanillic acid and dopamine sulfate (from dopamine), normetanephrine, vanillylmandelic acid, and methoxyhydroxyphenylglycol (from norepinephrine), and metanephrine (from epinephrine). Plasma levels of catechols and their metabolites have related but distinct sources and therefore reflect different functions of catecholamine systems. This article provides an update about plasma levels of catechols and their metabolites and the relevance of those levels to some issues in human health and disease.

Goldstein, L. B. (2003). "Amphetamines and related drugs in motor recovery after stroke." Phys Med Rehabil Clin N Am 14(1 Suppl): S125-34, x.
Studies in laboratory animals indicate that the rate and extent of functional recovery after focal brain injury can be modulated by drugs affecting specific central neurotransmitters. Preliminary clinical studies suggest that similar drug effects may occur in humans recovering from stroke. Combined with principles derived from the laboratory, these clinical studies provide important insights to guide the rational design of trials aimed at determining the clinical use of this approach to improving poststroke recovery.

Gordin, A., S. Kaakkola, et al. (2003). "Position of COMT inhibition in the treatment of Parkinson's disease." Adv Neurol 91: 237-50.

Goth, M. I., E. Hubina, et al. (2003). "Physiological and pathological angiogenesis in the endocrine system." Microsc Res Tech 60(1): 98-106.
Formation of new blood vessels occurs in many physiological states (during development of the embryo, cycling changes of the female reproductive tract), as well as in pathological processes (such as diabetic retinopathy and wound healing). Angiogenesis has been shown to be related to tumor formation, prognosis, and response to treatment in many tumor types. Intratumoral microvessels can be related to tumor behavior or hormone secretion in different endocrine tumors. For example, invasive prolactinomas are more vascular than noninvasive adenomas; a surgical approach is more successful in macroprolactinomas with lower microvessel density. A higher number of microvessels have been found in papillary thyroid carcinomas during recurrences. A correlation between microvessel count and prognosis in papillary and medullary thyroid carcinomas has been suggested. Several stimulating and inhibiting factors involved in the regulation of angiogenesis have been identified. Among them, vascular endothelial growth factor (VEGF) has been shown to be critically involved in angiogenesis and also in the neovascularization of solid tumors. Dopamine agonists (already in clinical use for prolactinomas) have potent inhibitory actions on VEGF signaling, and thus may be a new tool in antiangiogenic therapy. Secretion of VEGF in the great majority of human pituitary adenomas is inhibited by dexamethasone. This suggests that glucocorticoids can be considered in the treatment of certain pituitary tumors. The cyclic nature of angiogenesis in the female reproductive tract indicates that stimulation or inhibition of paracrine angiogenic factors may lead to new approaches for being able to influence reproductive endocrine disorders. Experimental and clinical aspects of interactions between angiogenic factors and tumor growth of the endocrine system are also discussed.

Grunblatt, E., R. Schlosser, et al. (2003). "Preclinical versus clinical neuroprotection." Adv Neurol 91: 309-28.

Gudelsky, G. A. and B. K. Yamamoto (2003). "Neuropharmacology and neurotoxicity of 3,4-methylenedioxymethamphetamine." Methods Mol Med 79: 55-73.
The existing data indicate that MDMA produces long-term deficits in markers of 5-HT axon terminals in the rodent brain. Increased cleavage of the cytoskeletal protein tau, impairment of axonal transport, and functional consequences associated with a 5-HT depleting regimen of MDMA support the view that MDMA induces structural brain damage, that is, axonal degeneration. A confluence of oxidative stress and bioenergetic stress induced by MDMA is hypothesized to underlie the process of MDMA neurotoxicity (Fig. 3). The actions of MDMA on the 5-HT transporter to promote free radical formation and/or intracellular calcium may synergize with MDMA-induced disturbances in cellular energetics and hyperthermia to effect selective toxicity to 5-HT axon terminals.

Gupta, S. (2003). "Safety in treating bipolar disorder." J Fam Pract Suppl: S26-9.

Guttman, M., S. J. Kish, et al. (2003). "Current concepts in the diagnosis and management of Parkinson's disease." Cmaj 168(3): 293-301.
Parkinson's disease is a progressive neurological disorder characterized by rest tremor, bradykinesia, rigidity and postural instability. The cause is unknown, but growing evidence suggests that it may be due to a combination of environmental and genetic factors. Treatment during the early stage of Parkinson's disease has evolved, and evidence suggests that dopamine agonist monotherapy may prevent the response fluctuations that are associated with disease progression. L-dopa therapy, however, remains the most efficacious treatment. Treatment during the advanced stage focuses on improving control of a number of specific clinical problems. Successful management of motor response fluctuations (e.g., "wearing off," on-off fluctuations, nighttime deterioration, early morning deterioration and dyskinesias) and of psychiatric problems is often possible with specific treatment strategies. Surgical treatment is an option for a defined patient population.

Hadj Tahar, A., R. Grondin, et al. (2003). "New insights in Parkinson's disease therapy: can levodopa-induced dyskinesia ever be manageable." Adv Neurol 91: 51-64.

Hain, T. C. and M. Uddin (2003). "Pharmacological treatment of vertigo." CNS Drugs 17(2): 85-100.
This review discusses the physiology and pharmacological treatment of vertigo and related disorders. Classes of medications useful in the treatment of vertigo include anticholinergics, antihistamines, benzodiazepines, calcium channel antagonists and dopamine receptor antagonists. These medications often have multiple actions. They may modify the intensity of symptoms (e.g. vestibular suppressants) or they may affect the underlying disease process (e.g. calcium channel antagonists in the case of vestibular migraine). Most of these agents, particularly those that are sedating, also have a potential to modulate the rate of compensation for vestibular damage. This consideration has become more relevant in recent years, as vestibular rehabilitation physical therapy is now often recommended in an attempt to promote compensation. Accordingly, therapy of vertigo is optimised when the prescriber has detailed knowledge of the pharmacology of medications being administered as well as the precise actions being sought. There are four broad causes of vertigo, for which specific regimens of drug therapy can be tailored. Otological vertigo includes disorders of the inner ear such as Meniere's disease, vestibular neuritis, benign paroxysmal positional vertigo (BPPV) and bilateral vestibular paresis. In both Meniere's disease and vestibular neuritis, vestibular suppressants such as anticholinergics and benzodiazepines are used. In Meniere's disease, salt restriction and diuretics are used in an attempt to prevent flare-ups. In vestibular neuritis, only brief use of vestibular suppressants is now recommended. Drug treatments are not presently recommended for BPPV and bilateral vestibular paresis, but physical therapy treatment can be very useful in both. Central vertigo includes entities such as vertigo associated with migraine and certain strokes. Prophylactic agents (L-channel calcium channel antagonists, tricyclic antidepressants, beta-blockers) are the mainstay of treatment for migraine-associated vertigo. In individuals with stroke or other structural lesions of the brainstem or cerebellum, an eclectic approach incorporating trials of vestibular suppressants and physical therapy is recommended. Psychogenic vertigo occurs in association with disorders such as panic disorder, anxiety disorder and agoraphobia. Benzodiazepines are the most useful agents here. Undetermined and ill-defined causes of vertigo make up a large remainder of diagnoses. An empirical approach to these patients incorporating trials of medications of general utility, such as benzodiazepines, as well as trials of medication withdrawal when appropriate, physical therapy and psychiatric consultation is suggested.

Halaris, A. (2003). "Neurochemical aspects of the sexual response cycle." CNS Spectr 8(3): 211-6.
What drives the human sexual response cycle? The human sexual response cycle is a highly complex phenomenon that encompasses many transmitters and transmitter systems centrally and peripherally. The endocrine system is also intricately involved in the brain and in the periphery organs. Integration of these systems is a function of the nervous system that ultimately produces a vast array of cognitive, emotional, physiological, and behavioral responses. Therefore, it is not surprising that a disturbance in even a single system will lead to dysfunction in one or more phases of the sexual response cycle. This article highlights the complex roles the aminergic system plays along with key hormones that are equally involved. The article also points out how rudimentary and fragmented our knowledge is in this field and how few controlled studies are available. The potential for development of specific agents that target selective sexual dysfunctions is exemplified in sildenafil, the first such agent ever to be brought to market.

Hamada, T., I. Hisatome, et al. (2003). "[Drug-induced hyperuricemia]." Nippon Rinsho 61 Suppl 1: 333-7.

Hassaballa, H. A. and R. A. Balk (2003). "Torsade de pointes associated with the administration of intravenous haloperidol." Am J Ther 10(1): 58-60.
Torsade de pointes is a malignant dysrhythmia that has been reported in a variety of clinical settings and associated with several pharmacologic agents. Patients with a prolonged QTc for heart rate are at higher risk for the development of this arrhythmia. We review the literature supporting the relationship of haloperidol to the development of this malignant dysrhythmia. Clinicians in the critical care setting should be aware of potentially lethal drug-induced ventricular tachydysrhythmias such as torsade de pointes.

Haustein, K. O. (2003). "Bupropion: pharmacological and clinical profile in smoking cessation." Int J Clin Pharmacol Ther 41(2): 56-66.
Chemistry, pharmacokinetics, pharmacology, clinical efficacy, adverse effects and dosage of bupropion hydrochloride (BP), an aminoketone antidepressant used in smoking cessation, are reviewed. The nicotinergic acetylcholine receptors are inhibited at clinically relevant concentrations of BP. BP does not inhibit monoamine oxidase, and it has minimal inhibitory effects on presynaptic noradrenaline and dopamine uptake. BP is rapidly absorbed after oral administration and demonstrates biphasic elimination with an elimination half-life of 11 - 14 hours. BP is extensively metabolized by oxidation and reduction to at least 6 metabolites, 2 of which may be active. The plasma levels of the erythro-amino alcohol of BP correlate with several side effects such as insomnia and dry mouth. Efficacy of BP(SR) in smoking cessation has been examined in several double-blind, randomized trials in which daily doses of 150 or 300 mg have been administered for 7 or 9 weeks. In addition, 1 study examined the combination of BP(SR) plus nicotine patch. The point prevalences of stopping smoking reached values between 21.2 and 38%, but they did not exceed those after nicotine replacement therapy alone. Long-term administration (52 weeks) of BP did not improve abstinence compared with placebo after a 2-year follow-up period. Thus, the efficacy of BP in smoking cessation is comparable to that of nicotine replacement therapy. However, BP possesses a broad spectrum of infrequent adverse effects and interferes with the degradation of several drugs such as tricyclic antidepressants, beta-recpetor blocking agents, class Ic-antiarrhythmics etc. As the risk-benefit ratio of BP is smaller than that of nicotine replacement, BP should be considered as a second-line treatment in smoking cessation.

Hays, J. T. and J. O. Ebbert (2003). "Bupropion for the treatment of tobacco dependence: guidelines for balancing risks and benefits." CNS Drugs 17(2): 71-83.
Tobacco use, particularly cigarette smoking, is now a global pandemic. The expected morbidity and mortality from smoking-attributable diseases will continue to rise for the next 30 years. In order to reduce this negative impact on worldwide health, effective therapy to aid smoking cessation must be provided to current smokers. Treatment for tobacco dependence involves the combination of behavioural therapies and pharmacological treatment. The most common pharmacological treatments include nicotine replacement therapy and non-nicotine medications, including antidepressants. The antidepressant with the greatest weight of evidence for efficacy in the treatment of tobacco dependence is bupropion. Sustained-release bupropion is approved for the treatment of tobacco dependence in over 50 countries worldwide. The efficacy of bupropion for the treatment of tobacco dependence is attributed to the blockage of dopamine reuptake in the mesolimbic dopaminergic system. This area of the brain is believed to mediate reward for nicotine use and for other drugs of dependence. Randomised, controlled clinical trials have shown that bupropion approximately doubles abstinence rates compared with placebo. In addition, long-term treatment with bupropion may reduce or delay smoking relapse. Bupropion also appears to be effective in the treatment of smokers who have recently relapsed and smokers with other comorbid psychiatric conditions. Bupropion has a good adverse events profile, but the risk exists for serious adverse effects such as seizures. Recent postmarketing surveillance reports have raised safety concerns about bupropion, although no causal relationship between bupropion and the reported serious adverse events or death has been established.

Henderson, A. (2003). "Domperidone. Discovering new choices for lactating mothers." AWHONN Lifelines 7(1): 54-60.

Hirsch, E. C., G. Orieux, et al. (2003). "Nondopaminergic neurons in Parkinson's disease." Adv Neurol 91: 29-37.

Homann, C. N., K. Wenzel, et al. (2003). "Sleep attacks--facts and fiction: a critical review." Adv Neurol 91: 335-41.

Horstink, M. W., E. Strijks, et al. (2003). "Estrogen and Parkinson's disease." Adv Neurol 91: 107-14.

Hudson, T. J., G. Sullivan, et al. (2003). "Economic evaluations of novel antipsychotic medications: a literature review." Schizophr Res 60(2-3): 199-218.
OBJECTIVE: To evaluate the evidence that novel antipsychotic medications offer a cost advantage compared to traditional antipsychotic medications. METHODS: Literature for this review was identified through a computerized search of Medline, Healthstar and Psyc-INFO databases inclusive from January 1989 to January 2002. Articles included in the review were required to include cost evaluation and to be published in peer-reviewed journals. RESULTS: Twenty-two studies met inclusion criteria. All five studies that used experimental designs found that second-generation antipsychotic medications were associated with a cost advantage or were cost-neutral, and, in some cases, improved quality of life. Of the ten studies using a pre-post design, four found an increase in total costs, six reported a decrease in total costs, and four reported increased effectiveness with use of a second-generation antipsychotic. All seven of the simulation studies reported a cost advantage for novel antipsychotics for specific patient populations under certain conditions. CONCLUSIONS: The majority of studies found that novel antipsychotics are at least cost-neutral and may offer cost advantages compared to traditional agents. Some studies also reported greater improvement in effectiveness and quality of life when novel antipsychotics were compared to traditional antipsychotic medications. However, it is difficult to draw firm conclusions given the small sample sizes and limited study designs available in this literature.

Hunot, S. and E. C. Hirsch (2003). "Neuroinflammatory processes in Parkinson's disease." Ann Neurol 53 Suppl 3: S49-58; discussion S58-60.
Parkinson's disease (PD) is a movement disorder characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, its cause remains unknown and the mechanism of nerve cell death uncertain. Apart from the massive loss of dopaminergic neurons, PD brains also show a conspicuous glial reaction together with signs of a neuroinflammatory reaction manifested by elevated cytokine levels and upregulation of inflammatory-associated factors such as cyclooxygenase-2 and inducible nitric oxide synthase. Mounting evidence also suggests a possible deleterious effect of these neuroinflammatory processes in experimental models of the disease. We propose that, in PD, neuroinflammation plays a role in the cascade of events leading to nerve cell death, thus propagating the neurodegenerative process. In this review, we summarize and discuss the latest findings regarding neuroinflammatory aspects in PD.

Hussain, T. and M. F. Lokhandwala (2003). "Renal dopamine receptors and hypertension." Exp Biol Med (Maywood) 228(2): 134-42.
Dopamine has been recognized as an important modulator of central as well as peripheral physiologic functions in both humans and animals. Dopamine receptors have been identified in a number of organs and tissues, which include several regions within the central nervous system, sympathetic ganglia and postganglionic nerve terminals, various vascular beds, the heart, the gastrointestinal tract, and the kidney. The peripheral dopamine receptors influence cardiovascular and renal function by decreasing afterload and vascular resistance and promoting sodium excretion. Within the kidney, dopamine receptors are present along the nephron, with highest density on proximal tubule epithelial cells. It has been reported that there is a defective dopamine receptor, especially D(1) receptor function, in the proximal tubule of various animal models of hypertension as well as in humans with essential hypertension. Recent reports have revealed the site of and the molecular mechanisms responsible for the defect in D(1) receptors in hypertension. Moreover, recent studies have also demonstrated that the disruption of various dopamine receptor subtypes and their function produces hypertension in rodents. In this review, we present evidence that dopamine and dopamine receptors play an important role in regulating renal sodium excretion and that defective renal dopamine production and/or dopamine receptor function may contribute to the development of various forms of hypertension.

Ibanez, A., C. Blanco, et al. (2003). "Genetics of pathological gambling." J Gambl Stud 19(1): 11-22.
Pathological gambling (PG) is an impulse control disorder and a model 'behavioral' addiction. Familial factors have been observed in clinical studies of pathological gamblers, and twin studies have demonstrated a genetic influence contributing to the development of PG. Serotonergic, noradrenergic, and dopaminergic dysfunction have been reported as biological factors contributing to the pathophysiology of PG. Molecular genetic techniques have been used to investigate the role of genetic factors in PG. Molecular genetic research has identified specific allele variants of candidate genes corresponding to these neurotransmitter systems to be associated with PG. Associations have been reported between pathological gamblers and allele variants of polymorphisms at dopamine receptor genes, the serotonin transporter gene, and the monoamine-oxidase A gene. Although preliminary data suggest that some of these differences are gender-specific, more research needs to be performed to substantiate gender-specific genetic contributions to the development of pathological gambling. The review of the current findings on genetics of PG suggests that liability to PG is in part mediated by genetic factors. Additional studies are needed to replicate and extend these findings, as well as to better understand the influence of specific allelic variants to differences in biological and behavioral functioning.

Inoue, T., Y. Kitaichi, et al. (2003). "[Treatment strategy of refractory depression and its presynaptic mechanism of action]." Nihon Shinkei Seishin Yakurigaku Zasshi 23(1): 11-20.
Most antidepressants used in Japan are reuptake inhibitors of monoamine, such as noradrenaline and serotonin. Incidence of refractory depression, which is resistant to at least two monoamine reuptake inhibitors, is 10-20%. ECT and the addition of lithium, thyroid hormones or dopamine agonists is used for the treatment of refractory depression. Bupropion and MAO inhibitors are also effective for refractory depression but not approved in Japan. The presynaptic mechanism of action of these antidepressants has been studied by in vivo microdialysis studies. Serotonin reuptake inhibitors increase extracellular serotonin concentrations in the brain. Noradrenaline reuptake inhibitors increase extracellular noradrenaline concentrations in the brain, and increase extracellular dopamine concentrations in the frontal cortex, but not in the nucleus accumbens or striatum. ECT and MAO inhibitors increase extracellular serotonin concentrations in the brain, and ECT, bupropion and MAO inhibitors increase extracellular noradrenaline concentrations in the brain. In contrast to monoamine reuptake inhibitors, ECT, bupropion and MAO inhibitors increase extracellular dopamine concentrations not only in the frontal cortex but also in the nucleus accumbens and striatum. The facilitation of mesolimbic or nigrostriatal dopamine neurotransmission may be the mechanism of action behind these treatments' efficacies for refractory depression. Although there are only a few studies concerning the mechanism of action of augmentation therapy, recent studies demonstrated that subchronic lithium treatment increases basal concentrations of extracellular serotonin in the frontal cortex and hippocampus. Subchronic lithium further increases SSRI-induced increases in extracellular serotonin concentrations, and this effect is suggested to be the mechanism of action for lithium augmentation of antidepressants.

Isacson, O., L. M. Bjorklund, et al. (2003). "Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson's disease by stem cells." Ann Neurol 53 Suppl 3: S135-46; discussion S146-8.
New therapeutic nonpharmacological methodology in Parkinson's disease (PD) involves cell and synaptic renewal or replacement to restore function of neuronal systems, including the dopaminergic (DA) system. Using fetal DA cell therapy in PD patients and laboratory models, it has been demonstrated that functional motor deficits associated with parkinsonism can be reduced. Similar results have been observed in animal models with stem cell-derived DA neurons. Evidence obtained from transplanted PD patients further shows that the underlying disease process does not destroy transplanted fetal DA cells, although degeneration of the host nigrostriatal system continues. The optimal DA cell regeneration system would reconstitute a normal neuronal network capable of restoring feedback-controlled release of DA in the nigrostriatal system. The success of cell therapy for PD is limited by access to preparation and development of highly specialized dopaminergic neurons found in the A9 and A10 region of the substantia nigra pars compacta as well as the technical and surgical steps associated with the transplantation procedure. Recent laboratory work has focused on using stem cells as a starting point for deriving the optimal DA cells to restore the nigrostriatal system. Ultimately, understanding the cell biological principles necessary for generating functional DA neurons can provide many new avenues for better treatment of patients with PD.

Jaworski, J. N., A. Vicentic, et al. (2003). "CART peptides are modulators of mesolimbic dopamine and psychostimulants." Life Sci 73(6): 741-7.
CART peptide produces behavioral effects when injected into the VTA or nucleus accumbens. In the VTA, the peptide behaves like an endogenous psychostimulant and produces increased locomotor activity and conditioned place preference. Since this is blocked by dopamine receptor blockers, it presumably involves release of dopamine. But in the nucleus accumbens, CART peptide reduces the locomotor-increasing effects of cocaine. This suggests that the peptide is an interesting target for medications development.

Jenner, P. (2003). "Oxidative stress in Parkinson's disease." Ann Neurol 53 Suppl 3: S26-36; discussion S36-8.
Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinson's disease (PD). However, oxidative stress is intimately linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation. It is therefore difficult to determine whether oxidative stress leads to, or is a consequence of, these events. Oxidative damage to lipids, proteins, and DNA occurs in PD, and toxic products of oxidative damage, such as 4-hydroxynonenal (HNE), can react with proteins to impair cell viability. There is convincing evidence for the involvement of nitric oxide that reacts with superoxide to produce peroxynitrite and ultimately hydroxyl radical production. Recently, altered ubiquitination and degradation of proteins have been implicated as key to dopaminergic cell death in PD. Oxidative stress can impair these processes directly, and products of oxidative damage, such as HNE, can damage the 26S proteasome. Furthermore, impairment of proteasomal function leads to free radical generation and oxidative stress. Oxidative stress occurs in idiopathic PD and products of oxidative damage interfere with cellular function, but these form only part of a cascade, and it is not possible to separate them from other events involved in dopaminergic cell death.

Jenner, P. (2003). "The contribution of the MPTP-treated primate model to the development of new treatment strategies for Parkinson's disease." Parkinsonism Relat Disord 9(3): 131-7.
Current research into Parkinson's disease (PD) is directed at developing novel agents and strategies for improved symptomatic management. The aim of this research is to provide effective and maintained symptom control throughout the course of the disease without loss of efficacy and without priming the basal ganglia for the onset of dyskinesia. To achieve these objectives, it is important to have relevant animal models of PD in which new pharmacological agents and treatment strategies can be assessed prior to clinical assessment. At present, the most effective experimental model of PD is the methyl phenyl tetrahydropyridine (MPTP)-treated primate. Primates treated with MPTP develop motor disturbances resembling those seen in idiopathic PD, including bradykinesia, rigidity and postural abnormalities. In addition, MPTP-treated primates are responsive to all commonly used antiparkinsonian agents and display treatment-associated motor complications such as dyskinesia, wearing-off and on-off, which occur during the long-term treatment of the illness.This review examines how studies conducted in MPTP-treated primates have contributed to the development of dopaminergic therapies. There is now accumulating evidence that the pulsatile manner in which short-acting agents stimulate striatal dopamine receptors is a key contributing factor to the priming of the basal ganglia for dyskinesia induction. It has been suggested that providing more continuous stimulation of dopamine receptors will avoid the development of motor complications, particularly dyskinesia. So far, the actions of all commonly used antiparkinsonian drugs assessed in MPTP-treated primates have proved to be highly predictive of drug action in PD. These primate studies have demonstrated that long-acting dopamine agonists and levodopa given in combination with a catechol-O-methyl transferase (COMT) inhibitor (to increase its relatively short half-life), induce significantly less dyskinesia than occurs with standard levodopa therapy.

Joseph, A. M. and S. S. Fu (2003). "Safety issues in pharmacotherapy for smoking in patients with cardiovascular disease." Prog Cardiovasc Dis 45(6): 429-41.
Twenty percent of patients with cardiovascular disease smoke, and smoking cessation results in a dramatic decline in the relative risk of future cardiovascular events. Questions regarding the safety of nicotine-replacement therapy and bupropion SR for smoking cessation in patients with cardiovascular disease have arisen, in particular because of potential hemodynamic effects of these agents. There have been several randomized, controlled, clinical trials testing the safety of transdermal nicotine in patients with cardiovascular disease that failed to show an increased risk for cardiac events in active treatment conditions compared with placebo. Efficacy trials conducted in other patient populations also support the safety of nicotine-replacement use in cardiac disease patients. To date there is one randomized controlled trial to test bupropion for smoking cessation conducted in this population. Studies to test the efficacy of bupropion for smoking cessation and depression suggest it is safe to use in cardiac disease patients despite recent case reports of adverse events associated with bupropion use. Nicotine-replacement therapy and bupropion significantly increase long-term smoking cessation rates, and the benefits of cessation exceed the risks for pharmacotherapy in patients with cardiovascular disease.

Kalivas, P. W., S. Toda, et al. (2003). "The temporal sequence of changes in gene expression by drugs of abuse." Methods Mol Med 79: 3-11.

Kalsi, J. S., S. Minhas, et al. (2003). "Oral agents for erectile dysfunction." Hosp Med 64(5): 292-5.
Erectile dysfunction is a common disease affecting the lives of millions of men worldwide. Sildenafil was the first oral treatment licensed for male erectile dysfunction. However, there are now a number of other options available. In this article the currently available oral treatments are reviewed.

Kamitani, W., K. Tomonaga, et al. (2003). "[Borna disease virus infection]." Nippon Rinsho 61 Suppl 2: 128-34.

Kantak, K. M. (2003). "Anti-cocaine vaccines: antibody protection against relapse." Expert Opin Pharmacother 4(2): 213-8.
The past decade has seen the development of several vaccines against illicit-drugs. These include vaccines for producing antibodies against cocaine, heroin, methamphetamine and nicotine. The present focus is on anti-cocaine vaccines, as more research has been conducted with these vaccines than other vaccines targeted against a drug of abuse. Attention needs to be given to the structure of the hapten being conjugated, the characteristics of the carrier protein for conjugation with the hapten and the immunisation regimen for antibody production. These issues have an impact on the level of and variability in the anti-cocaine antibodies actively induced and, consequently, on the pharmacokinetic and pharmacodynamic properties of the vaccine. These issues also have an impact on the preclinical and clinical success of the vaccine in protecting against drug use and relapse. If an anti-cocaine vaccine is to be clinically useful, it must induce a sufficient level of antibody in the blood to prevent easy surmountability of protection by continued cocaine use and should be compatible with other treatment medications that may be simultaneously administered.

Kao, L. W., M. A. Kirk, et al. (2003). "Droperidol, QT prolongation, and sudden death: what is the evidence?" Ann Emerg Med 41(4): 546-58.
STUDY OBJECTIVE: Droperidol is a butyrophenone commonly used as an antiemetic and antipsychotic in the United States since US Food and Drug Administration (FDA) approval in 1970. Its labeling has recently been revised, with a black box warning for cases of QT prolongation leading to torsades de pointes and death. A black box warning is applied when serious adverse drug reactions are uncovered for medications. We sought to examine the evidence of a causal association suggested by the black box warning to aid clinicians in their risk-benefit analyses regarding further use of droperidol. METHODS: A literature search was undertaken to determine the evidence regarding the association between droperidol and QT prolongation or torsades de pointes. The evidence was then evaluated by using evidence-based medicine principles. In addition, a review of the FDA regulatory process is presented. RESULTS: Three clinical studies, 1 published abstract, and 7 case reports were reviewed. Available postmarketing surveillance data (MedWatch reports) were also reviewed. Applying the criteria of evidence-based medicine and Hill's criteria, the evidence is not convincing for a causal relationship between therapeutic droperidol administration and life-threatening cardiac events. CONCLUSION: The recent black box warning appears to have originated from postmarketing surveillance data rather than data reported in the peer-reviewed medical literature. Ongoing monitoring of drug safety and more definitive study appear appropriate.

Kapur, S. (2003). "Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia." Am J Psychiatry 160(1): 13-23.
OBJECTIVE: The clinical hallmark of schizophrenia is psychosis. The objective of this overview is to link the neurobiology (brain), the phenomenological experience (mind), and pharmacological aspects of psychosis-in-schizophrenia into a unitary framework. METHOD: Current ideas regarding the neurobiology and phenomenology of psychosis and schizophrenia, the role of dopamine, and the mechanism of action of antipsychotic medication were integrated to develop this framework. RESULTS: A central role of dopamine is to mediate the "salience" of environmental events and internal representations. It is proposed that a dysregulated, hyperdopaminergic state, at a "brain" level of description and analysis, leads to an aberrant assignment of salience to the elements of one's experience, at a "mind" level. Delusions are a cognitive effort by the patient to make sense of these aberrantly salient experiences, whereas hallucinations reflect a direct experience of the aberrant salience of internal representations. Antipsychotics "dampen the salience" of these abnormal experiences and by doing so permit the resolution of symptoms. The antipsychotics do not erase the symptoms but provide the platform for a process of psychological resolution. However, if antipsychotic treatment is stopped, the dysregulated neurochemistry returns, the dormant ideas and experiences become reinvested with aberrant salience, and a relapse occurs. CONCLUSIONS: The article provides a heuristic framework for linking the psychological and biological in psychosis. Predictions of this hypothesis, particularly regarding the possibility of synergy between psychological and pharmacological therapies, are presented. The author describes how the hypothesis is complementary to other ideas about psychosis and also discusses its limitations.

Keck, P. E., Jr. and S. L. McElroy (2003). "Aripiprazole: a partial dopamine D2 receptor agonist antipsychotic." Expert Opin Investig Drugs 12(4): 655-62.
This paper reviews the clinical pharmacology, efficacy and safety of the novel antipsychotic drug aripiprazole. All published citations regarding aripiprazole were reviewed using a Medline((R)) search (completed for citations through mid-year, 2002). In addition, abstracts from recent scientific meetings presenting data not yet published (nor peer-reviewed) were reviewed. Aripiprazole has a unique mechanism of action as a dopamine D2 partial agonist, serotonin 5-HT(1A) partial agonist and serotonin 5-HT(2A) antagonist. Like other new antipsychotics, aripiprazole has the profile of an atypical agent, with efficacy in the treatment of positive and negative symptoms of psychosis as well as mood symptoms, a low rate of neurological side effects and no significant adverse effect on serum prolactin concentrations. In addition, aripiprazole was not associated with significant weight gain or QTc prolongation in both acute and long-term treatment trials.

Khurana, S., V. Batra, et al. (2003). "Twenty-first century tobacco use: it is not just a risk factor anymore." Respir Med 97(4): 295-301.
Despite availability of effective treatments for nicotine addiction, smoking remains prevalent with serious health consequences. Most smokers recognize the ill effects of smoking but are unable to quit. Nicotine addiction may be viewed as any other chronic illness that results from exposure to a recognizable agent (tobacco) and manifests with a well-documented set of signs and symptoms. Much like any chronic disease, both environmental and genetic factors determine the occurrence and severity of this affliction. There has been recent focus on uncovering the genetic basis of nicotine addiction. In this article, we have attempted to briefly review the current evidence for the role of genetics in smoking as well as comment on available pharmacotherapeutic options for treating nicotine dependence.

Klinman, J. P. (2003). "The multi-functional topa-quinone copper amine oxidases." Biochim Biophys Acta 1647(1-2): 131-7.
The mature copper amine oxidases (CAOs) contain a tyrosine-derived 2,4,5-trihydroxyphenylalanyl quinone (topa quinone or TPQ) and a cupric ion in close proximity. Through a combination of structural, spectroscopic and kinetic analyses, a chemical mechanism for the self-processing of an active site tyrosine to TPQ has been proposed. Once formed, TPQ acts as a switch between the heterolytic transformation of amine substrates to aldehydes, via a pyridoxal phosphate-like Schiff base complex, and one electron chemistry involving reduction of molecular oxygen. The relationship between the biogenetic and catalytic processes is discussed.

Knegtering, H., A. E. van der Moolen, et al. (2003). "What are the effects of antipsychotics on sexual dysfunctions and endocrine functioning?" Psychoneuroendocrinology 28 Suppl 2: 109-23.
The literature is reviewed and preliminary results of new studies are presented showing that treatment with classical antipsychotics, as well as risperidone, induces sexual dysfunctions in 30-60% of the patients. These antipsychotics also frequently induce amenorrhoea and galactorrhoea.Although comparative studies are rare, it is likely that prolactin-sparing antipsychotics, as recently shown in a randomized trial of olanzapine versus risperidone, induce less sexual side effects.From these studies, it becomes apparent that prolactin elevation induced by classical antipsychotics and risperidone is probably a factor in inducing sexual dysfunctions, amenorrhoea and galactorrhoea. The role of other factors inducing sexual dysfunctions like sedation, proportional, variant -blockade, testosterone, dopamine, and serotonin is discussed. Finally, it is concluded that sexual and hormonal effects of antipsychotics, although clearly important, are often neglected in research as in clinical practice. Lowering the dosage or switching to a prolactin-sparing antipsychotic often reduces sexual side effects, amenorrhoea, and galactorrhoea.

Korczyn, A. D. (2003). "Dopaminergic drugs in development for Parkinson's disease." Adv Neurol 91: 267-71.

Kumar, A., Z. Huang, et al. (2003). "Mechanisms of motor complications in treatment of Parkinson's disease." Adv Neurol 91: 193-201.

Lambert, T. J. and D. J. Castle (2003). "Pharmacological approaches to the management of schizophrenia." Med J Aust 178 Suppl: S57-61.
Pharmacological treatment remains the mainstay of the management of schizophrenia. Older, "typical" antipsychotics carry a significant burden of side effects, notably extrapyramidal and neurocognitive side effects. Newer, "atypical" agents carry a lower risk of extrapyramidal side effects. They appear to have added benefit for treating negative and cognitive symptoms of schizophrenia, and hence can enhance the quality of life of some patients. The choice of particular agents for individual patients requires a balancing of efficacy and side effects. Medication is only one element of what should be an individualised comprehensive treatment plan for people with schizophrenia.

Langfelder, K., M. Streibel, et al. (2003). "Biosynthesis of fungal melanins and their importance for human pathogenic fungi." Fungal Genet Biol 38(2): 143-58.
For more than 40 years fungi have been known to produce pigments known as melanins. Predominantly these have been dihydroxyphenylalanine (DOPA)-melanin and dihydroxynaphthalene (DHN)-melanin. The biochemical and genetical analysis of the biosynthesis pathways have led to the identification of the genes and corresponding enzymes of the pathways. Only recently have both these types of melanin been linked to virulence in some human pathogenic and phytopathogenic fungi. The absence of melanin in human pathogenic and phytopathogenic fungi often leads to a decrease in virulence. In phytopathogenic fungi such as Magnaporthe grisea and Colletotrichum lagenarium, besides other possible functions in pathogenicity, DHN-melanin plays an essential role in generating turgor for plant appressoria to penetrate plant leaves. While the function of melanin in human pathogenic fungi such as Cryptococcus neoformans, Wangiella dermatitidis, Sporothrix schenckii, and Aspergillus fumigatus is less well defined, its role in protecting fungal cells has clearly been shown. Specifically, the ability of both DOPA- and DHN-melanins to quench free radicals is thought to be an important factor in virulence. In addition, in several fungi the production of fungal virulence factors, such as melanin, has been linked to a cAMP-dependent signaling pathway. Many of the components involved in the signaling pathway have been identified.

Langlois, M., F. Richer, et al. (2003). "New perspectives on dystonia." Can J Neurol Sci 30 Suppl 1: S34-44.
Dystonia is a syndrome of sustained muscular contractions with numerous underlying etiologies. This review examines the varied phenomenology of dystonias, its evolving classification including recent genetic data as well as its clinical investigation and treatment. Although age of onset, anatomical distribution and family history are key elements of the investigation of dystonia, classification increasingly relies on etiologic and genetic criteria. Physiological abnormalities in striato-cortical circuits are common in dystonia but the pathophysiology is still unclear. In recent years, a great deal has been learned on the more common primary dystonias such as primary torsion dystonia and on dystonia-plus syndromes such as dopamine responsive dystonia. Treatment of dystonia has also evolved and there are now a number of therapeutic agents with clear beneficial effects including anticholinergics, benzodiazepines, and botulinum toxin and there is growing interest in neurofunctional surgery including deep brain stimulation.

Larsen, J. P. (2003). "Sleep disorders in Parkinson's disease." Adv Neurol 91: 329-34.

Lata, P. F. and D. L. Pigarelli (2003). "Chronic metoclopramide therapy for diabetic gastroparesis." Ann Pharmacother 37(1): 122-6.
OBJECTIVE: To review the safety and efficacy of chronic metoclopramide for diabetic gastroparesis. DATA SOURCES: Medical literature was accessed through MEDLINE (1965 to October 2002) and PubMed (1965 to October 2002). Key search terms included metoclopramide; diabetic gastroparesis; and dyskinesia, drug induced. DATA SYNTHESIS: Metoclopramide is often used for diabetic gastroparesis, despite the risk of tardive dyskinesia. Published information is limited regarding long-term efficacy and toxicity of metoclopramide. The literature was assessed concerning these topics. CONCLUSIONS: Limited data do not provide sufficient evidence to conclude whether metoclopramide is efficacious for chronic use. Routine monitoring may mitigate the risk associated with metoclopramide therapy.

Lau, Y. S. and G. E. Meredith (2003). "From drugs of abuse to parkinsonism. The MPTP mouse model of Parkinson's disease." Methods Mol Med 79: 103-16.

Lavenstein, B. L. (2003). "Treatment approaches for children with Tourette's syndrome." Curr Neurol Neurosci Rep 3(2): 143-8.
Tourette's syndrome has been of neurologic and psychiatric interest since the original description of this condition by Gilles de la Tourette in 1885, and it has been associated with a wide variety of treatments over the years. With the advent of advances in neurochemistry and neuropharmacology, a neurobiologic approach has emerged with the application of many drugs from the fields of neurology and psychiatry. In addition, many of the comorbid conditions that coexist, such as attention deficit disorder and obsessive compulsive disorder (OCD), are amenable to both pharmacologic and behavioral approaches. Drug treatment has included dopamine receptor blockers for tics, dopamine agonists, dopamine depletors, and stimulants for attention deficit hyperactivity disorder (ADHD), noradrenergic drugs for tics and ADHD, serotonergic drugs for OCD, and chemical denervation for involuntary movements with the use of botulinum toxin and stereotactic surgery. It is the purpose of this review to outline the various approaches that are currently available as treatments, realizing that as new drugs are introduced in neurology and psychiatry, they too will find their way into treatment options.

Lavigne, G. J., T. Kato, et al. (2003). "Neurobiological mechanisms involved in sleep bruxism." Crit Rev Oral Biol Med 14(1): 30-46.
Sleep bruxism (SB) is reported by 8% of the adult population and is mainly associated with rhythmic masticatory muscle activity (RMMA) characterized by repetitive jaw muscle contractions (3 bursts or more at a frequency of 1 Hz). The consequences of SB may include tooth destruction, jaw pain, headaches, or the limitation of mandibular movement, as well as tooth-grinding sounds that disrupt the sleep of bed partners. SB is probably an extreme manifestation of a masticatory muscle activity occurring during the sleep of most normal subjects, since RMMA is observed in 60% of normal sleepers in the absence of grinding sounds. The pathophysiology of SB is becoming clearer, and there is an abundance of evidence outlining the neurophysiology and neurochemistry of rhythmic jaw movements (RJM) in relation to chewing, swallowing, and breathing. The sleep literature provides much evidence describing the mechanisms involved in the reduction of muscle tone, from sleep onset to the atonia that characterizes rapid eye movement (REM) sleep. Several brainstem structures (e.g., reticular pontis oralis, pontis caudalis, parvocellularis) and neurochemicals (e.g., serotonin, dopamine, gamma aminobutyric acid [GABA], noradrenaline) are involved in both the genesis of RJM and the modulation of muscle tone during sleep. It remains unknown why a high percentage of normal subjects present RMMA during sleep and why this activity is three times more frequent and higher in amplitude in SB patients. It is also unclear why RMMA during sleep is characterized by co-activation of both jaw-opening and jaw-closing muscles instead of the alternating jaw-opening and jaw-closing muscle activity pattern typical of chewing. The final section of this review proposes that RMMA during sleep has a role in lubricating the upper alimentary tract and increasing airway patency. The review concludes with an outline of questions for future research.

Le Crom, S., M. Kapsimali, et al. (2003). "Dopamine receptors for every species: gene duplications and functional diversification in Craniates." J Struct Funct Genomics 3(1-4): 161-76.
The neuromodulatory effects of dopamine on the central nervous system of craniates are mediated by two classes of G protein-coupled receptors (D1 and D2), each comprising several subtypes. A systematic isolation and characterization of the D1 and D2-like receptors was carried out in most of the Craniate groups. It revealed that two events of gene duplications took place during vertebrate evolution, before or simultaneously to the emergence of Gnathostomes. It led to the conservation of two-to-four paralogous receptors (subtypes), depending on the species. Additional duplication of dopamine receptor gene occurred independently in the teleost fish lineage. Duplicated genes were maintained in most of the vertebrate groups, certainly by the acquisition of a few functional characters, specific of each subtypes, as well as by discrete changes in their expression territories in the brain. The evolutionary scenario elaborated from these data suggests that receptor gene duplications were the necessary conditions for the expansion of vertebrate forebrain to occur, allowing dopamine systems to exert their fundamental role as modulator of the adaptive capabilities acquired by vertebrate species.

Lepor, N. E. (2003). "A review of contemporary prevention strategies for radiocontrast nephropathy: a focus on fenoldopam and N-acetylcysteine." Rev Cardiovasc Med 4 Suppl 1: S15-20.
The mechanism most likely responsible for the development of radiocontrast nephropathy (RCN) is contrast-induced renal tubular ischemia. At this time, intravenous hydration remains the mainstay for preventing RCN. The antihypertensive agent fenoldopam has been shown in a canine model, as well as in small, retrospective, prospective, and randomized human evaluations, to be effective for preventing RCN. In addition, studies have reported the ability of the free radical scavenger N-acetylcysteine (NAC) to prevent RCN. The clinical trial data for NAC, however, are not consistent regarding this effect, which, if present, appears to be modest and perhaps restricted to lower-risk clinical scenarios.

Leri, F., J. Bruneau, et al. (2003). "Understanding polydrug use: review of heroin and cocaine co-use." Addiction 98(1): 7-22.
The use of cocaine by heroin-dependent individuals, or by patients in methadone or buprenorphine maintenance treatment, is substantial and has negative consequences on health, social adjustment and outcome of opioid-addiction treatment. The pharmacological reasons for cocaine use in opioid-dependent individuals, however, are poorly understood and little is known about the patterns of heroin and cocaine co-use. We reviewed anecdotal evidence suggesting that cocaine is co-used with opioid drugs in a variety of different patterns, to achieve different goals. Clinical and preclinical experimental evidence indicates that the simultaneous administration of cocaine and heroin (i.e. 'speedball') does not induce a novel set of subjective effects, nor is it more reinforcing than either drug alone, especially when the doses of heroin and cocaine are high. There is mixed evidence that the subjective effects of cocaine are enhanced in individuals dependent on opioids, although it is clear that cocaine can alleviate the severity of symptoms of withdrawal from opioids. We also reviewed preclinical studies investigating possible neurobiological interactions between opioids and cocaine, but the results of these studies have been difficult to interpret mainly because the neurochemical mechanisms mediating the motivational effects of cocaine are modified by dependence on, and withdrawal from, opioid drugs. Our analysis encourages further systematic investigation of cocaine use patterns among opioid-dependent individuals and in laboratory animals. Once clearly identified, pharmacological and neuroanatomical methods can be employed in self-administering laboratory animals to uncover the neurobiological correlates of specific patterns of co-use.

Licata, S. C. and R. C. Pierce (2003). "The roles of calcium/calmodulin-dependent and Ras/mitogen-activated protein kinases in the development of psychostimulant-induced behavioral sensitization." J Neurochem 85(1): 14-22.
Although the development of behavioral sensitization to psychostimulants such as cocaine and amphetamine is confined mainly to one nucleus in the brain, the ventral tegmental area (VTA), this process is nonetheless complex, involving a complicated interplay between neurotransmitters, neuropeptides and trophic factors. In the present review we present the hypothesis that calcium-stimulated second messengers, including the calcium/calmodulin-dependent protein kinases and the Ras/mitogen-activated protein kinases, represent the major biochemical pathways whereby converging extracellular signals are integrated and amplified, resulting in the biochemical and molecular changes in dopaminergic neurons in the VTA that represent the critical neuronal correlates of the development of behavioral sensitization to psychostimulants. Moreover, given the important role of calcium-stimulated second messengers in the expression of behavioral sensitization, these signal transduction systems may represent the biochemical substrate through which the transient neurochemical changes associated with the development of behavioral sensitization are translated into the persistent neurochemical, biochemical and molecular alterations in neuronal function that underlie the long-term expression of psychostimulant-induced behavioral sensitization.

Lima, M. S., A. A. Reisser, et al. (2003). "Antidepressants for cocaine dependence." Cochrane Database Syst Rev(2): CD002950.
BACKGROUND: Cocaine dependence is a common and serious condition, which has become a substantial public health problem. The past decade has witnessed a sustained search for an effective pharmacotherapeutic agent for the treatment of cocaine dependence. While administration of cocaine acutely increases intercellular dopamine, serotonin, and norepinephrine levels by blocking their presynaptic reuptake, chronic cocaine abuse leads to down-regulation of monoamine systems. Post-cocaine use depression and cocaine craving may be linked to this down-regulation. Antidepressant pharmacotherapy, by augmenting monoamine levels, may alleviate cocaine abstinence symptomatology, as well as relieving dysphoria and associated craving by general antidepressant action. OBJECTIVES: To conduct a systematic review of all RCTs on the use of antidepressants for treating cocaine dependence. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Cochrane Library, issue 4, 2000), MEDLINE (from 1966 - 2000), EMBASE (from 1980 - 2000), LILACS (from 1982 - 2000), PsycLIT (from 1974 - 2000), Biological Abstracts (1982 to 2000). Other searches:reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. SELECTION CRITERIA: The inclusion criteria for all randomised controlled trials were that they should focus on the use of antidepressants on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. MAIN RESULTS: 18 studies were included in the review, with 1177 people randomised. Positive urine sample for cocaine metabolites was the main efficacy outcome, with no significant results obtained regardless of the type of antidepressant. Compared to other drugs, desipramine performed better but showing just a non significant trend with heterogeneity present as revealed by the chi-square test (8.6, df=3; p=0.04). One single trial showed imipramine performed better than placebo in terms of clinical response according to patient's self-report. A similar rate of patients remaining in treatment was found for both patients taking desipramine or placebo. Results from one single trial suggest fluoxetine patients on SSRIs are less likely to dropout. Similar results were obtained for trials where patients had additional diagnosis of opioid dependence and/or were in methadone maintenance treatment. REVIEWER'S CONCLUSIONS: There is no current evidence supporting the clinical use of antidepressants in the treatment of cocaine dependence. Given the high rate of dropouts in this population, clinicians may consider adding psychotherapeutic supportive measures aiming to keep patients in treatment.

Lingford-Hughes, A. R., S. J. Davies, et al. (2003). "Addiction." Br Med Bull 65: 209-22.
Alcohol and psycho-active substance misuse has far-reaching social, psychological and physical consequences. Advances in neuroimaging technology have allowed neurobiological theories of addiction to become better characterized. We describe the neurobiology of dependence, withdrawal, abstinence and craving states in alcohol, stimulant and opiate misuse. Structural neuroimaging techniques such as CT and MRI with new analytical approaches such as voxel-based morphometry have shown wide-spread changes in stimulant and opiate abuse and atrophy, particularly in the frontal lobes, in alcoholism. Functional neuroimaging techniques such as PET, SPECT and fMRI reveal altered regional cerebral activity by all drugs of abuse. The neurochemistry of addiction, particularly involving dopamine, serotonin, opiate and GABA, has been studied with PET and SPECT and similarities between all drugs of abuse have been found such as reduced dopaminergic markers. The evidence derived from these advances in neuroimaging is likely to herald the emergence of new biological treatments in this important field.

Lingford-Hughes, A. and D. Nutt (2003). "Neurobiology of addiction and implications for treatment." Br J Psychiatry 182: 97-100.

Liu, B. and J. S. Hong (2003). "Neuroprotective effect of naloxone in inflammation-mediated dopaminergic neurodegeneration. Dissociation from the involvement of opioid receptors." Methods Mol Med 79: 43-54.

Liu, B. and J. S. Hong (2003). "Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention." J Pharmacol Exp Ther 304(1): 1-7.
Evidence from postmortem analysis implicates the involvement of microglia in the neurodegenerative process of several degenerative neurological diseases, including Alzheimer's disease and Parkinson's disease. It remains to be determined, however, whether microglial activation plays a role in the initiation stage of disease progression or occurs merely as a response to neuronal death. Activated microglia secrete a variety of proinflammatory and neurotoxic factors that are believed to induce and/or exacerbate neurodegeneration. In this article, we summarize recent advances on the study of the role of microglia based on findings from animal and cell culture models in the pathogenesis of neurodegenerative diseases, with particular emphasis on Parkinson's disease. In addition, we also discuss novel approaches to potential therapeutic strategies.

Loonam, T. M., P. A. Noailles, et al. (2003). "Substance P and cholecystokinin regulate neurochemical responses to cocaine and methamphetamine in the striatum." Life Sci 73(6): 727-39.
The mechanism of action of drugs of abuse like cocaine and amphetamines has been studied extensively in the dopamine terminal field areas of the caudate-putamen (CPu) and the nucleus accumbens (NAc) of the rodent brain. These brain regions contain several neuropeptides that must play important roles in the normal physiological functions of these brain regions. The study of neuropeptide physiology in the context of the neurobiological responses to drugs of abuse may shed some light on the intrinsic mechanism of action of neuropeptides of the CPu and the NAc. The neuropeptides substance P (SP) and cholecystokinin (CCK) are present in the striatum where they could play an important role regulating the effects of psychostimulants like cocaine and amphetamines (methamphetamine [METH] is a long acting derivative of d-amphetamine). These highly addictive agents induce the release of dopamine (DA) (and other catecholamines) from dopaminergic terminals of the striatum. The excessive release of DA in the striatum and the NAc has been implicated in the habit-forming properties of these drugs. In order to study the contribution of SP and CCK in the striatum during psychostimulant treatment, we employed selective non-peptide neurokinin-1 (NK-1) and cholecystokinin-2 (CCK-2) receptor antagonists that readily cross the blood brain barrier. We infused the neurokinin-1 receptor (NK-1R) antagonist, L-733,060, into the striatum of freely moving rats via a microdialysis probe in order to assess the effects of SP on cocaine-induced DA overflow in the striatum. Infusion of the NK-1R antagonist prior to a systemic injection of cocaine (10 mg/kg i.p.) significantly attenuated DA overflow in the striatum. Conversely, infusion of a CCK-2 receptor (CCK-2R) antagonist, L-369,293, through the microdialysis probe evoked DA overflow in the striatum in the absence of cocaine and potentiated DA overflow after a single injection of cocaine (10 mg/kg i.p.). Exposure to METH (10 mg/kg 4x at two-hour intervals) produced deficits of dopamine transporters (DAT) in mice striatum that are detectable three days after the treatment and are long lasting. Pre-treatment (i.p. injections) with the NK-1R antagonist, WIN-51,708 30 minutes before the 1st and 4th injections of METH prevented the loss of DAT in the striatum. Moreover, pre-treatment with the NK-1R antagonist prevents METH-induced cell death. Taken together, these results demonstrate that the NK-1R and the CCK-2R are important modulators of the actions of the psychostimulants cocaine and METH. Neuropeptide receptors represent an important control point mediating the effects of the neurotransmitter DA in the striatum of the rodent brain.

Mandel, S., O. Weinreb, et al. (2003). "Using cDNA microarray to assess Parkinson's disease models and the effects of neuroprotective drugs." Trends Pharmacol Sci 24(4): 184-91.
The remarkable progress made by molecular biology and molecular genetics during the past decade, and the advent of the novel tools of genomics and proteomics, are expected to reveal differential expression profiles of thousands of genes and proteins involved in the degeneration of dopamine-containing cells in Parkinson's disease and allow more focused treatments according to individual genotypes. Of particular interest is the application of microarrays in drug discovery and design to identify 'fingerprints' as potential candidate targets for drug intervention. The major microarray findings relevant to Parkinson's disease and its neurotoxin-induced animal and cell models will be discussed, with particular reference to the neuroprotective therapeutic potential that could arise from the development of drugs 'a la carte'.

Mandel, S., E. Grunblatt, et al. (2003). "Genes and oxidative stress in parkinsonism: cDNA microarray studies." Adv Neurol 91: 123-32.

Mangiavacchi, M. and E. Gronda (2003). "[Inotropic agents in advanced and refractory heart failure]." Ital Heart J 4(1 Suppl): 3-7.

Marek, K., D. Jennings, et al. (2003). "Dopamine agonists and Parkinson's disease progression: what can we learn from neuroimaging studies." Ann Neurol 53 Suppl 3: S160-6; discussion S166-9.

Marek, K., D. Jennings, et al. (2003). "Single-photon emission tomography and dopamine transporter imaging in Parkinson's disease." Adv Neurol 91: 183-91.

Markley, H. G. (2003). "Topical agents in the treatment of cluster headache." Curr Pain Headache Rep 7(2): 139-43.
This article discusses topical intranasal medications in the treatment of cluster headache.

Marles, S. L., M. Reed, et al. (2003). "Humeroradial synostosis, ulnar aplasia and oligodactyly, with contralateral amelia, in a child with prenatal cocaine exposure." Am J Med Genet 116A(1): 85-9.
Humeral "bifurcation" due to humeroradial synostosis, and amelia are both very rare limb anomalies. We report on a Canadian. Aboriginal boy with both these limb deficiencies. The family history was unremarkable, but he was exposed prenatally to cocaine at the time of limb development. Humeroradial synostosis with ulnar aplasia has been reported by several authors. The majority of cases are unilateral. When both upper limbs arms are involved, cases with oligodactyly often have asymmetrical limb deficiencies and have all been sporadic to date. Some appear to represent cases of the femur-fibula-ulna or FFU complex. Affected individuals with normal hands usually have symmetrical defects and show an autosomal recessive pattern of inheritance. Limb deficiencies have been reported in several infants exposed prenatally to cocaine and have been inducible in animal models. Most are terminal transverse defects or deficiencies of middle digits. When more than one limb is involved, the defects are usually asymmetric. Our case appears to be one of the most severely affected children reported to date.

Marras, C. and A. E. Lang (2003). "Measuring motor complications in clinical trials for early Parkinson's disease." J Neurol Neurosurg Psychiatry 74(2): 143-6.

Martin, W. R. and M. Wieler (2003). "Treatment of Parkinson's disease." Can J Neurol Sci 30 Suppl 1: S27-33.
Parkinson's disease is a progressive neurodegenerative disorder that demands a holistic approach to treatment. Both pharmacologic and nonpharmacologic interventions play an important role in the comprehensive management of this disorder. While levodopa remains the single most effective medication for symptomatic treatment, dopamine agonists are playing an increasingly important role. Motor complications of dopaminergic therapy are a significant issue, particularly in patients with more advanced disease who have been on levodopa for several years. All therapeutic interventions must be tailored to the individual and modified as the disease progresses, with the goal of minimizing significant functional disability as much as possible.

Marwick, T. H. (2003). "Stress echocardiography." Heart 89(1): 113-8.

Mathur, V. S. (2003). "The role of the DA1 receptor agonist fenoldopam in the management of critically ill, transplant, and hypertensive patients." Rev Cardiovasc Med 4 Suppl 1: S35-40.
Fenoldopam, a selective agonist of dopamine-1 receptors, is a regional and systemic vasodilator. In randomized, controlled clinical trials, fenoldopam has been found to preserve renal function in situations of potential renal ischemia, such as during radiocontrast administration, cardiac and peripheral vascular surgery, liver transplantation, and treatment of severe hypertension. Fenoldopam lowers blood pressure in patients with hypertension, but has little or no effect on blood pressure in those who are normotensive. The role of fenoldopam in managing critically ill, transplant, and hypertensive patients is reviewed in this article.

McKeith, I. G., D. J. Burn, et al. (2003). "Dementia with Lewy bodies." Semin Clin Neuropsychiatry 8(1): 46-57.
The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.

Melis, M. R. and A. Argiolas (2003). "Central oxytocinergic neurotransmission: a drug target for the therapy of psychogenic erectile dysfunction." Curr Drug Targets 4(1): 55-66.
A group of oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus and projecting to extrahypothalamic brain areas (e.g. hippocampus, medulla oblongata and spinal cord) control penile erection. Activation of these neurons by dopamine and dopamine agonists, excitatory amino acids (N-methyl-D-aspartic acid) or oxytocin itself, or by electrical stimulation leads to penile erection, while their inhibition by GABA and GABA agonists or by opioid peptides and opiate-like drugs inhibits this sexual response. The activation of oxytocinergic neurons in the paraventricular nucleus by dopamine, oxytocin and excitatory amino acids is apparently secondary to the activation of nitric oxide (NO) synthase. NO in turn activates, by a mechanism that is as yet unidentified, the release of oxytocin from oxytocinergic neurons in extrahypothalamic brain areas. Several peptide analogues of hexarelin, a growth hormone releasing peptide, also induce penile erection when injected into the paraventricular nucleus and, to a lesser extent, systemically, apparently by acting on a specific receptor to activate oxytocinergic neurons as shown for the above drugs and oxytocin. Paraventricular oxytocinergic neurons and mechanisms similar to those reported above are also involved in the expression of penile erection in physiological contexts, namely when penile erection is induced in the male by the presence of an inaccessible receptive female, which is considered a model for psychogenic impotence in man, as well as during copulation. These findings show that paraventricular oxytocinergic neurons projecting to extra-hypothalamic brain areas and to the spinal cord are a likely target for the treatment of erectile dysfunction of central origin.

Merza, Z. (2003). "Modern treatment of acromegaly." Postgrad Med J 79(930): 189-93; quiz 192-4.
Acromegaly is an endocrine disorder characterised by increased morbidity and mortality. It is usually caused by a growth hormone secreting pituitary adenoma and is manifested by a variety of clinical features. Surgery is usually the treatment of choice, however over the last few years, several new methods of treatment have been developed. A recent consensus on the targets for treatment has led to multiple studies being conducted to assess the efficacy of the currently available options. This review examines the evidence for and against these treatments.

Misu, Y., K. Kitahama, et al. (2003). "L-3,4-Dihydroxyphenylalanine as a neurotransmitter candidate in the central nervous system." Pharmacol Ther 97(2): 117-37.
Historically, 3,4-dihydroxyphenylalanine (DOPA) has been believed 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 mainly in baroreflex neurotransmission in the lower brainstem and in delayed neuronal death by transient ischemia in the striatum and the hippocampal CA1 region of rats.

Mitamura, K. (2003). "[Antiviral agents for influenza]." Nippon Rinsho 61 Suppl 2: 798-803.

Moldrich, R. X. and P. M. Beart (2003). "Emerging signalling and protein interactions mediated via metabotropic glutamate receptors." Curr Drug Target CNS Neurol Disord 2(2): 109-22.
Metabotropic glutamate receptors (mGlu) are GTP-binding (G) protein-coupled receptors (GPCRs) that are involved in learning and memory, cardiovascular control and motor function. Their structure and pharmacology has been reviewed recently in Current Drug Targets: CNS and Neurological Disorders (Vol. 1, Issue 3) where their roles in a variety of neurological disorders were highlighted. The present review focuses on the emerging evidence for interactions of mGlu receptors with other GPCRs in the CNS at the membrane interface and amongst signaling cascades in the cytosol (e.g. intracellular Ca(2+), cAMP and scaffolding proteins). While initially non-selective activity was thought to be responsible for many atypical responses, increasing evidence points to GPCR interactions in neurons and glia, with adrenoceptors, adenosine receptors, dopamine receptors and muscarinic receptors. For example, group II mGlu receptors were found to be required for group I mGlu receptor induction of long-term potentiation at the postsynaptic terminal. Increasing evidence demonstrates the intimate interaction of adenosine receptors and mGlu receptors, particularly in the regulation of neurotransmitter release. While adenosine itself can be released from astrocytes by co-activation of group II mGlu and beta-adrenergic receptors. Given the complexity of neurological disorders such as ischemic stroke, Alzheimer's disease and epilepsy, exploitation mGlu receptor-associated GPCR interactions may prove efficacious in the treatment of such disorders.

Montastruc, J. L., L. Schmitt, et al. (2003). "[Pathological gambling behavior in a patient with Parkinson's disease treated with levodopa and bromocriptine]." Rev Neurol (Paris) 159(4): 441-3.
The occurrence of a pathological gambling behavior in a 61-year-old patient with idiopathic Parkinson's disease treated with dopaminergic drugs is reported. This is the first case reported with bromocriptine. The main characteristics and the mechanism of this recently described and a unexpected, adverse drug reaction are discussed.

Montgomery, J. H. and J. L. Tekell (2003). "Adjunctive quetiapine treatment of the polydipsia, intermittent hyponatremia, and psychosis syndrome: a case report." J Clin Psychiatry 64(3): 339-41.

Montorsi, F., A. Salonia, et al. (2003). "Pharmacological management of erectile dysfunction." BJU Int 91(5): 446-54.
Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. Many drugs are now available for treating ED; oral pharmacotherapy represents the first-line option for most patients with ED. Sildenafil, an inhibitor of the enzyme phosphodiesterase type 5, is currently the most widely prescribed oral agent and has a very satisfactory efficacy-safety profile in all patient categories. Apomorphine SL is a dopamine D1- and D2-receptor agonist which has recently been approved for marketing in Europe. It is best selected for treating patients with mild to moderate ED. Vardenafil and tadalafil are new phosphodiesterase type 5 inhibitors which are expected to be approved this year. Both of them have significant positive efficacy-safety profiles. Patients who do not respond to oral pharmacotherapy or who cannot use it are good candidates for intracavernosal and intraurethral therapy. Alprostadil is the most widely used drug, both for injection therapy and for the intraurethral route. The efficacy of second-line treatment is high but the attrition rate remains significant.

Moret, C., B. Grimaldi, et al. (2003). "The role and therapeutic potential of 5-HT-moduline in psychiatry." Semin Clin Neuropsychiatry 8(2): 137-46.
The endogenous neuropeptide, 5-HT-moduline, selectively and allosterically interacts with 5-HT(1B) receptors. By binding at a site distinct from that bound by 5-HT, 5-HT-moduline induces structural changes in 5-HT(1B) receptors or stabilizes a particular conformation of these receptors. These conformational changes ultimately lead to the prevention of 5-HT binding resulting in desensitization of these receptors and reduction of the serotonergic function. The efficacy of 5-HT(1B) receptor agonists, for example, has been shown to be reduced by this peptide in vitro and behaviorally. In addition, 5-HT-moduline increases 5-HT release, which is regulated by presynaptic 5-HT(1B) autoreceptors. The release of 5-HT-moduline itself is increased after acute restraint stress in rats, whereas deactivation of 5-HT-moduline by specific antibodies in mice prevents the development of anxiety in a classic behavioral model, suggesting a potential role of the peptide in the control of anxiety. It is thus hypothesized that agents inhibiting the effect of 5-HT-moduline could have anxiolytic activity. Because the serotonergic activity is known to play a key role in psychiatric disorders such as depression and anxiety, compounds capable of mimicking or inhibiting the activity of 5-HT-moduline can represent novel antidepressants or anxiolytics.

Muntener, M., S. Suter, et al. (2003). "[Erectile dysfunction: reasonable diagnostics and treatment in general practice]." Schweiz Rundsch Med Prax 92(5): 179-86.
The availability of efficacious oral drugs has radically changed the diagnostic and therapeutic approach to erectile dysfunction. Complicated examinations as well as invasive treatment options have been widely abandoned. Instead the management of impotent men has become much more pragmatic and focused on the symptom. Consequently only a minority of impotent men needs to be referred to an urologist, which makes the therapy of erectile dysfunction increasingly attractive for general practitioners. However, successful treatment first of all still needs time and a genuine interest in the field of erectile dysfunction. In this article a reasonable diagnostic evaluation of impotent patients in general practice is described. Furthermore indication and use of little or non-invasive therapies are discussed.

Myhrer, T. (2003). "Neurotransmitter systems involved in learning and memory in the rat: a meta-analysis based on studies of four behavioral tasks." Brain Res Brain Res Rev 41(2-3): 268-87.
From previous literature, it appears that most classical neurotransmitter systems can in some way influence learning and memory in the rat. A matter of crucial interest is, however, whether the chemical systems contribute in a similar manner or whether they have different abilities to support cognitive processes. The purpose of the present study was to investigate this issue. The investigation was carried out by reviewing relevant studies of neurochemistry and cognition. Inclusion criteria were set for selection of behavioral tasks to be elucidated and for studies employing acceptable tasks. Morris water maze, radial maze, passive avoidance, and spontaneous alternation met the criteria for inclusion, and a table for each of these tests summarizes the neurochemical results of the studies accepted for inclusion. In this way, a reliable comparability of results from relevant studies was obtained. The comparisons revealed that for both systemic and targeted infusions of agents the neurochemical systems possess different abilities to influence learning and memory. Calculation of impact factors (percentage of significant effects of chemical agents like agonists, antagonists, neurotoxins) showed that glutamate was ranking highest (93), followed by GABA (81), dopamine (81), acetylcholine (81), serotonin (55), and norepinephrine (48). No task specific roles were observed for the transmitter systems. The highest sensitivity (percentage of significant effects) to interference with neurochemical systems was found for the spontaneous alternation task (86), followed by water maze (76), passive avoidance (72), and radial maze (58). The multiple memory systems in the rat brain can hardly be related to specific transmitter systems, because of the great extent of interactions between the systems.

Noble, E. P. (2003). "D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes." Am J Med Genet 116B(1): 103-25.
The D2 dopamine receptor (DRD2) has been one of the most extensively investigated gene in neuropsychiatric disorders. After the first association of the TaqI A DRD2 minor (A1) allele with severe alcoholism in 1990, a large number of international studies have followed. A meta-analysis of these studies of Caucasians showed a significantly higher DRD2 A1 allelic frequency and prevalence in alcoholics when compared to controls. Variants of the DRD2 gene have also been associated with other addictive disorders including cocaine, nicotine and opioid dependence and obesity. It is hypothesized that the DRD2 is a reinforcement or reward gene. The DRD2 gene has also been implicated in schizophrenia, posttraumatic stress disorder, movement disorders and migraine. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in brains of subjects who carry the DRD2 A1 allele. In addition, pleiotropic effects of DRD2 variants have been observed in neurophysiologic, neuropsychologic, stress response, personality and treatment outcome characteristics. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the treatment of these disorders.

Norbury, R., W. J. Cutter, et al. (2003). "The neuroprotective effects of estrogen on the aging brain." Exp Gerontol 38(1-2): 109-17.
The population of the western world is ageing. This increase in the elderly population will inevitably mean a rise in the prevalence of age-related cognitive decline and late-onset neuropsychiatric disorder, such as Alzheimer's disease (AD). There are sex differences in the incidence and age of onset of these disorders. Sex steroids and sex chromosomes are therefore implicated in their pathophysiology. We have identified relevant past and current literature using a Medline search and from the references of relevant papers. These were then reviewed and relevant articles have been summarized and included in the review. Evidence is presented for the wide-ranging actions of estrogen in the brain at the cellular, metabolic and neurotransmitter levels as well as from the cognitive, AD, depression and cerebrovascular perspectives. The authors conclude that it is unlikely that estrogen will become a stand-alone treatment for any of these disorders, although there may still be a role as an adjunctive treatment and as a prophylactic measure.

Nussmeier, N. A. (2003). "Improving perioperative outcomes in patients with end-stage heart failure." Rev Cardiovasc Med 4 Suppl 1: S29-34.
In the United States alone, more than 4.5 million people are affected by heart failure, with more than 500,000 new cases diagnosed each year. Although cardiac transplantation remains the "gold-standard" surgical treatment for heart failure unresponsive to maximal medical therapy, the chronic shortage of donor hearts has necessitated clinical trials of other surgical options. Over the past two decades, research, technological progress, and extensive clinical experience have resulted in the application of ventricular assist device (VAD) technology to a broader population of heart-failure patients, as these devices have proven to be viable therapeutic alternatives for therapy of end-stage heart failure. All patients undergoing cardiac transplantation or VAD insertion have multiorgan dysfunction as a result of irreversible, severe ventricular dysfunction resulting in low cardiac output. Recently, fenoldopam has been described as a vasodilator that might be useful in patients with decompensated heart failure, particularly in the perioperative setting. As a selective dopamine-1 receptor agonist, fenoldopam causes vasodilation in the systemic, renal, mesenteric, coronary, and pulmonary vasculature. Potentially, the pharmacologic properties of fenoldopam could be successfully exploited in patients undergoing medical or surgical treatment of end-stage heart failure. Controlled randomized trials are needed to demonstrate improvement in cardiopulmonary or renal outcomes in such patients.

O'Donnell, P. (2003). "Dopamine gating of forebrain neural ensembles." Eur J Neurosci 17(3): 429-35.
Dopamine may exert different actions depending on a number of factors. A common view is that D1 receptors may be responsible for excitatory actions whereas D2 receptors are involved in inhibitory actions. However, this position cannot be reconciled with several findings indicating otherwise. The role of dopamine on forebrain neural ensembles may be better understood in the light of functional states of the system. Pyramidal cortical neurons and striatal medium spiny neurons alternate between two membrane potential states ('up' and 'down') that could shape dopamine actions. It is proposed that D1 receptors can act as state-stabilizers by sustaining up states and thereby facilitating plasticity mechanisms by providing postsynaptic depolarization and increasing NMDA function. In this way, dopamine can sustain activity in depolarized units. This action is accompanied by a decrease in cell firing (perhaps mediated by D2 receptors), which renders the cells responsive only to strong stimuli. The result would be a net increase in signal-to-noise ratio in a selected assembly of neurons.

Oxford, J. S., S. Bossuyt, et al. (2003). "Treatment of epidemic and pandemic influenza with neuraminidase and M2 proton channel inhibitors." Clin Microbiol Infect 9(1): 1-14.
A small armentarium of anti-influenza drugs now exists, and includes the M2 blockers (amantadine and rimantadine) and the neuraminidase inhibitors (Relenza and Tamiflu). The neuraminidase inhibitors have certain advantages, including a broader spectrum of antiviral activity, including influenza A and B viruses. On the other hand, there is now much clinical experience with the M2 blockers, and these drugs are inexpensive. It is clear that influenza in different community groups needs to be managed in specific and targeted ways. For example, in the over-65-years and at-risk groups, vaccination will remain a mainstay of disease prevention. However, up to 40% of those in these groups may fail to receive vaccine, and therefore the antivirals can be used therapeutically, or, in defined circumstances, as prophylactics. At present, influenza is hardly managed in the community. The infrequent global outbreaks, pandemics, present further problems. The more extensive use of the two classes of antivirals, and also vaccines, in the important interpandemic years will provide a very significant investment in health benefits in the face of a new pandemic virus in an otherwise completely vulnerable population.

Padberg, F. and H. J. Moller (2003). "Repetitive transcranial magnetic stimulation : does it have potential in the treatment of depression?" CNS Drugs 17(6): 383-403.
Transcranial magnetic stimulation (TMS) has become a major research tool in experimental clinical neurophysiology as a result of its potential to noninvasively and focally stimulate cortical brain regions. Currently, studies are being conducted to investigate whether repetitive TMS (rTMS)-mediated modulation of cortical function may also provide a therapeutic approach in neurological and psychiatric disorders. Preclinical findings have shown that prefrontal rTMS can modulate the function of fronto-limbic circuits, which is reversibly altered in major depression. rTMS has also been found to exert effects on neurotransmitter systems involved in the pathophysiology of major depression (e.g. stimulates subcortical dopamine release and acts on the hypothalamic pituitary adrenal axis, which is dysregulated in depression).To date, numerous open and controlled clinical trials with widely differing stimulation parameters have explored the antidepressant potential of rTMS. Though conducted with small sample sizes, the majority of the controlled trials demonstrated significant antidepressant effects of active rTMS compared with a sham condition. Effect sizes, however, varied from modest to substantial, and the patient selection focused on therapy-resistant cases. Moreover, the average treatment duration was approximately 2 weeks, which is short compared with other antidepressant interventions. Larger multicentre trials, which would be mandatory to demonstrate the antidepressant effectiveness of rTMS, have not been conducted to date.A putative future application of rTMS may be the treatment of patients who did not tolerate or did not respond to antidepressant pharmacotherapy before trying more invasive strategies such as electroconvulsive therapy and vagus nerve stimulation. Theoretically, rTMS may be also applied early in the course of disease in order to speed up and increase the effects of antidepressant pharmacotherapy. However, this application has not been a focus of clinical trials to date. Research efforts should be intensified to further investigate the effectiveness of rTMS as an antidepressant intervention and to test specific applications of the technique in the treatment of depressive episodes.

Pagel, J. F. and P. Helfter (2003). "Drug induced nightmares--an etiology based review." Hum Psychopharmacol 18(1): 59-67.
OBJECTIVE: Recent clinical trials have included patient complaints of nightmares as a category of reportable medication side effects. This study integrates that data into current experimental and theoretical research of drug effects that may alter dreaming and nightmares. The objective is to provide a clinical and theoretical framework useful in categorizing the potential and reported drug effects on nightmares. METHODOLOGY: This study reviews case reports and clinical trials that have reported nightmares or alterations in dreaming occurring secondary to medication usage. These data are analysed as to the probability of the drug/nightmare association, and integrated into current electrophysiological and neurochemical theories of dreaming and nightmares. RESULTS: Pharmacological agents affecting the neurotransmitters norepinephrine, serotonin and dopamine are clearly associated with patient reports of nightmares. Agents affecting immunological response to infectious disease are likely to induce nightmares in some patients. A possible association exists between reports of nightmares and agents affecting the neurotransmitters acetylcholine, GABA and histamine, as well as for some anesthetics, antipsychotics and antiepileptic agents. CONCLUSION: By utilizing our current experimental and theoretical knowledge base, the potential etiology of a majority of reported drug effects on nightmares can be classified. These data support current neurochemical theories of dreaming, as well as suggesting that the biochemical basis for dreaming and nightmare induction may be more complex than generally suggested.

Pietrangeli, P., S. Nocera, et al. (2003). "Is the catalytic mechanism of bacteria, plant, and mammal copper-TPQ amine oxidases identical?" Biochim Biophys Acta 1647(1-2): 152-6.
This short review is mostly concerned with the work carried out in Rome on the copper amine oxidase from bovine serum (BSAO). The first target was the copper oxidation state and its relationship with the organic cofactor. It was found that copper is not reduced on reaction with amines under anaerobic conditions or along the catalytic cycle and that it is not within bonding distance of the quinone cofactor. The copper stability in the oxidised state was supported by BSAO ability to oxidise benzylhydrazine, a slow substrate, in the presence of N,N-diethyldithiocarbamate (DDC) and by the substantial catalytic activity of Co(2+)-substituted BSAO. Parallel work established that only one subunit of the dimeric enzyme readily binds reagents of the carbonyl group. Flexible hydrazides with a long aromatic tail were found to be highly specific inhibitors, suggesting the presence of an extended hydrophobic region at the catalytic site. A study by stopped-flow transient spectroscopy and steady state kinetics led to the formulation of a simplified, yet complete and consistent, catalytic mechanism for BSAO that was compared with that available for lentil seedling amine oxidase (LSAO). As in other copper amine oxidases, BSAO is inactivated by H(2)O(2) produced in the catalytic reaction, while the cofactor is stabilised in its reduced state. A conserved tyrosine hydrogen-bonded to the cofactor might be oxidised.

Pliszka, S. R. (2003). "Non-stimulant treatment of attention-deficit/hyperactivity disorder." CNS Spectr 8(4): 253-8.
Stimulants are a highly efficacious and safe treatment for attention-deficit/hyperactivity disorder (ADHD), with 75% to 90% of patients responding well if two different stimulants (amphetamine and methylphenidate) are used. Nonetheless, a subset of ADHD patients will either fail to respond to stimulants or have side effects that preclude their use (tics, severe loss of appetite, marked insomnia). For such patients, there are a number of non-stimulant agents that serve as second-line treatments. Tricyclic antidepressants (TCAs) are the most studied of these drugs. They are superior to placebo in the treatment of ADHD and may reduce abnormal movements in patients with ADHD/tic disorder. TCAs often produce side effects of sedation, dry mouth, and constipation. Bupropion is superior to placebo in the treatment of ADHD and has a more favorable side-effect profile than the TCAs. A new selective norepinephrine reuptake inhibitor, atomoxetine, has been shown to be efficacious in the treatment of ADHD and has recently received an approvable letter from the Food and Drug Administration. The a-agonists clonidine and guanfacine have also been used as alternative agents in ADHD, though the controlled data are more limited. A recent controlled clinical trial suggests a combination of methylphenidate and clonidine has advantages in the treatment of comorbid ADHD and tics over either medication alone. Clinical guidelines for each of these agents, as well as their use in combination with stimulants in comorbid conditions, will be discussed.

Prabhakar, R., P. E. Siegbahn, et al. (2003). "A theoretical study of the dioxygen activation by glucose oxidase and copper amine oxidase." Biochim Biophys Acta 1647(1-2): 173-8.
Glucose oxidase (GO) and copper amine oxidase (CAO) catalyze the reduction of molecular oxygen to hydrogen peroxide. If a closed-shell cofactor (like FADH(2) in GO and topaquinone (TPQ) in CAO) is electron donor in dioxygen reduction, the formation of a closed-shell species (H(2)O(2)) is a spin forbidden process. Both in GO and CAO, formation of a superoxide ion that leads to the creation of a radical pair is experimentally suggested to be the rate-limiting step in the dioxygen reduction process. The present density functional theory (DFT) studies suggest that in GO, the creation of the radical pair induces a spin transition by spin orbit coupling (SOC) in O(2)(-)(rad), whereas in CAO, it is induced by exchange interaction with the paramagnetic metal ion (Cu(II)). In the rate-limiting step, this spin-transition is suggested to transform the O(2)(-)(rad)-FADH(2)(+)(rad) radical pair in GO and the Cu(II)-TPQ (triplet) species in CAO, from a triplet (T) to a singlet (S) state. For CAO, a mechanism for the O[bond]O cleavage step in the biogenesis of TPQ is also suggested.

Rao, M. L. and H. Kolsch (2003). "Effects of estrogen on brain development and neuroprotection--implications for negative symptoms in schizophrenia." Psychoneuroendocrinology 28 Suppl 2: 83-96.
Increasing evidence during the last few years suggests that there are gender-specific differences in schizophrenia, influencing the age of onset, treatment outcome and the prevalence of negative symptoms. With respect to the latter in postmortem brain and cerebrospinal fluid of schizophrenic patients with negative symptoms a reduction of dopaminergic activity became evident. Measures of noradrenergic activity, dopamine beta-hydroxylase and the metabolite MHPG, appear to decrease with brain atrophy seen in patients with negative symptoms. Serotonergic activity tends to be low in patients with impaired cognitive function as is seen in negative schizophrenia. In these patients ventricular enlargement is associated with the severity of negative symptoms, low monoamine activity and low cerebral glucose metabolism.On the other hand atypical antipsychotic drugs that modulate also glutamate receptor activity, suggest an additional alternative mechanism of antipsychotic action beyond aminergic neurotransmitters. These drugs improve glutamatergic transmission and decrease negative symptoms; this suggests a glutamatergic deficiency as an extension of the dopamine model.The glutamate-dopamine interaction illustrates the importance of cross-talk between projections to the cortex, striatum, and lower brainstem for the expression of negative symptomatology. On the other hand, estradiol-17beta the most potent female sex hormone influences not only primary and secondary sexual characteristics but also embryonal and fetal growth as well as development of the brain aminergic networks, which are involved in schizophrenia. Estradiol-l7beta possesses neuroprotective properties, which are relevant for the course of schizophrenia and this may explain the pronounced gender differences with respect to progression and therapeutic response of schizophrenia. The present review attempts an update and synthesis of the information about the hormonal influence on neuronal pathways in negative symptoms of schizophrenia. It shows that estradiol-l7beta influences transporters and receptors as well as the morphological appearance of neuronal systems and that it may be an integral part of the neuroprotective system ameliorating schizophrenia.

Reif, A. and K. P. Lesch (2003). "Toward a molecular architecture of personality." Behav Brain Res 139(1-2): 1-20.
Epidemiological studies provided a large body of evidence that personality dimensions are influenced by genetic factors and that the genetic component is highly complex, polygenic, and epistatic. However, consistent findings on the genetic basis of personality have yet remained sparse. In recent years, molecular genetics has begun to identify specific genes coding in particular for components of the serotonergic and dopaminergic neurotransmitter systems representing quantitative trait loci (QTLs) for behavioral traits. The QTL concept suggests that complex traits are not attributable to single genes. According to this polygenic model, the genetic basis of personality and behavior and its pathological variations thus results from additive or nonadditive interactions of various genes. As the number of suitable candidate genes constantly increases, the QTL model provides a reasonable explanation for the genetic basis of personality and its disorders. In this review, the current knowledge on the impact of a large number of candidate gene polymorphisms (e.g. variations in serotonin and dopamine receptor and serotonin transporter genes) on personality and temperament is summarized. Additionally, investigations of gene-gene and gene-environment interactions in humans and animals, which currently intensify the identification of genes that underlie behavioral variations, are examined. The findings converge on the notion that a probabilistic rather than deterministic impact of genes on the expression of behavior will contribute to the demystification of behavioral disorders.

Richard, I., B. Perrouin-Verbe, et al. (2003). "[Pharmacological treatment of post-traumatic behavioural disorders]." Ann Readapt Med Phys 46(1): 49-57.
OBJECTIVE: Literature review of the data concerning pharmacologic treatment of post-traumatic behavioural disorders. This review is limited to the treatment of agitation, excitation, mood lability, hostility and agressivity as defined by the NRS and excludes pharmacologic treatment of mental slowness, cognitive disorders and depression. METHODS: Medline interrogation using keywords Traumatic Brain Injury, Agitation, Agressivity, Behaviour, Pharmacology, Neuroleptics, Benzodiazepines, Carbamazepine, Valproate, Buspirone, SSRI, Propanolol, Methylphenidate and review of recent contents. The data finally includes 29 original studies. RESULTS: The overall level of evidence is quite low as the data mainly consist in open studies and case reports. These data and data from reviews or didactic articles suggest the efficiency of a variety of treatments. Mood-stabilizing antiepileptics, and specially carbamazepine constitute together with SSRI antidepressants the first choices. Some data suggest efficiency of buspirone, methylphenidate and atypic neuroleptics. Lithium requires close monitoring but is probably efficient. It is difficult to conclude concerning propanolol. CONCLUSION: The available data is in favour of the use of CBZ and SSRI antidepressants. Further studies are required. It is necessary to establish clear evidence of the efficiency of CBZ and assess the effects of methylphenidate, which is almost not prescribed in France.

Rotzinger, S. and F. J. Vaccarino (2003). "Cholecystokinin receptor subtypes: role in the modulation of anxiety-related and reward-related behaviours in animal models." J Psychiatry Neurosci 28(3): 171-81.
Cholecystokinin (CCK) is an abundant and widely distributed neuropeptide that plays a modulatory role in a variety of behaviours. This paper focuses on the role of CCK in modulating anxiety-related and reward-related behaviours in key brain regions of the amygdala and mesolimbic dopamine system, respectively. The role of CCK in mediating aspects of these behaviours has been studied in a variety of behavioural paradigms, but inconsistent results have led to confusion regarding the precise role of the receptor subtypes in mediating behaviour. The confusion in the literature may come in part from the diverse behavioural paradigms that are used, the differences in regional effects of CCK manipulations in different areas and at different receptor subtypes in these areas and the dependence of the behavioural outcome on the baseline state of arousal of the animal. Evidence on the role of CCK in anxiety-related and reward-related behaviours in various animal models indicates that CCK-B receptors in the basolateral amygdala are important mediators of anxiety-related behaviours and that CCK-A and CCK-B receptors in the nucleus accumbens are important in mediating different aspects of reward-related behaviour. Emphasis is placed upon the role of CCK as a neuromodulator that is recruited only under conditions of high frequency neuronal firing.

Safer, D. J., J. M. Zito, et al. (2003). "Concomitant psychotropic medication for youths." Am J Psychiatry 160(3): 438-49.
OBJECTIVE: This study reviewed the clinical research and practice literature relating to the prevalence and patterns of concomitant psychotropic medication given to youths with emotional and behavioral disorders. METHOD: A MEDLINE search from 1996 through spring 2002, including a review of references from relevant published articles and reports, was undertaken to identify available information on concomitant psychotropic medication for youths. RESULTS: The data supporting concomitant psychotropic medication for youths are almost exclusively based on case reports and small-scale, nonblind assessments. In the mid-1990s, over 20% of outpatient youths treated in community mental health centers and over 40% of youths treated in inpatient psychiatric facilities were given concomitant psychotropic medication. The rate has since increased. Psychiatrists more than primary care physicians prescribe concomitant psychotropic medication, and they show great variability in their prescribing habits. Youths with aggressive behavior, male gender, severe emotional illness, and disabling social maladjustment are most likely to receive concomitant psychotropic medication. CONCLUSIONS: Substantive systematic evidence is needed to clarify this increasingly common, inadequately researched child psychopharmacologic practice.

Saint-Cyr, J. A. (2003). "Frontal-striatal circuit functions: context, sequence, and consequence." J Int Neuropsychol Soc 9(1): 103-27.
The exact role of the basal ganglia in both the motor and non-motor domains has proven elusive since it is virtually impossible to refer to its function in isolation of cortical, and especially frontal cortical circuits. The result is that we often speak of frontal-striatal circuits and functions but this still leaves us in the dark when trying to specify basal ganglia information processing. A critical review of the data from both basic science and clinical studies suggests that we should break down processing along a temporal continuum, including the domains of context, sequential information processing, and feedback or reinforcement (i.e., the consequences of action). This analysis would cut across other theoretical constructs, such as attention, central executive, memory, and learning functions, traditionally employed in the neuropsychological literature. Under specified behavioral constraint, the basal ganglia can then be seen to be involved in fundamental aspects of attentional control (often covert), in the guidance of the early stages of learning (especially reinforcement-based, but also encoding strategies in explicit paradigms), and in the associative binding of reward to cue salience and response sequences via dopaminergic mechanisms. Parkinson's disease is considered to offer only a limited view of basal ganglia function due to partial striatal depletion of dopamine and the potential involvement of other structures and transmitters in its pathology. It is hoped that the present formulation will suggest new heuristic research strategies for basal ganglia research, permitting a closer link to be established between neurophysiological, functional imaging and neuropsychological paradigms.

Salamone, J. D., M. Correa, et al. (2003). "Nucleus accumbens dopamine and the regulation of effort in food-seeking behavior: implications for studies of natural motivation, psychiatry, and drug abuse." J Pharmacol Exp Ther 305(1): 1-8.
For several decades, it has been suggested that dopamine (DA), especially in nucleus accumbens, mediates the primary reinforcing characteristics of natural stimuli such as food, as well as drugs of abuse. Yet, several fundamental aspects of primary food reinforcement, motivation, and appetite are left intact after interference with accumbens DA transmission. Recent studies have shown that accumbens DA is involved in responsiveness to conditioned stimuli and activational aspects of motivation. In concurrent choice tasks, accumbens DA depletions cause animals to reallocate their choice behavior in the direction of instrumental behaviors that involve less effort. Also, an emerging body of evidence has demonstrated that the effects of accumbens DA depletions on instrumental food-seeking behavior can vary greatly depending upon the task. For example, some schedules of reinforcement are insensitive to the effects of DA depletions, whereas others are highly sensitive (e.g., large fixed ratios). Accumbens DA depletions slow the rate of operant responding, blunt the rate-facilitating effects of moderate-sized ratios, and enhance the rate-suppressing effects of very large ratios (i.e., produce ratio strain). Accumbens DA may be important for enabling rats to overcome behavioral constraints, such as work-related response costs, and may be critical for the behavioral organization and conditioning processes that enable animals to engage in vigorous responses, such as barrier climbing, or to emit large numbers of responses in ratio schedules in the absence of primary reinforcement. The involvement of accumbens DA in activational aspects of motivation has implications for energy-related disorders in psychiatry, as well as aspects of drug-seeking behavior.

Salter, M. W. (2003). "D1 and NMDA receptors hook up: expanding on an emerging theme." Trends Neurosci 26(5): 235-7.
In the dominant paradigm for functional interactions between G-protein-coupled receptors (GPCRs) and ligand-gated ion channels, the mantra is that the interactions are indirect, indirect, indirect. It is commonly understood that activating GPCRs engages one or more sets of intracellular signaling cascades that indirectly affect the function or localization of a cohort of ligand-gated ion channels. Conversely, stimulating ligand-gated channels, particularly those that are permeable to Ca(2+), indirectly produces effects on GPCRs and/or on GPCR-activated signaling cascades. The foundation of this dichotomous world-view shook (just a little) when it was discovered that D5 dopamine receptors bind directly to GABA(A) receptors, and that this direct interaction reciprocally affects the signaling of both types of receptor. Now, D1 dopamine receptors also have got into the act!

Schapira, A. H. and C. W. Olanow (2003). "Rationale for the use of dopamine agonists as neuroprotective agents in Parkinson's disease." Ann Neurol 53 Suppl 3: S149-57; discussion S157-9.

Schmidt, U. (2003). "Aetiology of eating disorders in the 21(st) century: new answers to old questions." Eur Child Adolesc Psychiatry 12 Suppl 1: I30-7.
This paper reviews the aetiology of the eating disorders, anorexia nervosa and bulimia nervosa, which is generally thought of as multi-factorial in nature. In recent years with the advent of new bio-technologies interest in the exploration of the contribution of biological, in particular genetic factors to the origins of these disorders has been revived. The challenge for the future is to understand better the relative importance of biological and psychosocial risk-factors and how these factors interact. Moreover, there is a need for a greater appreciation of the developmental perspective in the origins of eating disorders.

See, R. E., R. A. Fuchs, et al. (2003). "Drug addiction, relapse, and the amygdala." Ann N Y Acad Sci 985: 294-307.
Evidence has extensively implicated the amygdala in the associative learning process for appetitive reinforcers. Recent interest has focused on the role of the amygdala in the learned associations that occur during the process of drug addiction and relapse. Using an animal model of relapse after chronic cocaine self-administration, we found that rats reinstate extinguished lever responding for conditioned stimuli (tone + light) previously paired with cocaine or heroin ("conditioned-cued reinstatement"). The basolateral amygdala (BLA) complex plays a critical role in this behavior, because permanent lesions or reversible pharmacologic inactivation of the BLA attenuates conditioned-cued reinstatement without affecting cocaine self-administration or cocaine-primed reinstatement. Conditioned-cued reinstatement appears to be mediated in part by dopamine inputs to the BLA, as intra-BLA infusion of a dopamine D1 receptor antagonist blocks reinstatement, whereas intra-BLA infusion of amphetamine potentiates reinstatement. Furthermore, the BLA is also necessary for acquisition of associative learning with cocaine-paired stimuli. Disruption of neural activity within the BLA by sodium channel blockade or muscarinic receptor blockade just before acquisition of stimulus-cocaine associations blocks the ability of conditioned stimuli to elicit conditioned-cued reinstatement after extinction. Together, these results reveal the importance of the amygdala as part of a corticolimbic circuit mediating both the acquisition and the expression of conditioning that plays a critical role in relapse to drug-seeking behavior.

Shabsigh, R. and A. G. Anastasiadis (2003). "Erectile dysfunction." Annu Rev Med 54: 153-68.
Erectile dysfunction (ED) is a highly prevalent and often undertreated condition. It may be a symptom of underlying, chronic illness and can have a negative impact on quality of life, psychosocial health, and relationships. The aging of the population, as well as the introduction of new treatment options, such as sildenafil, has led to increased public awareness of this disorder. New oral therapeutic agents are on the horizon. This article provides an overview of the physiology of erection, the pathophysiology of ED, and modern patient evaluation. Management options, including traditional therapeutic approaches as well as the new generation of oral agents, are also presented.

Shale, J. H., C. M. Shale, et al. (2003). "A review of the safety and efficacy of droperidol for the rapid sedation of severely agitated and violent patients." J Clin Psychiatry 64(5): 500-5.
BACKGROUND: Droperidol had become a standard treatment for sedating severely agitated or violent patients in both psychiatric and medical emergency departments. However, several recent articles have suggested that droperidol may have a quinidine-like effect similar to that of thioridazine in inducing dysrhythmia. METHOD: In view of the recent U.S. Food and Drug Administration (FDA) position regarding the use of thioridazine, the authors reviewed the literature regarding droperidol and dysrhythmia in a MEDLINE search for the years 1960-2002 using the search terms droperidol, dysrhythmia, QTc interval, and sudden death as well as their own experience in using droperidol in a busy psychiatric emergency department. This review was done before the FDA's very recent and peremptory warning about droperidol. RESULTS: The authors report that, in treating approximately 12,000 patients over the past decade, they have never experienced a clinically significant adverse dysrhythmic event using droperidol to sedate severely agitated or violent patients. CONCLUSION: The authors conclude that, in clinical practice, droperidol is an extremely effective and safe method for treating severely agitated or violent patients. While in theory droperidol may prolong the QT interval to an extent similar to thioridazine, in clinical use there is no pattern of sudden deaths analogous to those that provoked the FDA warning about thioridazine.

Sheinbaum, R., C. Ignacio, et al. (2003). "Contemporary strategies to preserve renal function during cardiac and vascular surgery." Rev Cardiovasc Med 4 Suppl 1: S21-8.
Mortality rates associated with perioperative acute renal failure (ARF) range from 60% to 90%. The major causes of ARF are prerenal factors that decrease renal blood flow; intrarenal factors that have a direct effect on tubules, interstitium, or glomeruli; and postrenal factors that obstruct urine outflow. Current strategies to provide perioperative renal protection include maintaining adequate renal O2 delivery, suppressing renovascular vasoconstriction, renovascular vasodilatation, maintaining tubular flow, decreasing renal cellular O2 consumption, and attenuating reperfusion injury. A study of patients undergoing elective repair of a thoracoabdominal aortic aneurysm (TAAA) found that the use of the selective dopamine-1 receptor agonist fenoldopam was associated with reductions in mortality, dialysis requirements, and lengths of stay in the hospital and intensive care unit. The study authors suggest that the improved patient outcomes and hospital-utilization data resulting from the use of fenoldopam were directly related to the protection of renal function during surgery and a reduction of postoperative renal complications.

Shim, H. and Z. L. Harris (2003). "Genetic defects in copper metabolism." J Nutr 133(5 Suppl 1): 1527S-31S.
Genetic defects in copper metabolism highlight the delicate balance mammalian systems have developed to maintain normal copper homeostasis. Menkes disease, the mottled mouse, the Atox-1-deficient mouse and the ctr1 knockout mouse reveal the importance of adequate copper intake during embryogenesis and early development, especially in the central nervous system. The toxicity associated with excess copper as manifest in Wilson disease, the toxic milk mouse, the LEC rat and copper toxicosis in the Bedlington terrier demonstrate the profound cellular susceptibility to copper overload, in particular, in the brain and liver. Ceruloplasmin (Cp) contains 95% of the copper found in human serum, and inherited loss of this protein results in diabetes, retinal degeneration and neurodegeneration. Despite normal copper metabolism, aceruloplasminemic patients and the Cp knockout mouse have disturbed iron homeostasis and mild hepatic copper retention. These genetic disorders of copper metabolism provide valuable insight into the mechanisms regulating copper homeostasis and models to further dissect the role of this essential metal in health and disease.

Siderowf, A. and M. Stern (2003). "Update on Parkinson disease." Ann Intern Med 138(8): 651-8.
This Update reviews developments in the pathophysiology and treatment of Parkinson disease during the past several years. In the area of pathophysiology, studies have addressed the contribution of environmental factors such as caffeine and pesticides. Large-scale epidemiologic studies have also expanded the role genetic factors are thought to play. Detailed studies of kindreds with familial Parkinson disease due to alpha-synuclein and parkin have catalyzed basic science investigations into the pathologic mechanisms of the disease. These studies have led to the development of a pathophysiologic model of Parkinson disease that emphasizes abnormal protein aggregation. Studies of treatment have clarified the relative roles of l-dopa and dopamine agonists in early Parkinson disease and shown the potential for surgical interventions, particularly deep-brain stimulation, to relieve the symptoms of advanced, medically refractory disease.

Silverdale, M. A., S. H. Fox, et al. (2003). "Potential nondopaminergic drugs for Parkinson's disease." Adv Neurol 91: 273-91.

Smith, R., J. Lotharius, et al. (2003). "[Free radicals and ailing proteins--the culprits behind Parkinson disease?]." Lakartidningen 100(15): 1324-6, 1329-30.
Parkinson's disease is one of the most common neurodegenerative diseases, and affects approximately 1% of the population over 65 years of age. Many different insults appear to be involved in the etiology of the disease, among them environmental toxins and mitochondrial dysfunction. During the past five years, mutations in five different genes have been linked to rare, familial forms of Parkinson's disease. One of the mutated proteins, alpha-synuclein is normally implicated in synaptic plasticity and vesicle function. Dysfunction of this protein might lead to increased cytoplasmic dopamine levels. Since cytoplasmic dopamine is readily prone to autooxidation and enzymatic degradation--processes which generate reactive oxygen species--failure to properly store dopamine into vesicles might lead to oxidative stress. Indeed, nigral tissue from idiopathic Parkinson's disease patients shows signs of oxidative damage. In this article we propose that dopamine-induced oxidative stress might be a common final pathway in the pathogenesis of the disease.

Soares, B. G., M. S. Lima, et al. (2003). "Dopamine agonists for cocaine dependence." Cochrane Database Syst Rev(2): CD003352.
BACKGROUND: Cocaine dependence is a common and serious condition, which has become nowadays a substantial public health problem. There is a wide and well documented range of consequences associated to chronic use of this drug, such as medical, psychological and social problems, including the spread of infectious diseases (e.g. AIDS, hepatitis and tuberculosis), crime, violence and neonatal drug exposure. Therapeutic management of the cocaine addicts includes an initial period of abstinence from the drug. During this phase the subjects may experience, besides the intense craving for cocaine, symptoms such as depression, fatigue, irritability, anorexia, and sleep disturbances. It was demonstrated that the acute use of cocaine may enhance dopamine transmission and chronically it decreases dopamine concentrations in the brain. Pharmacological treatment that affects dopamine could theoretically reduce these symptoms and contribute to a more successful therapeutic approach. OBJECTIVES: To evaluate the efficacy and acceptability of dopamine agonists for treating cocaine dependence. SEARCH STRATEGY: Electronic searches of Cochrane Library, EMBASE, MEDLINE, PsycLIT, Biological Abstracts and LILACS; reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence, was performed for the primary version of this review in 2001. Another search of the electronic databases was done in December of 2002 for this update. The specialised register of trials of the Cochrane Group on Drugs and Alcohol was searched until February 2003. SELECTION CRITERIA: The inclusion criteria for all randomised controlled trials were that they should focus on the use of dopamine agonists on the treatment of cocaine dependence. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. MAIN RESULTS: Seventeen studies were included, with 1224 participants randomised. Amantadine, bromocriptine, and pergolide were the drugs evaluated. The main outcomes evaluated were positive urine sample for cocaine metabolites, for efficacy, and retention in treatment, as an acceptability measure. There were no significant differences between interventions, and in trials where participants had primary cocaine dependence or had additional diagnosis of opioid dependence and/or were in methadone maintenance treatment. REVIEWER'S CONCLUSIONS: Current evidence does not support the clinical use of dopamine agonists in the treatment of cocaine dependence. Given the high rate of dropouts in this population, clinicians may consider adding other supportive measures aiming to keep patients in treatment.

Steketee, J. D. (2003). "Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants." Brain Res Brain Res Rev 41(2-3): 203-28.
The mesocorticolimbic dopamine system, which arises in the ventral tegmental area and innervates the nucleus accumbens, among numerous other regions, has been implicated in processes associated with drug addiction, including behavioral sensitization. Behavioral sensitization is the enhanced motor-stimulant response that occurs with repeated exposure to psychostimulants. The medial prefrontal cortex (mPFC), defined as the cortical region that has a reciprocal innervation with the mediodorsal nucleus of the thalamus, is also a terminal region of the mesocorticolimbic dopamine system. The mPFC contains pyramidal glutamatergic neurons that serve as the primary output of this region. These pyramidal neurons are modulated by numerous neurotransmitter systems, including gamma-aminobutyric acidergic interneurons and dopaminergic, noradrenergic, serotonergic, glutamatergic, cholinergic and peptidergic afferents. Changes in interactions between these various neurotransmitter systems in the mPFC may lead to alterations in behavioral responses. For example, recent studies have demonstrated a role for decreased mPFC dopaminergic transmission in the development of psychostimulant-induced behavioral sensitization. The present review will discuss the anatomical organization of the mPFC including descriptions of innervation patterns and receptor localization of the various neurotransmitter systems of this region. Data supporting or suggesting a role for each of these mPFC transmitter systems in the development of behavioral sensitization to cocaine and amphetamine will be presented. Finally a model of the mPFC that may be useful in directing future research efforts on the cortical mechanisms involved in the development of sensitization will be proposed.

Stewart, D. E. (2003). "Physical symptoms of depression: unmet needs in special populations." J Clin Psychiatry 64 Suppl 7: 12-6.
Over two thirds of people suffering from depression complain of pain with or without reporting psychological symptoms. Many people have trouble expressing internal emotions, consider mental illness to be a stigma, or simply assume depressive symptoms relate to their personal situations and therefore do not seek treatment. Physical symptoms are more prevalent among women, the elderly, the poor, children, culturally diverse populations, the medically ill, and the imprisoned. Because of a dual mechanism of action, medications such as duloxetine and venlafaxine may be useful in treating the physical symptoms as well as depressive symptoms in these special populations.

Stewart, P. M. (2003). "Pegvisomant: an advance in clinical efficacy in acromegaly." Eur J Endocrinol 148 Suppl 2: S27-32.
Acromegaly is a chronic disorder invariably caused by a growth hormone (GH)-secreting pituitary tumour and is characterised by disabling symptoms (sweating, arthralgia, headache, paraesthesiae, fatigue), significant comorbidities (diabetes mellitus, hypertension, sleep apnoea), and premature mortality. Symptomatic control can be achieved by lowering insulin-like growth factor-I (IGF-I) concentrations to within the age-adjusted normal range, and survival can be improved to match that of the general population. However, even with optimal surgery and current medical therapies (dopamine agonists, somatostatin analogues), 30% to 50% of patients do not achieve target concentrations of IGF-I and GH. Pegvisomant is a new GH-receptor antagonist that blocks GH activity by inhibiting functional dimerisation of GH-receptors. Given as subcutaneous injections at dosages of 10 mg, 15 mg, or 20 mg/day for 3 Months, pegvisomant normalised serum IGF-I concentrations in, respectively, 54%, 81%, and 89% of acromegalic patients. Moreover, long-term pegvisomant therapy normalised IGF-I concentrations in 97% of patients treated for 12 Months or longer, with no evidence of tachyphylaxis. Pegvisomant is the most effective medical therapy, reported to date, in terms of normalisation of circulating IGF-I concentrations. In addition, pegvisomant appears to be safe and well tolerated. Although additional long-term studies are required to further assess safety, the introduction of this innovative treatment should allow for optimal disease control in patients with acromegaly.

Stiver, G. (2003). "The treatment of influenza with antiviral drugs." Cmaj 168(1): 49-56.
Influenza vaccination with current inactivated vaccines homologous to the prevalent wild-type virus can reduce influenza illness in 75%-80% of healthy adults. Vaccine is recommended for all individuals with chronic underlying diseases and for those aged 65 years or older. Although influenza vaccination is still advocated for patients with blunted immunity, protection rates are not as high, running at 40% for frail institutionalized elderly people. The influenza antiviral agents amantadine or rimantadine, zanamivir and oseltamivir can modify the severity of illness and reduce the duration of illness by about 1.5-2.5 days. Amantadine inhibits only influenza A. Resistant virus may emerge in up to 33% of amantadine-treated patients in the first 5 days of treatment and be transmitted to susceptible close contacts. Side effects are usually mild in short courses of treatment. The neuraminidase inhibitor drugs zanamivir and oseltamivir act on both influenza A and B. Treatment is most effective when given within 30-36 hours after the onset of illness, and the earlier the better. Influenza should be treated with antiviral drugs in unvaccinated and vaccinated high-risk patients, as well as immunosuppressed patients with influenza-like illness, in periods of confirmed influenza prevalence. These drugs may be of great value in the event of a major viral antigenic shift that causes pandemic influenza, if an adequate supply can be sustained.

Stocchi, F. and C. W. Olanow (2003). "Neuroprotection in Parkinson's disease: clinical trials." Ann Neurol 53 Suppl 3: S87-97; discussion S97-9.
Advances in our understanding of the cause and pathogenesis of Parkinson's disease (PD) have permitted the rational selection of putative neuroprotective agents for study in PD. However, the list of agents that might provide neuroprotective effects derived from laboratory studies is daunting, and we face the challenge of determining which agents to bring to the clinic and how to find the resources (patients and funds) to properly study so many promising therapeutic opportunities.1 Appropriate outcome variables that are not confounded by any symptomatic effect of the drug and are acceptable to clinicians and regulatory authorities also remain to be defined. The first clinical trials designed to test the capacity of putative neuroprotective agents to alter the natural history of PD have now been performed and illustrate some of these problems. The DATATOP (Deprenyl and Tocopherol Antioxidant Therapy of PD) study used the time to reach a disease milestone in untreated PD patients (ie, need for levodopa) as the primary end point. However, interpretation of results was confounded by the drug's symptomatic effect. The SINDEPAR (Sinemet-Deprenyl-Parlodel) study used the change in motor score between initial visit and final visit after washout of all study medications as the primary end point. However, here too there were concerns about confounding symptomatic effects, because antiparkinsonian medications have now been shown to have a long duration response that can persist for weeks and perhaps even months after withdrawal. More recent studies have used surrogate markers of the integrity of nigrostriatal function such as striatal uptake of fluorodopa on positron emission tomography (PET) or beta-CIT-on single-photon emission computerized tomography (SPECT) as primary outcome measures. However, it has not yet been confirmed that striatal uptake of these isotopes does in fact correlate with the remaining number of dopamine neurons or terminals, and the possibility of a confounding pharmacological effect has not yet been completely excluded. To date, no drug has been established to have a neuroprotective effect in PD, and none has been approved for a neuroprotective indication. Furthermore, regulatory agencies have not yet agreed that any of the outcome measures currently used will be acceptable for approval of a new drug. Resolution of these issues is of critical importance to convince pharmaceutical companies to expend the hundreds of millions of dollars necessary to bring a new drug to market. Drugs that already have been approved in PD for their symptomatic effects, such as dopamine agonists or propargylamines (eg, selegiline), offer the best opportunity for establishing that a drug is neuroprotective in PD in the immediate future, but herein also lies the difficulty of establishing that any benefits observed are not solely because of the drug's symptomatic properties. Currently, this will most likely entail demonstrating that the drug provides benefit for PD patients for both imaging and clinical markers of disease progression.

Stocchi, F., L. Vacca, et al. (2003). "Are there clinically significant differences between dopamine agonists." Adv Neurol 91: 259-66.

Stoessl, A. J. and R. de la Fuente-Fernandez (2003). "Dopamine receptors in Parkinson's disease: imaging studies." Adv Neurol 91: 65-71.

Sugaya, N. (2003). "[Influenza]." Nippon Rinsho 61 Suppl 2: 135-40.

Sulkava, R. (2003). "Differential diagnosis between early Parkinson's disease and dementia with Lewy bodies." Adv Neurol 91: 411-3.

Swann, A. C. (2003). "Neuroreceptor mechanisms of aggression and its treatment." J Clin Psychiatry 64 Suppl 4: 26-35.
Aggression results from the interaction of multiple systems. It can be classified as predatory, impulsive, or based on a medical condition. The likelihood of aggression is increased by environmental overstimulation or stress, transmitter balances favoring dopamine and excitatory amino acid transmission over serotonin and gamma-aminobutyric acid transmission, and the presence of problems related to impulsivity. Treatments for aggression are based on the underlying causes and generally should combine pharmacologic and environmental or psychotherapeutic measures. Useful pharmacologic agents include mood stabilizers and atypical antipsychotics that combine dopaminergic and serotonergic actions. Drugs acting on nicotine receptors may deserve further attention. Nonpharmacologic measures include behavioral techniques aimed at reducing impulsivity, relapse prevention techniques for substance abuse, and anger management techniques.

Takeguchi, Y., Y. Miyamoto, et al. (2003). "[Severe hypotension during anesthesia in a patient on long-term antidepressant therapy]." Masui 52(3): 284-7.
A 71-year-old woman on chronic therapy with mianserine and amantadine was scheduled to undergo abdominal hysterectomy under spinal anesthesia. Following spinal anesthesia she developed hypotension refractory to continuous intravenous fluid infusion as well as multiple boluses of ephedrine. Because the maximum level of analgesia was T 8, general anesthesia was added using laryngeal mask airway. Immediately after anesthetic induction, a marked hypotension occurred. Blood pressure again did not respond to ephedrine but went up excessively to a small dose of epinephrine without any changes in heart rate. Epinephrine infusion at a low dose rate was needed to sustain the blood pressure during surgery. Both depletion of presynaptic norepinephrine store and down-regulation of postsynaptic beta-receptor may have led to abnormal response to catecholamines in this case.

Takimoto, Y., A. Inui, et al. (2003). "Orexigenic/anorexigenic signals in bulimia nervosa." Curr Mol Med 3(4): 349-60.
Bulimia nervosa (BN) and Anorexia Nervosa (AN) are currently classified as eating disorders (ED). Both disorders are the product of complex interaction between physiological and psychological and social processes; they are characterized by abnormal eating behavior. However, patients with BN differ from AN in their nutritional state and response of treatment with serotonin-selective reuptake inhibitor (SSRI) as well as frequency of comorbidity of mood and anxiety disorders. Although biological mechanisms of both BN and AN are largely unknown, excess of both feeding-stimulatory and feeding inhibitory signaling in AN have been indicated. This report reviews data that point to the hypothesis that dysregulation of monoaminergic and new peptidergic circuitry controlling food intake and energy expenditure play a major role in the eating behavior of BN.

Talley, N. J. (2003). "Update on the role of drug therapy in non-ulcer dyspepsia." Rev Gastroenterol Disord 3(1): 25-30.
Non-ulcer dyspepsia is common and is often confused with other diagnoses. It remains a condition identified by exclusion, and continues to be a challenge to manage. Currently, only a limited number of pharmacological options are available. Antacids are no more effective than placebo in treating nonulcer dyspepsia. H2-receptor antagonists appear to be superior to placebo in efficacy, but many of the studies suggesting this finding have had a suboptimal study design. Proton pump inhibitors have been shown to be superior to placebo, although questions remain as to whether the only subgroup that responds is comprised of patients with unrecognized gastroesophageal reflux disease. Studies have found that prokinetic agents are superior to placebo, but currently only a very limited number of agents within this class can be prescribed in the United States. Sparse data support the role of metoclopramide and its side effects limit its use even further. The eradication of Helicobacter pylori has a small but positive therapeutic benefit in non-ulcer dyspepsia, and can be considered in those confirmed to be infected. Sucralfate is unlikely to be effective, and misoprostol is ineffective. Bismuth alone is probably not efficacious. Tricyclic antidepressants may have a therapeutic role, but this is not firmly established and this class of medication should be reserved for resistant cases. Emerging therapies include drugs that relax the gastric fundus, such as buspirone or sumatriptan, and the new prokinetic tegaserod. Psychological therapies may play a role but studies of these therapies are limited. Therapy for non-ulcer dyspepsia remains challenging and is usually empiric; it will remain so until the mechanisms that induce symptoms of dyspepsia are better understood.

Tan, R. S. (2003). "Novel treatment options for overlapping yet distinct erectile dysfunction and andropause syndromes." Curr Opin Investig Drugs 4(4): 435-8.
The Food & Drug Administration has recently approved, or is in the process of approving newer drugs such as the phosphodiesterase inhibitors and apomorphine to treat men's health issues including erectile dysfunction. Increasing age results in a gradual hypogonadal state in men, for which different novel delivery systems of androgens are currently offered for the symptomatic patient. As such, many men are presenting to healthcare practitioners for the first time. The age of presentation for erectile dysfunction and andropause often overlaps, typically in the fifties and beyond, therefore, it makes sense to screen for erectile dysfunction in andropause patients and vice versa. Erectile dysfunction is usually a harbinger for other illnesses, such as coronary heart disease and depression. The hypogonadal state, likewise, could be a harbinger for other ill health states in men, including obesity, depression, osteoporosis and possibly memory loss. While the newer treatments for erectile dysfunction and andropause are distinctly different and targeted at symptom relief, the presentation of the patient with erectile dysfunction or andropause offers an excellent opportunity for screening for other health states and health education strategies.

Tan, S., B. Hermann, et al. (2003). "Dopaminergic mouse mutants: investigating the roles of the different dopamine receptor subtypes and the dopamine transporter." Int Rev Neurobiol 54: 145-97.

Taylor, D. (2003). "Ziprasidone in the management of schizophrenia : the QT interval issue in context." CNS Drugs 17(6): 423-30.
Ziprasidone is a new atypical antipsychotic recently marketed in a number of countries. Its main advantage over other atypical and typical drugs is its low propensity for causing weight gain. However, ziprasidone has been shown to prolong to some extent the cardiac corrected QT (QTc) interval, a property shared by a number of other antipsychotics.Prolongation of the QTc interval is linked to the ventricular tachyarrhythmia torsade de pointes, which is occasionally fatal, although the precise association between QTc changes and risk of sudden cardiac death has not been determined. QTc prolongation is certainly linked in some way to an increased risk of sudden cardiac death, and this may explain the recent, somewhat preliminary, reports of increased risk associated with use of some antipsychotics. Ziprasidone prolongs QTc to a moderate degree, though to a greater extent than quetiapine, risperidone, olanzapine and haloperidol. There is also preliminary evidence that ziprasidone blocks the delayed potassium rectifier channel in cardiac cells. Because of this, and despite the fact that no increased risk of arrhythmia or sudden death has been demonstrated for ziprasidone, some caution is required. Ziprasidone should be avoided in patients with some types of cardiac disease and with uncontrolled electrolyte disturbance. Coprescription of ziprasidone with other drugs that prolong the QT interval should be avoided where possible. When cross-tapering with other antipsychotics, care should be taken to avoid high total load of antipsychotics, and cross-tapering with drugs known to prolong QT interval at normal clinical doses should be avoided. Under most clinical circumstances, however, ziprasidone may be safely used without ECG monitoring or other special precautions. Its effect on QT interval and possible effect on risk of arrhythmia should be balanced with the observation that the drug has a more favourable effect on bodyweight and glucose homeostasis (and so perhaps cardiac risk) than many other antipsychotics.

Teismann, P., K. Tieu, et al. (2003). "Pathogenic role of glial cells in Parkinson's disease." Mov Disord 18(2): 121-9.
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of these neurons is associated with a glial response composed mainly of activated microglial cells and, to a lesser extent, of reactive astrocytes. This glial response may be the source of trophic factors and can protect against reactive oxygen species and glutamate. Alternatively, this glial response can also mediate a variety of deleterious events related to the production of pro-oxidant reactive species, and pro-inflammatory prostaglandin and cytokines. We discuss the potential protective and deleterious effects of glial cells in the SNpc of PD and examine how those factors may contribute to the pathogenesis of this disease.

Thomas, M. J. and R. C. Malenka (2003). "Synaptic plasticity in the mesolimbic dopamine system." Philos Trans R Soc Lond B Biol Sci 358(1432): 815-9.
Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that mediate all forms of experience-dependent plasticity. It has, however, been difficult to demonstrate directly that experience causes long-lasting changes in synaptic strength and that these mediate changes in behaviour. To address these potential functional roles of LTP and LTD, we have taken advantage of the powerful in vivo effects of drugs of abuse that exert their behavioural effects in large part by acting in the nucleus accumbens (NAc) and ventral tegmental area (VTA); the two major components of the mesolimbic dopamine system. Our studies suggest that in vivo drugs of abuse such as cocaine cause long-lasting changes at excitatory synapses in the NAc and VTA owing to activation of the mechanisms that underlie LTP and LTD in these structures. Thus, administration of drugs of abuse provides a distinctive model for further investigating the mechanisms and functions of synaptic plasticity in brain regions that play important roles in the control of motivated behaviour, and one with considerable practical implications.

Thomson, C. C. and N. A. Rigotti (2003). "Hospital- and clinic-based smoking cessation interventions for smokers with cardiovascular disease." Prog Cardiovasc Dis 45(6): 459-79.
Cigarette smoking is the leading preventable cause of death in the United States and a major risk factor for cardiovascular disease (CVD). Large observational epidemiologic studies conducted in diverse populations have demonstrated a strong association between smoking and CVD morbidity and mortality. Observational epidemiologic studies have also demonstrated a substantial benefit of smoking cessation on cardiovascular morbidity and mortality. Smoking cessation after myocardial infarction reduces subsequent cardiovascular mortality by nearly 50%. Therefore, the use of effective strategies to reduce the prevalence of tobacco use is a high priority for both the primary and secondary prevention of CVD. Effective smoking cessation interventions have been identified in randomized controlled trials in the general population of smokers. These methods, which include behavioral counseling and pharmacotherapy, are incorporated into clinical practice guidelines for physicians in the United States and Great Britain. A smaller but still substantial body of evidence demonstrates the efficacy of these interventions in hospital- and clinic-based settings for smokers with CVD. This evidence is sufficient to support the routine implementation of these smoking cessation methods in inpatient and outpatient settings for smokers with CVD.

Tierney, A. J., T. Kim, et al. (2003). "Dopamine in crayfish and other crustaceans: distribution in the central nervous system and physiological functions." Microsc Res Tech 60(3): 325-35.
Dopamine is widely distributed in the crustacean nervous system and has a diverse array of physiological effects. Immunocytochemical studies of several species have shown that dopamine- and/or tyrosine hydroxylase-containing cells occur in all ganglia of the central nervous system and that processes from some of these cells link ganglia of the ventral nerve cord. This study describes the distribution of tyrosine hydroxylase-containing cells in the central nervous system of a crayfish (Orconectes rusticus) and compares this information to available data from other species. The distribution of tyrosine hydroxylase (an enzyme in the synthetic pathway between tyrosine and dopamine) in O. rusticus is similar to that reported for marine species. However, differences were observed in the number of neurons in some ganglia and in the axonal projections of the L cell, which were more extensive in O. rusticus than in other species studied thus far. We also review the physiological effects of dopamine in crayfish and other crustaceans, focusing on the amine's actions in the endocrine, cardiovascular, and nervous systems, and on behavior when injected into freely-moving animals.

Tosini, G. and C. Fukuhara (2003). "Photic and circadian regulation of retinal melatonin in mammals." J Neuroendocrinol 15(4): 364-9.
Several studies have established that melatonin synthesis occurs in the retina of vertebrates, including mammals. In mammals, a subpopulation of photoreceptors (probably the cones) synthesize melatonin. Melatonin synthesis in the retina is elevated at night and reduced during the day in a fashion similar to events in the pineal gland. Both the MT1 and MT2 melatonin receptors are present in the retina and retinal melatonin does not contribute to circulating levels, suggesting that retinal melatonin acts locally as a neurohormone and/or neuromodulator. Melatonin synthesis in the retina of mammals is under the control of a circadian oscillator, and circadian rhythms in melatonin synthesis and/or release have been described for several species of mammals. These rhythms are present in vivo, persist in vitro, are entrained by light and are temperature compensated. The cloning of the gene responsible for the synthesis of the enzyme arylalkylamine N-acetyltransferase (the key enzyme in the melatonin biosynthetic pathway) has allowed studies of the molecular mechanisms responsible for the generation of retinal melatonin rhythmicity. The present review focuses on the cellular and molecular mechanisms that regulate melatonin synthesis. In particular, we discuss how the photic environment and the circadian clock interact in determining melatonin levels, in addition to the role that melatonin plays in retinal physiology.

Tozzi, F. and C. M. Bulik (2003). "Candidate genes in eating disorders." Curr Drug Target CNS Neurol Disord 2(1): 31-9.
Environmental influences, as well as biological and genetic factors influence risk for eating disorders. Family and twin studies have shown that eating disorders are familial and suggest the influence of genetic factors on their etiology. Positive associations have been observed for some candidate genes that have been studied (such as 5HT2A receptor gene); however, the field has been plagued by nonreplications. In this paper we review the extant association studies of eating disorders.

Tsui, J. K. (2003). "Treatment of dystonia in Parkinson's disease." Adv Neurol 91: 361-4.

Tyl, R. W. and M. A. Friedman (2003). "Effects of acrylamide on rodent reproductive performance." Reprod Toxicol 17(1): 1-13.
Acrylamide monomer causes peripheral neurotoxicity, mutagenicity, clastogenicity, male reproductive toxicity, prenatal lethality, and endocrine-related tumors in rodents. Acrylamide (and/or its metabolite glycidamide) binds to dopamine receptors and spermatid protamines and inhibits activity of kinesin and dyneine, resulting in interference with neuronal intracellular transport and sperm motility. Glycidamide binds to various proteins and DNA. Acrylamide at low doses decreases litter size, with rats more sensitive than mice. At higher doses, sperm morphology and motility and neurotoxicity are affected, which decreases mating frequency. Acrylamide does not affect female reproduction (females exhibit neurotoxicity). Dominant lethal mutations cause decreased newborn litter size. The mechanisms of action appear to be: (1) acrylamide/glycidamide binding to spermatid protamines, causing dominant lethality and effects on sperm morphology; and (2) acrylamide binding to motor proteins, causing distal axonopathy, including hindlimb weakness/paresis, and effects on mounting, sperm motility, and intromission. Glycidamide-induced mutations appear to play no role in reproductive or neurologic toxicity.

Ueno, K., H. Togashi, et al. (2003). "[Behavioral and pharmacological studies of juvenile stroke-prone spontaneously hypertensive rats as an animal model of attention-deficit/hyperactivity disorder]." Nihon Shinkei Seishin Yakurigaku Zasshi 23(1): 47-55.
The present study was undertaken to evaluate juvenile stroke-prone spontaneously hypertensive rats (SHRSP) as an animal model of attention-deficit/hyperactivity disorder (AD/HD). Juvenile SHRSP showed significant increases in horizontal ambulatory activity and vertical rearing activity in the open field as compared with genetic control Wistar-Kyoto rats (WKY). Anxiety-related behavior assessed by elevated plus-maze as an index of impulsivity, the entries into open arms and the spent time in the open arms of SHRSP were significantly higher than those of WKY. Spontaneous alternation behavior requiring attention and working memory in the Y-maze was significantly impaired in male, but not female, SHRSP when compared with sex-matched WKY. Hippocampal long-term potentiation formation, a cellular model of learning and memory, was not impaired in SHRSP. Methylphenidate, a first choice psychostimulant for AD/HD, significantly alleviated the hyperactivity in SHRSP. However, intense impulsivity of SHRSP was not improved by methylphenidate. Methylphenidate dose-dependently and significantly ameliorated the impaired spontaneous alteration behavior in male SHRSP. These results suggest that juvenile male SHRSP manifest problematic behavior resembling ADHD, namely inattention, hyperactivity and impulsivity. Methylphenidate alleviates the behavioral symptoms of hyperactivity and inattention. Thus, juvenile male SHRSP might be a useful behavioral animal model of AD/HD, from behavioral and pharmacological perspectives.

Ueno, S. (2003). "Genetic polymorphisms of serotonin and dopamine transporters in mental disorders." J Med Invest 50(1-2): 25-31.
Transporter-assisted uptake of serotonin (5-HT) and dopamine (DA) has been accounted for activities in human behavior or mental status, because they are the sites of action of widely used antidepressant and psychoactive drugs. Both the human serotonin transporter (5-HTT) and human dopamine transporter (DAT1) genes are good candidates for etiological involvement in various psychiatric conditions. The serotonin transporter gene has two types of functional polymorphisms. One is serotonin transporter linked polymorphic region (5-HTTLPR) consisting of length variation of the repetitive sequence containing 20-23-bp-long repeat elements in the 5'-upstream region of the gene. Another polymorphism is that serotonin transporter variable number of tandem repeats (5-HTTVNTR) in its second intron. Both polymorphisms affect the transcription ratio of 5-HTT gene and may modify neuronal transmission by changing its protein expression. On the other hand, DAT1 gene has a variable number of tandem repeats type polymorphism (DAT1VNTR) in the 3'-untranslated region of the mRNA, which was also reported to change its gene expression. So polymorphic variations of transporters would change the behavioral and neuropathological tendency. Here, the feature of those two transporters and their relations to psychiatric disorders are described.

Uitti, R. J. and Z. K. Wszolek (2003). "Dopamine agonists, sleep disorders, and driving in Parkinson's disease." Adv Neurol 91: 343-9.

Uyeki, T. M. (2003). "Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza." Pediatr Infect Dis J 22(2): 164-77.
BACKGROUND: Prompt testing for influenza can help guide clinical management of patients with suspected influenza. Three antiviral medications, amantadine, oseltamivir and zanamivir, are approved for treatment of influenza in children. Rimantadine and ribavirin have also been used. OBJECTIVES: To review the published evidence on clinically useful diagnostic tests and antiviral treatment for influenza virus infections in children. METHODS: Studies published from 1966 through September 2002 were reviewed on clinical diagnosis, immunofluorescence and rapid influenza tests and on antiviral treatment of influenza virus infections among pediatric populations. RESULTS: No studies assessed the accuracy of clinical diagnosis of influenza in children compared with viral culture. Compared with viral culture, direct immunofluorescence antibody and indirect immunofluorescence antibody tests for influenza had fair to moderate median sensitivities and high median specificities, whereas rapid influenza diagnostic tests had moderate median sensitivities and moderately high median specificities. No randomized, placebo-controlled studies were found of amantadine or rimantadine for treatment of influenza A. In a few separate controlled studies, oseltamivir, zanamivir and ribavirin each reduced symptom duration of influenza compared with placebo. CONCLUSIONS: Additional data are needed about the accuracy of clinical diagnosis of influenza in children. Although direct immunofluorescence antibody staining, indirect immunofluorescence antibody staining and rapid tests are moderately to reasonably accurate in detecting influenza virus infections in children, physicians should use clinical judgment and local surveillance data about circulating influenza viruses when interpreting test results. Further controlled studies of the efficacy, adverse effects and emergence of antiviral resistance during treatment of influenza are needed for all of the antiviral drugs.

van Laar, T. (2003). "Levodopa-induced response fluctuations in patients with Parkinson's disease: strategies for management." CNS Drugs 17(7): 475-89.
Fluctuations in response to levodopa in patients in the advanced stages of idiopathic Parkinson's disease occur frequently and are a difficult problem to treat. Patients who are treated with levodopa have an additional 10% risk of experiencing response fluctuations with each year of treatment: 50% of patients have this problem after 5 years of receiving levodopa therapy and almost 100% of patients after 10 years.The mechanisms by which response fluctuations occur are only partially understood and can be divided into three main types: (i) presynaptic neuronal degeneration leading to a lack of buffering of released levodopa, which is mainly related to wearing-off phenomena; (ii) postsynaptic changes in dopamine receptor sensitivity and number, partially caused by the presynaptic changes, which are clinically related to at-random response fluctuations; and (iii) pharmacokinetic and pharmacodynamic influences of exogenously administered dopaminergic agents.Several oral and parenteral treatment strategies are recommended to manage response fluctuations, such as optimisation of dopamine receptor agonist therapy in combination with a reduction of the levodopa load; use of slow-release levodopa formulations; use of catechol-O-methyltransferase inhibitors; an increase of levodopa dose frequency; use of high-dose amantadine; and intermittent or continuous use of apomorphine and/or levodopa. Continuous stimulation of dopamine receptors with dopaminergic agents is one of the crucial basic steps in the treatment of patients at an advanced stage of Parkinson's disease, and the preferential use of dopamine receptor agonists has proven to be successful in the prevention and treatment of response fluctuations.

van Vloten, W. A. (2003). "Pimozide: use in dermatology." Dermatol Online J 9(2): 3.
Pimozide is widely used in psychiatry for chronic psychoses, schizophrenia, the syndrome of Gilles de la Tourette and to a certain extent, also in dermatology. The only dermatological indication is for delusions of parasitosis. Though there is a good rationale for using pimozide in this disease, the majority of the studies on pimozide in dermatology are uncontrolled trials and case reports.

Vance, M. L. (2003). "Medical treatment of functional pituitary tumors." Neurosurg Clin N Am 14(1): 81-7.
Medical therapy with a dopamine agonist is the most effective for treatment of a prolactin-producing adenoma and is considered as primary treatment. Surgery and pituitary radiation are reserved for patients who either do not tolerate or do not respond to a dopamine agonist drug. A somatostatin analogue is effective medical therapy for patients with acromegaly, and this is usually administered if there is persistent GH hypersecretion after surgical resection. Medical treatment for patients with Cushing's disease is directed at the adrenal glands to reduce cortisol hypersecretion. Unfortunately, there is no effective medical therapy to reduce pituitary corticotropin production. Medical therapy for a gonadotrope adenoma with a dopamine agonist or somatostatin analogue has limited utility but is employed in patients who are unable to undergo surgery and may delay or prevent additional tumor growth. Many patients with a pituitary adenoma can be successfully treated with one treatment, either a dopamine agonist for a prolactinoma or surgery for other types of tumors. A substantial number of patients require multimodality therapy, however, including medical therapy, surgery, and pituitary radiation. Because the biologic behavior of pituitary adenomas varies considerably, a patient with a pituitary adenoma requires lifelong regular monitoring for hormone hypersecretion, tumor recurrence, and development of new pituitary hormone deficiency. A coordinated plan of care among endocrinologists, neurosurgeons, neuroophthalmologists, and radiation therapists is necessary to provide optimal care for these patients.

Vieyra, G., M. Moraga, et al. (2003). "[Distribution of DRD4 and DAT1 alleles from dopaminergic system in a mixed Chilean population]." Rev Med Chil 131(2): 135-43.
BACKGROUND: Genes for dopamine receptor DRD4 and dopamine transporter DAT1 are highly polymorphic. Two alleles of these genes, namely the DRD4.7 and the DAT1*9 are frequently associated to the attention deficit disorder with hyperactivity. In Europe, the allele for DRD4 receptor with four repetitions (DRD4.4) has the highest frequency, with a median of 69%, followed by DRD4.7, with a frequency of 15%. South American indigenous populations have higher frequencies for DRD4.7 (61%) than for DRD4.4 (29%). The ten repetition allele for DAT1 transporter has a high frequency among Europeans (72%) and Amerindians (100%). The allele DAT1*9 is the second most frequent allele. AIM: To study the frequency of DRD4 and DAT1 alleles in a Chilean population sample. MATERIAL AND METHODS: One hundred serum samples were obtained from blood donors in two public hospitals in Santiago. Polymorphic regions for DRD4 and DAT1 were amplified by polymerase chain reaction. RESULTS: The allele DRD4.4 had a frequency of 59% and DRD4.7 a frequency of 27%. The allele DAT1*10 had a frequency of 74%, followed by DAT 1*9, with a frequency of 23%. DISCUSSION: In a Chilean population sample, the frequency of DRD4 and DAT1 alleles was very similar to that of European populations.

Vila, M. and S. Przedborski (2003). "Targeting programmed cell death in neurodegenerative diseases." Nat Rev Neurosci 4(5): 365-75.

Wahlsten, D., P. Metten, et al. (2003). "Different data from different labs: lessons from studies of gene-environment interaction." J Neurobiol 54(1): 283-311.
It is sometimes supposed that standardizing tests of mouse behavior will ensure similar results in different laboratories. We evaluated this supposition by conducting behavioral tests with identical apparatus and test protocols in independent laboratories. Eight genetic groups of mice, including equal numbers of males and females, were either bred locally or shipped from the supplier and then tested on six behaviors simultaneously in three laboratories (Albany, NY; Edmonton, AB; Portland, OR). The behaviors included locomotor activity in a small box, the elevated plus maze, accelerating rotarod, visible platform water escape, cocaine activation of locomotor activity, and ethanol preference in a two-bottle test. A preliminary report of this study presented a conventional analysis of conventional measures that revealed strong effects of both genotype and laboratory as well as noteworthy interactions between genotype and laboratory. We now report a more detailed analysis of additional measures and view the data for each test in different ways. Whether mice were shipped from a supplier or bred locally had negligible effects for almost every measure in the six tests, and sex differences were also absent or very small for most behaviors, whereas genetic effects were almost always large. For locomotor activity, cocaine activation, and elevated plus maze, the analysis demonstrated the strong dependence of genetic differences in behavior on the laboratory giving the tests. For ethanol preference and water escape learning, on the other hand, the three labs obtained essentially the same results for key indicators of behavior. Thus, it is clear that the strong dependence of results on the specific laboratory is itself dependent on the task in question. Our results suggest that there may be advantages of test standardization, but laboratory environments probably can never be made sufficiently similar to guarantee identical results on a wide range of tests in a wide range of labs. Interpretations of our results by colleagues in neuroscience as well as the mass media are reviewed. Pessimistic views, prevalent in the media but relatively uncommon among neuroscientists, of mouse behavioral tests as being highly unreliable are contradicted by our data. Despite the presence of noteworthy interactions between genotype and lab environment, most of the larger differences between inbred strains were replicated across the three labs. Strain differences of moderate effects size, on the other hand, often differed markedly among labs, especially those involving three 129-derived strains. Implications for behavioral screening of targeted and induced mutations in mice are discussed.

Wells, S. and D. Murphy (2003). "Transgenic studies on the regulation of the anterior pituitary gland function by the hypothalamus." Front Neuroendocrinol 24(1): 11-26.
The anterior pituitary gland is composed of five different cell types secreting hormones whose functions include the regulation of post-natal growth (growth hormone, GH), lactation (prolactin, PRL), reproduction (luteinising hormone, LH, and follicle stimulating hormone, FSH), metabolism (thyroid stimulating hormone, TSH), and stress (adrenocorticotrophic hormone, ACTH). The synthesis and secretion of the anterior pituitary hormones is under the control of neuropeptides released from the hypothalamus into a capillary portal plexus which flows through the external zone of the median eminence to the anterior lobe. This review describes the ways that gene transfer technologies have been applied to whole animals in order to study the regulation of anterior pituitary function by the hypothalamus. The extensive studies on these neuronal systems, within the context of the physiological integrity of the intact organism, not only exemplify the successful application of transgenic technologies to neuroendocrine systems, but also illustrate the problems that have been encountered, and the challenges that lie ahead.

West, R. (2003). "Bupropion SR for smoking cessation." Expert Opin Pharmacother 4(4): 533-40.
Cigarette dependence is recognised as a life-threatening disorder which can be treated by behavioural support and/or medication. Bupropion hydrochloride sustained-release (Zyban trade mark, GlaxoSmithKline) is licensed in many countries including the US, Canada, UK, Australia and continental Europe to aid smoking cessation. The usual recommended dose is 150 mg b.i.d. taken for 7 - 14 days prior to the quit date, and then 6 - 8 weeks afterwards (figures vary across countries). Evidence from seven double-blind, placebo-controlled, randomised trials shows that it improves success at staying off cigarettes for at least 12 months by 9 - 10 percentage points. Taking into account estimates of subsequent cessation and relapse patterns in treated and untreated smokers, and the improvement in life-expectancy of smokers who manage to stop, the estimated cost/life/year saved from an episode of use of the medication is approximately UK pound 1000 or US$1500. Bupropion has CNS stimulant properties; the common side effects are dry mouth and sleep disturbance. Rare but serious side effects are anaphylactic/hypersensitivity reaction and seizure (both estimated at 1 in a 1000). The drug is contraindicated in patients with hypersensitivity to the drug or its metabolites, any seizure disorder, eating disorder, severe hepatic cirrhosis, history of bipolar disorder or in patients taking monoamine oxidase inhibitors. Extreme caution is advised where there are any predisposing factors that may reduce the seizure threshold. Bupropion sustained-release and nicotine replacement therapies are both considered as first-line treatments to aid smoking cessation. Ideally patients should also enrol in a structured behavioural support programme to boost their chances of success.

Wichmann, T. and M. R. DeLong (2003). "Functional neuroanatomy of the basal ganglia in Parkinson's disease." Adv Neurol 91: 9-18.

Widner, H. (2003). "Strategies to modify levodopa treatment." Adv Neurol 91: 229-36.

Wolf, F. W. and U. Heberlein (2003). "Invertebrate models of drug abuse." J Neurobiol 54(1): 161-78.
Susceptibility to drug addiction depends on genetic and environmental factors and their complex interactions. Studies with mammalian models have identified molecular targets, neurochemical systems, and brain regions that mediate some of the addictive properties of abused drugs. Yet, our understanding of how the primary effects of drugs lead to addiction remains incomplete. Recently, researchers have turned to the invertebrate model systems Drosophila melanogaster and Caenorhabditis elegans to dissect the mechanisms by which abused drugs modulate behavior. Due to their sophisticated genetics, relatively simple anatomy, and their remarkable molecular similarity to mammals, these invertebrate models should provide useful insights into the mechanisms of drug action. Here we review recent behavioral and genetic studies in flies and worms on the effects of ethanol, cocaine, and nicotine, three of the most widely abused drugs in the world.

Yoshimura, N. (2003). "[New insights into neural mechanisms controlling the micturition reflex]." Nippon Yakurigaku Zasshi 121(5): 290-8.
The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. This activity is in turn controlled by neural circuits in the brain, spinal cord, and peripheral ganglia. During urine storage, the outlet is closed and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. The brain rostral to the pons (diencephalon and cerebral cortex) is also involved in excitatory and inhibitory regulation of the micturition reflex. Various transmitters including dopamine, serotonin, norepinephrine, GABA, excitatory and inhibitory amino acids, opioids, acetylcholine, and neuropeptides are implicated in the modulation of the micturition reflex in the central nervous system. Therefore, injury or diseases of the nervous system, as well as drugs and disorders of the peripheral organs, can produce bladder and urethral dysfunctions such as urinary frequency, urgency and incontinence, or inefficient bladder emptying.

Yu, Q., D. F. Larson, et al. (2003). "Heart disease, methamphetamine and AIDS." Life Sci 73(2): 129-40.
Methamphetamine (MA) not only affects the nervous system but also has cardiac toxicity and immunosuppressive properties. This manuscript will provide support that there is a relationship between MA use and heart disease as well as immune dysfunction. The cardiovascular manifestations of acute MA use include tachycardia, atrioventricular arrhythmias, myocardial ischemia, myocardial ischemia and hypertension, resulting in cardiac lesions. Chronic use of MA causes cardiomyopathy including cellular infiltration, myocardial hypertrophy, myocardium rupture and fibrosis. The increased catecholamine levels are responsible for the cardiac lesions induced by MA. The additional problem with MA use is its potential to disrupt the immune system function leading to suppression of mitogen-stimulated lymphocyte, a reduction in circulating lymphocyte numbers and alternation T-lymphocyte cytokine secretion as well as B cell proinflammatory cytokine secretion. Concomitant MA use and Human Immunodeficiency Virus (HIV) infection not only enhances immunosuppression associated with HIV but also increases the heart disease occurrence with a coincidentally complication of AIDS or AIDS medications.

Zeuzem, S. (2003). "[Combination therapy for chronic viral hepatitis C]." Dtsch Med Wochenschr 128(8): 370-4.

Zhou, F. M., C. Wilson, et al. (2003). "Muscarinic and nicotinic cholinergic mechanisms in the mesostriatal dopamine systems." Neuroscientist 9(1): 23-36.
The striatum and its dense dopaminergic innervation originating in the midbrain, primarily from the substantia nigra pars compacta and the ventral tegmental area, compose the mesostriatal dopamine (DA) systems. The nigrostriatal system is involved mainly in motor coordination and in disorders such as Tourette's syndrome, Huntington's disease, and Parkinson's disease. The dopaminergic projections from the ventral tegmental area to the striatum participate more in the processes that shape behaviors leading to reward, and addictive drugs act upon this mesolimbic system. The midbrain DA areas receive cholinergic innervation from the pedunculopontine tegmentum and the laterodorsal pontine tegmentum, whereas the striatum receives dense cholinergic innervation from local interneurons. The various neurons of the mesostriatal systems express multiple types of muscarinic and nicotinic acetylcholine receptors as well as DA receptors. Especially in the striatum, the dense mingling of dopaminergic and cholinergic constituents enables potent interactions. Evidence indicates that cholinergic and dopaminergic systems work together to produce the coordinated functioning of the striatum. Loss of that cooperative activity contributes to the dysfunction underlying Parkinson's disease.

Zolk, O. and N. Thurauf (2003). "[Risperidone]." Dtsch Med Wochenschr 128(24): 1353-6.

           

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