(2001). "[Parkinson disease: diagnostic and therapeutic criteria]." Presse Med 30(8): 379-85.

(2001). "How schizophrenia develops: new evidence and new ideas." Harv Ment Health Lett 17(8): 1-4.

Absil, P., M. Baillien, et al. (2001). "The control of preoptic aromatase activity by afferent inputs in Japanese quail." Brain Res Brain Res Rev 37(1-3): 38-58.
This review summarizes current knowledge on the mechanisms that control aromatase activity in the quail preoptic area, a brain region that plays a key role in the control of reproduction. Aromatase and aromatase mRNA synthesis in the preoptic area are enhanced by testosterone and its metabolite estradiol, but estradiol receptors of the alpha subtype are not regularly colocalized with aromatase. Estradiol receptors of the beta subtype are present in the preoptic area but it is not yet known whether these receptors are colocalized with aromatase. The regulation by estrogen of aromatase activity may be, in part, trans-synaptically mediated, in a manner that is reminiscent of the ways in which steroids control the activity of gonadotropic hormone releasing hormone neurons. Aromatase-immunoreactive neurons are surrounded by dense networks of vasotocin-immunoreactive and tyrosine hydroxylase-immunoreactive fibers and punctate structures. These inputs are in part steroid-sensitive and could therefore mediate the effects of steroids on aromatase activity. In vivo pharmacological experiments indicate that catecholaminergic depletions significantly affect aromatase activity presumably by modulating aromatase transcription. In addition, in vitro studies on brain homogenates or on preoptic-hypothalamic explants show that aromatase activity can be rapidly modulated by a variety of dopaminergic compounds. These effects do not appear to be mediated by the membrane dopamine receptors and could involve changes in the phosphorylation state of the enzyme. Together, these results provide converging evidence for a direct control of aromatase activity by catecholamines consistent with the anatomical data indicating the presence of a catecholaminergic innervation of aromatase cells. These dopamine-induced changes in aromatase activity are observed after several hours or days and presumably result from changes in aromatase transcription but rapid non-genomic controls have also been identified. The potential significance of these processes for the physiology of reproduction is critically evaluated.

Adams, J. D., Jr., M. L. Chang, et al. (2001). "Parkinson's disease--redox mechanisms." Curr Med Chem 8(7): 809-14.
Parkinson's disease occurs in 1% of people over the age of 65 when about 60% of the dopaminergic neurons in the substantia nigra of the midbrain are lost. Dopaminergic neurons appear to die by a process of apoptosis that is induced by oxidative stress. Oxygen radicals abstract hydrogen from DNA forming DNA radicals that lead to DNA fragmentation, activation of DNA protective mechanisms, NAD depletion and apoptosis. Oxygen radicals can be formed in dopaminergic neurons by redox cycling of MPP+, the active metabolite of MPTP. This redox cycling mechanism involves the reduction of MPP+ by a number of enzymes, especially flavin containing enzymes, some of which are found in mitochondria. Tyrosine hydroxylase is present in all dopaminergic neurons and is responsible for the synthesis of dopamine. However, tyrosine hydroxylase can form oxygen radicals in a redox mechanism involving its cofactor, tetrahydrobiopterin. Dopamine may be oxidized by monoamine oxidase to form oxygen radicals and 3,4-dihydroxyphenylacetaldehyde. This aldehyde may be oxidized by aldehyde dehydrogenase with the formation of oxygen radicals and 3,4-dihydroxyphenylacetic acid. The redox mechanisms of oxygen radical formation by MPTP, tyrosine hydroxylase, monoamine oxidase and aldehyde dehydrogenase will be discussed. Possible clinical applications of these mechanisms will be briefly presented.

Ahlskog, J. E. (2001). "Parkinson's disease: medical and surgical treatment." Neurol Clin 19(3): 579-605, vi.
It has been over three decades since the introduction of L-dihydroxyphenylalanine or levodopa therapy for Parkinson's disease (PD). The early levodopa trials were driven by recognition of a profound cerebral dopamine deficiency state in this disorder. Whereas dopamine fails to cross the blood brain barrier and hence is ineffective as therapy, the amino acid precursor, dopa, is transported across this barrier and provides a substrate for dopamine synthesis. Levodopa is converted to dopamine within the brain by dopa decarboxylase, replenishing central dopamine stores and potentially reversing the motor symptoms of PD.

Alexopoulos, G. S. (2001). ""The depression-executive dysfunction syndrome of late life": a specific target for D3 agonists?" Am J Geriatr Psychiatry 9(1): 22-9.

Allen, R. P. and C. J. Earley (2001). "Restless legs syndrome: a review of clinical and pathophysiologic features." J Clin Neurophysiol 18(2): 128-47.
Restless legs syndrome (RLS), although long ignored and still much underdiagnosed, disrupts the life and sleep considerably of those who have it. Recent clinical and basic research provides for better definition and pathophysiologic understanding of the disorder. The body of knowledge about this disorder has been expanding rapidly during the past decade and it has altered our concepts of this disorder. This review of RLS covers history, diagnosis, morbidity of sleep disturbance, relation to periodic limb movements in both sleep and waking, secondary causes, severity assessment methods, phenotypes for possible genetic patterns, epidemiology, pathophysiology, and medical treatment considerations. The emphasis on pathophysiology includes consideration of central nervous system localization, neurotransmitter and other systems involved, and the role of iron metabolism. Studies to date support the authors' recently advanced iron-dopamine model of RLS.

Alper, K. R. (2001). "Ibogaine: a review." Alkaloids Chem Biol 56: 1-38.

Altwein, J. E. and F. U. Keuler (2001). "Oral treatment of erectile dysfunction with apomorphine SL." Urol Int 67(4): 257-63.
Apomorphine SL (Ixense, Uprima) is a new oral medication shown to be effective in the treatment of erectile dysfunction. This compound is a dopaminergic agonist with affinity for dopamine receptor sites - mostly D(2) - within the brain known to be involved in sexual function. Apomorphine induces selective activation in the nucleus paraventricularis leading to erectogenic signals. More than 5,000 men with erectile dysfunction participated in phase II/III clinical trials assessing the safety and efficacy of doses ranging from 2 to 6 mg. The most favorable risk/benefit ratio is seen with a dose-optimization regimen of 2-3 mg: the 3-mg dose provides efficacy comparable to that of 4 mg but with fewer side effects. Consequently, review of clinical studies focuses on data with the 2- to 3-mg dose, the registered dose for use in clinical practice. The primary efficacy endpoint in most clinical trials with apomorphine SL was the percentage of attempts resulting in erections firm enough for intercourse - one of the most rigorous endpoints used in ED trials to date. These data were collected from both patients and their partners by reviewing entries in patient diaries and partner BSFI questionnaires. Secondary endpoints included percentage of attempts resulting in intercourse and improvement in ED severity based on the International Index of Erectile Function (IIEF). The proportion of attempts resulting in erections firm enough for intercourse was 49.4% with 3 mg compared with the baseline value of 24.3%. Partner evaluations corresponded with those of the patients. Erections occurred between 18 and 19 min after taking apomorphine SL 2 or 3 mg. The most common side effect was nausea which declined with continued use. Vasovagal syncope was reported in <0.2% of men, and was preceded by clear prodromal symptoms. Thus, apomorphine SL is an effective, well-tolerated drug for erectile dysfunction.

Amar, K. (2001). "Overview of restless legs syndrome." Hosp Med 62(8): 487-9.
Restless legs syndrome is a common movement and sleep disorder, which can significantly reduce quality of life. Restless legs syndrome is probably related to dopamine imbalance and may have a primary or secondary aetiology. It is greatly underdiagnosed, yet potentially treatable.

Amenta, F., A. Ricci, et al. (2001). "The dopaminergic system in hypertension." Clin Exp Hypertens 23(1-2): 15-24.
Dopamine exerts cardiovascular and renal actions mediated through interaction with specific dopamine receptors. Dopamine receptors are cell surface receptors coupled to G-proteins and classified into two main super families based on biochemical, pharmacological and molecular characteristics. The dopamine D1-like receptor super family includes D1 and D5 receptors, known also in rodents as D1A and D1B sites. These receptors are linked to stimulation of adenylate cyclase. The dopamine D2-like receptor super family includes D2, D3 and D4 receptors. These receptors are linked to inhibition of adenylate cylase or not related with this enzyme activity. They also interfere with opening of Ca+2 channels and are linked to stimulation of K+ receptors. Dopamine receptor subtypes are expressed in brain as well as in extracerebral structures such as the heart, blood vessels, carotid body, kidney, adrenal gland, parathyroid gland and gastrointestinal tract. In the kidney, which represents the peripheral organ where dopamine receptors were more extensively investigated, dopamine receptors are involved in regulation of hemodynamic, electrolyte and water transport, as well as renin secretion. Hypertension-related dopamine receptor changes were also investigated primarily in the kidney. Defective renal dopamine production and/or dopamine receptor function have been reported in human primary hypertension as well as in genetic models of animal hypertension. There may be a primary defect in D1-like receptors and an altered signalling system in the proximal tubules that lead to reduced dopamine-mediated effects on renal sodium excretion in hypertension. Studies on the influence of hypertension on dopamine D2-like receptors are sparse Disruption of either D1A or D3 receptors at the gene level causes hypertension in mice. Using peripheral blood lymphocytes as possible markers of the status of dopamine receptors in essential hypertension, no changes of dopamine D1-like receptors were noticeable, whereas an increase of dopamine D2-like receptors likely representing an up-regulation mechanism was reported. Available information collectively indicates an involvement of peripheral dopaminergic system in hypertension consisting either in impaired receptor transduction mechanisms and/or in receptor loss. A better knowledge of molecular bases of these changes may contribute to the development of specific therapeutic approaches in the future.

Ananth, J., K. S. Burgoyne, et al. (2001). "How do the atypical antipsychotics work?" J Psychiatry Neurosci 26(5): 385-94.
Understanding the action of atypical antipsychotics is useful in exploring the pathophysiology of schizophrenia and in synthesizing drugs that improve various domains of psychopathology without unwanted side effects. In animal models, atypical antipsychotic drugs appear to have a preferential action in the limbic dopaminergic system. Regionally specific action has been studied by measuring the amount of Fos protein produced in a particular brain region as a consequence of a drug's effects on the c-fos gene. Evidence suggests that the atypical and typical antipsychotic drug-induced increases in Fos levels in the nucleus accumbens are related to improvements in positive symptoms, whereas Fos increases in the prefrontal cortex, with the atypical antipsychotics only, correlate with negative symptom improvement. The extrapyramidal effects seen with typical antipsychotics are thought to be related to Fos increases in the striatonigral pathway. However, studies of Fos levels in specific brain regions reveal only the site of action, not the mode of action. The finding that atypicality is related to surmountable D2 dopamine receptor blocking provides another venue to define and explore atypical antipsychotic drug action.

Andersen, J. K. (2001). "Do alterations in glutathione and iron levels contribute to pathology associated with Parkinson's disease?" Novartis Found Symp 235: 11-20; discussion 20-5.
A growing body of evidence has implicated oxidative stress as an important factor in the neuropathology associated with Parkinson's disease. Dopaminergic nigrostriatal neurons, the predominant cells lost in Parkinson's, are believed to be highly prone to oxidative damage due to the propensity for dopamine to auto-oxidize and thereby produce elevated levels of hydrogen peroxide and catecholamine quinones. Hydrogen peroxide formed during this process can either be converted by iron to form highly reactive hydroxyl radicals or removed through reduction by glutathione. Glutathione can also conjugate with quinones formed during dopamine oxidation preventing them from facilitating the release of iron from the iron-storage molecule ferritin. Alterations in both iron and glutathione levels in the substantia nigra have been correlated with the neuronal degeneration accompanying Parkinson's disease but a direct causative role for either has yet to be definitively proved. We will discuss the use of genetically engineered cell and mouse lines generated in our laboratory as models to examine the role that alterations in iron and glutathione levels may play in neurodegeneration of dopaminergic neurons of the substantia nigra associated with Parkinson's disease, and how these two parameters may interact with one another to bring this about.

Andersson, K. E. (2001). "Pharmacology of penile erection." Pharmacol Rev 53(3): 417-50.
Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents, but also by visual, olfactory, and imaginary stimuli. The reflex involves both autonomic and somatic efferents and is modulated by supraspinal influences. Several central transmitters involved in the erectile control have been identified. Dopamine, acetylcholine, nitric oxide (NO), and peptides, such as oxytocin and adrenocorticotropic/alpha-melanocyte-stimulating hormone, seem to have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. Peripherally, the balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa and determines the functional state of the penis. Noradrenaline contracts both corpus cavernosum and penile vessels via stimulation of alpha(1)-adrenoceptors. Neurogenic NO is considered the most important factor for relaxation of penile vessels and corpus cavernosum. The role of other mediators released from nerves or endothelium has not been definitely established. Erectile dysfunction (ED) may be due to inability of penile smooth muscles to relax. This inability can have multiple causes. However, patients with ED respond well to the pharmacological treatments that are currently available. The drugs used are able to substitute, partially or completely, the malfunctioning endogenous mechanisms that control penile erection. Most drugs have a direct action on penile tissue facilitating penile smooth muscle relaxation, including prostaglandin E(1), NO donors, phosphodiesterase inhibitors, and alpha-adrenoceptor antagonists. Dopamine receptors in central nervous centers participating in the initiation of erection have been targeted for the treatment of ED. Apomorphine, administered sublingually, is the first of such drugs.

Andersson, K. E. (2001). "Neurophysiology/pharmacology of erection." Int J Impot Res 13 Suppl 3: S8-S17.
Despite considerable advances, both the central regulation of erection with processing of various stimuli, and the different steps involved in neurotransmission, impulse propagation and intracellular transduction of neural signals in penile smooth muscles, are still incompletely known. Centrally as well as peripherally, many transmitters and transmitter systems are involved. Dopamine, nitric oxide, oxytocin and ACTH/alpha-MSH, seem to have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. Peripherally, the balance between contractant (eg noradrenaline, endothelins, angiotensins) and relaxant (eg NO, VIP and related peptides, prostanoids) factors controls the degree of contraction of the smooth muscle of the corpora cavernosa, and determines the functional state of the penis. Neurogenic NO is considered the most important factor for relaxation of penile vessels and corpus cavernosum. The roles of other putative transmitters/mediators and of various intracellular mechanisms, producing relaxation of vascular and corpus cavernosum smooth muscle, have not been established. For example, recent findings have suggested a role of Rho/Rho-kinase in the regulation of cavernosal tone, and that Rho-kinase antagonism could be a new potential principle for the treatment of erectile dysfunction. Further research in this area may be rewarding.

Andersson, K. E. (2001). "Pharmacology of erectile function and dysfunction." Urol Clin North Am 28(2): 233-47.
Central regulation of the erectile process involves several transmitters, including dopamine, serotonin, noradrenaline, and nitric oxide, and peptides, such as oxytocin and ACTH/alpha-MSH. These systems may be targets for future drugs designed to treat erectile dysfunction. Peripherally, the different steps involved in neurotransmission, impulse propagation, and intracellular transduction of neural signals in penile smooth muscles need further investigation. Continued studies of the interactions between different transmitters/modulators may reveal new combination therapies. Increased knowledge of the changes in penile tissues associated with erectile dysfunction may explain the pathogenetic mechanisms and help to prevent the disorder.

Angrist, B., J. Rotrosen, et al. (2001). "Commentary on: "Differential effects of amphetamine and neuroleptics on negative vs. positive symptoms in schizophrenia." Psychopharmacology (1980) 72:17-19." Psychopharmacology (Berl) 158(3): 219-21.

Anton, R. F. (2001). "Pharmacologic approaches to the management of alcoholism." J Clin Psychiatry 62 Suppl 20: 11-7.
Our understanding of alcohol craving, both as a cause for chronic abuse and relapse and as a target for intervention, has been refined significantly in recent years. For example, craving experienced during alcohol withdrawal may be mediated by gamma-aminobutyric acid (GABA) and glutamate receptor mechanisms, whereas the memory of the rewarding aspects of alcohol may be mediated by dopamine, opiate, and glutamate systems. Therefore, pharmacologic treatments for alcohol dependence may be targeted to numerous pathways. This article will discuss animal and clinical studies of the opioid antagonists (primarily naltrexone), acamprosate, and disulfiram. The side effects and treatment recommendations for each drug will also be reviewed.

Aoki, Y. (2001). "Polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans as endocrine disrupters--what we have learned from Yusho disease." Environ Res 86(1): 2-11.
Polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans (PCDFs) are persistent environmental pollutants. In some areas wildlife reproduction has been affected by these compounds, which are recognized as endocrine disrupters. In 1968 in northern Kyushu in Japan about 2000 people were poisoned by PCBs and PCDFs (pyrolysis products of PCBs) which contaminated rice oil. Their condition was named "Yusho" disease. A similar poisoning by PCBs in Taiwan was named "Yu-Cheng" disease. The major symptoms of Yusho disease were dermal and ocular lesions, but some of the symptoms, such as irregular menstrual cycles and altered immune responses, were notable with respect to the endocrine disrupting activities of PCBs and related compounds. Several important observations relevant to the mechanisms of Yusho have been made from animal studies. For example, a coplanar PCB congener was shown to cause atrophy of the thymus and PCB administration was thought to alter androgen metabolism. The most tragic aspect of Yusho and Yu-Cheng diseases was the exposure of children to PCBs. In the case of Yu-Cheng, children exposed to PCBs in utero and lactationally were reported to have poor cognitive development. Intellectual impairment was also observed in children born to women who had eaten fish contaminated with PCBs in the United States. From animal studies, alterations in thyroid hormone status, modulation of protein kinase C, and changes in dopamine levels, etc. were proposed as the possible mechanisms for the adverse effects of PCBs on brain development. Whereas coplanar PCB and related congeners, e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin, induce gene expression via a ligand-dependent transactivating factor, the arylhydrocarbon receptor, alternative pathways for gene expression, e.g., c-Src and cross talk with the MAP kinase pathway, are also reviewed with respect to understanding the toxic mechanisms of these compounds. Finally, the "precautionary principle" is discussed for prevention of the health hazards caused by exposure to endocrine disrupters.

Aou, S. (2001). "[Physiology of appetite and feeding behavior: introduction]." Nippon Rinsho 59(3): 407-12.
Food intake is regulated by the central nervous system depending on macronutrients and environmental changes. The hypothalamus is the target of hunger and satiety signals arising from the peripheral organs and the brain. Noradrenaline-neuropeptide Y and opioid-galanine are involved in carbohydrate and fat intake, respectively, while serotonin-CCK-insulin and dopamine-cyclic dipeptides systems inhibit them. Histamine and proinflammatory cytokines are involved in stress- and sickness-induced anorexia. Leptin accelerated intrahypothalamic anorexic mechanisms executed by POMC/CART and CRH but suppresses orexigenic mechanisms promoted by NPY and orexin. Although these mechanisms elegantly regulate appetite and feeding behavior, disruption of weight control has been accelerated and the incidence of obesity and eating disorder are dramatically increasing recent years in our modern society. New approach may be necessary to solve the problems of weight control.

Aperia, A. (2001). "Regulation of sodium/potassium ATPase activity: impact on salt balance and vascular contractility." Curr Hypertens Rep 3(2): 165-71.
Na+,K+-ATPase distributes ions between the intracellular and extracellular space and is responsible for total-body sodium homeostasis. The activity of this ion pump is regulated by catecholamines and peptide hormones; by the ligand of Na+,K+-ATPase, ouabain; and by direct interaction with cytoskeleton proteins. This review summarizes recent advances in the field of short-term regulation of Na+,K+-ATPase and the implications of these advances for the regulation of blood pressure. Renal Na+,K+-ATPase activity is bidirectionally regulated by natriuretic and antinatriuretic hormones, and a shift in the balance between these forces may lead to salt retention and hypertension. Dopamine plays a key role in this interactive regulation. By inhibiting vascular Na+,K+-ATPase activity, an excess of circulating ouabain may increase calcium concentration in vascular cells and lead to increased vascular contractility. Finally, mutations in cytoskeleton proteins may stimulate renal Na+,K+-ATPase activity by way of protein/protein interaction and lead to salt retention and hypertension. Abnormalities in the systems regulating Na+,K+-ATPase should be explored further in the search for the multiple causes of essential hypertension.

Arafah, B. M. and M. P. Nasrallah (2001). "Pituitary tumors: pathophysiology, clinical manifestations and management." Endocr Relat Cancer 8(4): 287-305.
Pituitary tumors are frequently encountered intracranial neoplasms. They present with a variety of clinical manifestations that include symptoms and signs of excessive hormone secretion by the tumor, signs of hormone deficits by the normal pituitary gland and others related to expansion of the tumor mass and the resulting compression of surrounding structures such as the optic chiasm and cranial nerves. Advances in molecular biology, immunocytochemical staining and imaging, and the introduction of new treatment options have improved our understanding of the natural history of these adenomas and their management. Available treatments include surgical, medical and radiation therapy. Although the primary treatment for each tumor type may vary, it is important to consider all available options and select the most applicable for that patient. The interaction of all members of management team, including the primary care provider, the endocrinologist and the neurosurgeon in selecting the treatment course can only improve therapeutic outcome. Regardless of the initial choice of treatment,follow-up of all patients should be maintained indefinitely. The managing physician should be familiar with the natural history and long-term complications of pituitary adenomas, and with the side effects of treatments given over the years.

Argiolas, A. and H. Hedlund (2001). "The pharmacology and clinical pharmacokinetics of apomorphine SL." BJU Int 88 Suppl 3: 18-21.

Argyropoulos, S. V., C. J. Bell, et al. (2001). "Brain function in social anxiety disorder." Psychiatr Clin North Am 24(4): 707-22.
What have these studies revealed about SAD? First, few studies have been performed so far, with even fewer replications. Most of the work has been exploratory in nature and follows the paradigms used in PD. This approach has been justifiably criticized. The use of psychological (naturalistic) challenges may be more appropriate in SP than chemical challenges. The paradigms of public speaking, autobiographical scripts, or similar behavioral challenges merit further use, exploration, and validation if symptoms resembling those of the condition proper are to be induced in experimental circumstances. However, some tentative conclusions can be drawn from the research performed so far. There is no enough evidence to support the presence of structural brain abnormality in SAD. Admittedly, such a finding would have been very unlikely. On the other hand, evidence of subtle functional abnormalities is accumulating. On the nosologic question, there appear to be differences from PD. While in some challenges (e.g., CO2 and pentagastrin) the two conditions differ only in degree, in others (e.g., lactate, caffeine, and flumazenil), the separation is clearer. Equally, there is a strong argument to differentiate the generalized from the specific form of social anxiety on the basis of substantial (albeit accidental) findings outlined earlier. More sophisticated neuroimaging techniques, directly comparing patients from both groups before and after pharmacologic or psychological treatment, should provide more conclusive evidence on this issue. What might also help future research is the integration of biological investigations with specific personality profiles. In one study, SAD patients scored low in novelty seeking, self-directedness and cooperativeness and high in harm avoidance. It has been hypothesized that such results indicate serotonergic and dopaminergic dysregulation, which is consistent with the findings described earlier. The best evidence for neurotransmitter abnormality so far is for altered dopamine function at the level of the basal ganglia, either pre- or postsynaptic, which may result in reduced basal ganglia function so that the normal fluidity of social motor functions (e.g., smiling, eye movements, and speech) are impaired, thus leading to the cognitive symptoms of social anxiety and the subsequent generation of avoidance behavior. Such patients should respond poorly to antipsychotics, and additional challenges with these drugs could be used to test this theory. Furthermore, more research needs to be done to elucidate the mechanism by which SSRIs work in SAD. Neuroanatomical models of social anxiety (Fig. 4) [see structure: Text], explaining the site of action of drugs and psychological treatments, have been proposed in recent years. Central to these models is the notion of an innate anxiety circuit, which could be tentatively identified with the behavioral inhibition system, the septohippocampal system. This area receives 5-HT, NE, and dopamine input and has connections with the cortex and limbic structures. The relevance of these models remains to be assessed in experiments that are specifically designed to test them.

Armstrong, S. C. and K. L. Cozza (2001). "Med-psych drug-drug interactions update." Psychosomatics 42(5): 435-7.

Aversa, A. and A. Fabbri (2001). "New oral agents for erectile dysfunction: what is changing in our practice?" Asian J Androl 3(3): 175-9.
Erectile dysfunction (ED) is a highly prevalent disorder affecting an estimated 152 million men worldwide and is associated with a variety of behavioral risk factors, such as cigarette smoking and excessive alcohol consumption, as well as numerous age-related medical conditions, notably type-2 diabetes mellitus and cardiovascular disease. A rational step-wise approach which includes comprehensive medical and sexual history, a focused physical examination and essential laboratory tests such as fasting glucose, lipid profile and testosterone assay is to be preferred. Current diagnostic work-up does not recommend any of the specialized tests which were previously considered mandatory-i. e. penile pharmacotesting, Duplex ultrasound and nocturnal penile tumescence. Hormonal replacement therapy is appropriate only in the hypogonadal male with ED. Prior to direct intervention, the physician should consider altering modifiable risk factors or causes, although frequently insufficient to reverse ED completely. When indicated, oral therapy with new molecules (phosphodiesterase inhibitors or apomorphine) is the first-line treatment for the majority of patients because of potential benefits and lack of invasiveness.

Ayers, S. and J. D. Tobias (2001). "Bupropion overdose in an adolescent." Pediatr Emerg Care 17(2): 104-6.
Bupropion is a relatively new monocyclic antidepressant whose mechanism of action remains unknown. In addition to its use as an antidepressant, it has also been suggested to be effective in children with attention deficit hyperactive disorder and more recently as an aid in the cessation of cigarette smoking. The latter indication has resulted in an increase in its use and therefore an increased availability in households. To date, reports of overdoses in pediatric patients are limited. We report a 14-year-old boy who ingested 1.5 to 3 g of bupropion in a suicide attempt. Previous reports of bupropion ingestions and its management are discussed.

Azmitia, E. C. (2001). "Neuronal instability: implications for Rett's syndrome." Brain Dev 23 Suppl 1: S1-S10.
The maturational changes in the brain and spinal cord do not linearly proceed from immature in infants to mature in adults. Dendrites dynamically extend or retract as neurotrophic factors fluctuate. In certain cases mature neurons can be seen soon after birth, and in other cases immature neurons can be identified in the aged brain. Monoamine 'neurotransmitter'; such as serotonin (5-HT), dopamine and norepinephrine appear to function as Maintenance Growth Factors since they must be present in order to produce their maturational actions. Serotonin neurons contain TRK-B receptors and are sensitive to availability of the trophic factor, BDNF. 5-HT also functions by promoting the release of the glial extension factor, S-100beta. 5-HT and S-100beta can provide maturational signals to a variety of neurons, in both cortical and subcortical areas, and appear to be involved in regulating the maturation and release of acetylcholine and dopamine. We have shown that activation of the 5-HT1A receptor is particularly effective in inducing growth of stunted neurons. The mechanism of action of the 5-HT1A receptor involves both a direct inhibition on c-AMP and pCREB formation in postsynaptic neurons and a release of S-100beta from glial cells. Both these events are capable of stabilization and elaboration of the cytoskeleton of the neuron and inhibition of apoptosis. 5-HT1A receptors have been shown to effectively reverse stunted neurons and microencephaly produced in animal models of fetal alcohol syndrome and prenatal cocaine administration. I discuss the implications for regressive disorders such as Rett's syndrome and autism, and the feasibility of treatments with 5-HT1A agonists in children with developmental disorders.

Backman, L. and L. Farde (2001). "Dopamine and cognitive functioning: brain imaging findings in Huntington's disease and normal aging." Scand J Psychol 42(3): 287-96.
Recent brain imaging studies in Huntington's disease (HD) and normal aging suggest a relationship between central dopaminergic neurotransmission and cognitive performance. Results demonstrate substantial losses in dopamine (DA) function in both HD and aging. Moreover, HD patients and older adults show deficits across multiple cognitive domains, including episodic memory, speed of processing, and executive functioning. Although few studies are available at present, there is converging evidence that multiple measures of pre- and postsynaptic DA biochemistry are (a) highly interrelated, and (b) strongly associated with the cognitive deficits that accompany HD and aging. There is also emerging evidence that DA neurotransmission influences cognitive performance independent of HD or age. In general, the research reviewed in this article indicates that the nigrostriatal DA system is an important component of a frontostriatal circuitry that is critically involved in cognitive functioning.

Bakker, J. M., F. van Bel, et al. (2001). "Neonatal glucocorticoids and the developing brain: short-term treatment with life-long consequences?" Trends Neurosci 24(11): 649-53.
Although synthetic glucocorticoids are frequently used in hospital for the prevention of chronic lung disease in premature infants, major concern has arisen about the possible long-term consequences of these treatments. Animal research provides evidence for the idea that neonatal glucocorticoid treatment enhances susceptibility to autoimmune disease in adult life. Altered functioning of the hypothalamo-pituitary-adrenal axis, and/or changes at higher brain levels might underlie alterations in disease susceptibility.

Balfour, D. J. (2001). "The pharmacology underlying pharmacotherapy for tobacco dependence: a focus on bupropion." Int J Clin Pract 55(1): 53-7.
Tobacco dependence remains the major preventable cause of early mortality and morbidity in the developed world. The primary reinforcer of the dependence is the nicotine present in tobacco smoke and, for many smokers, successful treatment depends upon breaking this dependence. Until recently, the only specific pharmacotherapy available for tobacco dependence was nicotine replacement therapy (NRT). Although this approach does significantly increase long-term cessation rates, it is by no means a panacea for the many smokers who require help to quit. Recently, a new drug, bupropion (Zyban), has been licensed as an additional pharmacological aid for smoking cessation. This commentary discusses the mechanisms that may account for its efficacy in this indication and considers the impact its introduction may have on the approach of healthcare systems to the treatment of tobacco dependence.

Ballesteros, J. A., L. Shi, et al. (2001). "Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors." Mol Pharmacol 60(1): 1-19.
The availability of a high-resolution structure of rhodopsin now allows us to reconsider research attempts to understand structure-function relationships in other G protein-coupled receptors (GPCRs). A comparison of the rhodopsin structure with the results of previous sequence analysis and molecular modeling that incorporated experimental results demonstrates a high degree of success for these methods in predicting the helix ends and protein-protein interface of GPCRs. Moreover, the amino acid residues inferred to form the surface of the binding-site crevice based on our application of the substituted-cysteine accessibility method in the dopamine D(2) receptor are in remarkable agreement with the rhodopsin structure, with the notable exception of some residues in the fourth transmembrane segment. Based on our analysis of the data reviewed, we propose that the overall structures of rhodopsin and of amine receptors are very similar, although we also identified localized regions where the structure of these receptors may diverge. We further propose that several of the highly unusual structural features of rhodopsin are also present in amine GPCRs, despite the absence of amino acids that might have thought to have been critical to the adoption of these features. Thus, different amino acids or alternate microdomains can support similar deviations from regular alpha-helical structure, thereby resulting in similar tertiary structure. Such structural mimicry is a mechanism by which a common ancestor could diverge sufficiently to develop the selectivity necessary to interact with diverse signals, while still maintaining a similar overall fold. Through this process, the core function of signaling activation through a conformational change in the transmembrane segments that alters the conformation of the cytoplasmic surface and subsequent interaction with G proteins is presumably shared by the entire Class A family of receptors, despite their selectivity for a diverse group of ligands.

Bankson, M. G. and K. A. Cunningham (2001). "3,4-Methylenedioxymethamphetamine (MDMA) as a unique model of serotonin receptor function and serotonin-dopamine interactions." J Pharmacol Exp Ther 297(3): 846-52.
(+)-3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy"; "X"; "E") is a popular recreational amphetamine analog that produces a unique set of effects in humans and animals. MDMA use is often associated with dance parties called "raves", but its use has increased in all segments of society and around the world. Like amphetamine, MDMA elicits hyperactivity when administered to rodents. Unlike amphetamine, which has effects mediated by the release of dopamine (DA) from nerve terminals, MDMA-induced hyperactivity is thought to be dependent upon the release of 5-hydroxtryptamine (5-HT). However, MDMA elicits large increases in synaptic concentrations of both DA and 5-HT, and the interaction between these neurotransmitters may account for the unique characteristics of the drug. Comparisons between MDMA, the selective DA releaser amphetamine, and the selective 5-HT releaser fenfluramine are used in the present discussion to highlight the ability of MDMA to model the locomotor activation induced by the interaction of DA and 5-HT. Furthermore, this review summarizes evidence to suggest that the influence of 5-HT receptors on behavioral function is dependent upon the specific neurochemical environment evoked by a given drug, specifically discussed here with regard to the interaction between 5-HT and DA systems.

Bantick, R. A., J. F. Deakin, et al. (2001). "The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics?" J Psychopharmacol 15(1): 37-46.
Increasing attention is being directed towards the role of the serotonergic system in the neurochemistry of schizophrenia and antipsychotic drug treatment. This review considers the 5-HT1A receptor in this context. In patients with schizophrenia, the majority of post-mortem studies have reported increases in 5-HT1A receptor density in the prefrontal cortex in the approximate range 15-80%. Although the pathophysiological significance of this finding is unclear, given the location of a major proportion of these receptors on pyramidal cells, it may reflect an abnormal glutamatergic network. In terms of drug treatment, 5-HT1A agonists clearly display anticataleptic activity in rats. In addition, 5-HT1A agonists consistently increase dopamine release in the prefrontal cortex in rodents, which is an effect that might be predicted to improve negative symptoms. 5-HT1A agonists augment classical neuroleptics in some rat models of antipsychotic action and may be capable of modulating the glutamatergic network therapeutically. Despite the encouraging preclinical data, there is a paucity of clinical studies of 5-HT1A agonist augmentation of neuroleptics in the treatment of schizophrenia. However, the clinical relevance may be clarified by the atypical antipsychotic drugs clozapine, quetiapine and ziprasidone which combine D2 receptor antagonism and 5-HT1A agonism. In conclusion, given the increased prefrontal 5-HT1A receptor density in the illness, and the anticataleptic activity of 5-HT1A agonists combined with their ability to evoke prefrontal dopamine release, there is now a sufficient rationale to examine thoroughly the role of the 5-HT1A receptor in schizophrenia and antipsychotic drug treatment.

Barber, R., A. Panikkar, et al. (2001). "Dementia with Lewy bodies: diagnosis and management." Int J Geriatr Psychiatry 16 Suppl 1: S12-8.
OBJECTIVE: To summarize the clinical, pathological, imaging and treatment aspects of dementia with Lewy bodies (DLB). METHOD: Review of literature (MEDLINE). RESULTS: DLB is the second most common form of degenerative dementia, accounting for up to 20% of cases in the elderly. It is characterized by fluctuating cognitive impairment, spontaneous parkinsonism and recurrent visual hallucinations. Consensus clinical criteria have been published and have been shown to have high specificity, but they may still lack sensitivity. Pathologically, DLB may be classified as a Lewy body (LB) disorder and/or as an alpha-synucleinopathy. It is probable that a spectrum of LB disorders exists with the clinical features reflecting the distribution and severity of pathology. Although both DLB and Alzheimer's disease (AD) show a reduction in pre-synaptic cholinergic transmission from the basal forebrain, in DLB there are also deficits in cholinergic transmission from brain stem nuclei. Post-synaptic cortical muscarinic receptors are more functionally intact in DLB suggesting potential responsiveness to cholinergic enhancement. Neuroimaging findings indicate a relative preservation of medial temporal lobe structures in DLB but similar distribution of white matter changes on MRI compared with AD. Defects in nigrostriatal dopamine pathways in DLB have been demonstrated with functional neuroimaging using ligands highlighting pre- and post-synaptic dopaminergic systems. Preliminary studies also indicate subtle differences in perfusion patterns on SPECT with a greater degree of occipital hypoperfusion in DLB compared with AD. Accurate diagnosis of DLB is clinically important as the management of psychosis and behavioural disturbances is complicated by sensitivity to neuroleptic medication. There is accumulating evidence to suggest that DLB may be particularly amenable to cholinergic enhancers. The clinical management of DLB is considered using a four step approach: making a diagnosis; identification of problem symptoms; appropriate non-pharmacological interventions; and pharmacological interventions. CONCLUSIONS: Consensus criteria for probable DLB have high specificity-a positive clinical diagnosis is likely to be correct. Treatment choices must consider effects upon motor, cognitive and psychiatric symptoms. Non-pharmacological management is an essential first step, as is reduction or withdrawal of drugs with potential adverse effects. Neuroleptic sensitivity reactions appear less likely to occur with the newer atypical antipsychotics. Cholinesterase inhibitors have been shown in open-label studies and one placebo RCT to be well tolerated and effective in treating cognitive and psychiatric symptoms in DLB. They may become first-line treatments.

Barontini, M., M. C. Garcia-Rudaz, et al. (2001). "Mechanisms of hypothalamic-pituitary-gonadal disruption in polycystic ovarian syndrome." Arch Med Res 32(6): 544-52.
Although the pathogenesis of polycystic ovarian syndrome (PCOS) is still controversial, a series of investigations has demonstrated an array of neuroendocrine abnormalities as a major component of the syndrome. From a neuroendocrine perspective, patients with PCOS exhibit an accelerated frequency and/or higher amplitude of LH pulses, augmentation of LH secretory burst mass, and a more disorderly LH release. Elevated in vitro LH bioactivity and a preponderance of basic LH isoforms, which correlate positively with elevated serum 17-hydroxyprogesterone, androstenedione, and testosterone concentrations, also characterize adolescents with PCOS. Heightened GnRH drive of gonadotropin secretion and a steroid-permissive milieu appear to jointly promote elevated secretion of basic LH isoforms. Positive feedback is implied, because hypersecretion of highly bioactive LH in PCOS probably contributes to inordinate androgen output. However, the precise nature of feedback disruption remains uncertain. Indeed, recent data suggest that PCOS is marked by anomalies of both feedforward and feedback signaling between GnRH/LH and ovarian androgens. From a single hormone perspective, the individual patterns of LH and androstenedione release are consistently more irregular in patients with PCOS. Bihormonal analysis has disclosed concomitant uncoupling of the pairwise synchrony of LH and testosterone, LH and androstenedione, and testosterone and androstenedione secretion. The foregoing ensemble of findings points to deterioration of both orderly uniglandular and coordinate bihormonal output in PCOS. Additional studies are needed to establish the primary pathophysiologic mechanisms underlying this disorder.

Barzilai, A., E. Melamed, et al. (2001). "Is there a rationale for neuroprotection against dopamine toxicity in Parkinson's disease?" Cell Mol Neurobiol 21(3): 215-35.
Parkinson's disease is a progressive neurological disease caused by rather selective degeneration of the dopaminergic neurons in the substantia nigra. Though subject to intensive research, the etiology of this nigral loss is still undetermined and treatment is basically symptomatic. The current major hypothesis is that nigral neuronal death in PD is due to excessive oxidative stress generated by auto and enzymatic oxidation of the endogenous neurotransmitter dopamine (DA), the formation of neuromelanin (NM) and the presence of a high concentration of iron. In this review article although we concisely describe the effects of NM and iron on neuronal survival, we mainly focus on the molecular mechanisms of DA-induced apoptosis. DA exerts its toxic effects through its oxidative metabolites either in vitro or in vivo The oxidative metabolites then activate a very intricate web of signals, which culminate in cell death. The signal transduction pathways and genes, which are associated with DA toxicity are described in detail.

Baumann, M. H., J. Pablo, et al. (2001). "Comparative neuropharmacology of ibogaine and its O-desmethyl metabolite, noribogaine." Alkaloids Chem Biol 56: 79-113.

Beal, M. F. (2001). "Experimental models of Parkinson's disease." Nat Rev Neurosci 2(5): 325-34.
Research into the pathogenesis of Parkinson's disease has been rapidly advanced by the development of animal models. Initial models were developed by using toxins that specifically targeted dopamine neurons, the most successful of which used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a toxin that causes parkinsonism in man. More recently, the identification of alpha-synuclein mutations as a rare cause of Parkinson's disease has led to the development of alpha-synuclein transgenic mice and Drosophila. Here, I discuss the merits and limitations of these different animal models in our attempts to understand the physiology of Parkinson's disease and to develop new therapies.

Beinfeld, M. C. (2001). "An introduction to neuronal cholecystokinin." Peptides 22(8): 1197-200.
This issue of Peptides was inspired by a gathering of CCK researchers at the first Neuronal Cholecsytokinin Gordon Conference. The papers in this issue reflect the diversity of CCK research and demonstrate how the field has matured. Reviews describe the regulation of CCK gene expression and CCK release, the nature of the hormone binding site of the CCK A receptor, interaction of CCK, dopamine and GABA, the role of CCK in thermoregulation, sexual behavior and satiety in rodents and humans. The research articles document features of cardiovascular regulation, reduced cocaine sensitization and decreased satiety in rats that lack the CCK A receptor. Pro CCK processing in neuroblastoma cells and the elevation of CCK levels in CSF in a model of chronic pain are detailed in other articles. Three articles using different behavioral paradigms in rat and sheep examine CCK in learning and memory. Two articles that examine CCK in different behaviors that have a dopaminergic component are included. Other articles describe the interaction between a 5HT(3) antagonist and CCK-induced satiety and c-fos activation and document secretion of oxytocin and vasopressin in female patients and controls in response to CCK 4 administration.There is good reason to believe that the future is bright for research on CCK. With the organization of national and international meetings, CCK researchers have a forum for communication. Opportunities for cooperation and collaboration have never been better. The easy integration of academic basic and clinical science with industrial science bodes very well for the advancement of our understanding of the multiple roles that CCK plays in the brain and for the future development of CCK-based therapies.

Bek, M. J., G. M. Eisner, et al. (2001). "Dopamine receptors in hypertension." Mt Sinai J Med 68(6): 362-9.
There is increased awareness of the role of dopamine in cardiovascular function, renal function and systemic blood pressure regulation. Growing evidence indicates that each of the five dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms distinct for that particular subtype. Some dopamine receptors regulate blood pressure by influencing the central and peripheral nervous system, while others influence renal function and release of renin, aldosterone and vasopressin. This review summarizes the physiology and pathophysiology of the peripheral dopaminergic system and our current understanding of the role of individual dopamine receptors in the pathophysiology of human essential hypertension.

Bellomo, R. and D. D. Giantomasso (2001). "Noradrenaline and the kidney: friends or foes?" Crit Care 5(6): 294-8.
Septic shock, systemic inflammation and pharmacological vasodilatation are often complicated by systemic hypotension, despite aggressive fluid resuscitation and an increased cardiac output. If the physician wishes to restore arterial pressure (>80-85 mmHg), with the aim of sustaining organ perfusion pressure, the administration of systemic vasopressor agents, such as noradrenaline, becomes necessary. Because noradrenaline induces vasoconstriction in many vascular beds (visibly in the skin), however, it may decrease renal and visceral blood flow, impairing visceral organ function. This unproven fear has stopped clinicians from using noradrenaline more widely. In vasodilated states, unlike in normal circulatory conditions, however, noradrenaline may actually improve visceral organ blood flow. Animal studies show that the increased organ perfusion pressures achieved with noradrenaline improve the glomerular filtration rate and renal blood flow. There are no controlled human data to define the effects of noradrenaline on the kidney, but many patient series show a positive effect on glomerular filtration rate and urine output. There is no reason to fear the use of noradrenaline. If it is used to support a vasodilated circulation with a normal or increased cardiac output, it is likely to be the kidney's friend not its foe.

Bellomo, R. and C. Ronco (2001). "The renal effects of noradrenaline and dopamine." Contrib Nephrol(132): 146-57.

Benedetti, M. S. (2001). "Biotransformation of xenobiotics by amine oxidases." Fundam Clin Pharmacol 15(2): 75-84.
Although the cytochrome P450 (CYP) system ranks first in terms of catalytic versatility and the wide range of xenobiotics it detoxifies or activates to reactive intermediates, the contribution of amine oxidases and in particular of monoamine oxidases (MAOs) to the metabolism of xenobiotics is far from negligible but has been largely neglected. In this review on the involvement of amine oxidases in the metabolism of xenobiotics, the major characteristics reported for the CYP system (protein, reaction, tissue distribution, subcellular localisation, substrates, inhibitors, inducers, genetic polymorphism, impact of different physiopathological conditions on the activity, turnover) will be compared, whenever possible, with the corresponding characteristics of amine oxidases (MAOs in particular). The knowledge of the involvement of MAO-A, -B or both in the metabolism of a drug allows us to predict interactions with selective or non-selective MAO inhibitors (e.g. the metabolism of a drug deaminated by both forms of MAO is not necessarily inhibited in vivo by a selective MAO-A or -B inhibitor). If a drug is metabolized by MAOs, competitive interactions can occur with other drugs that are MAO substrates, e.g. with beta-adrenoceptor agonists and antagonists, prodrugs of dopamine, serotonin 5-HT1-receptor agonists as well as with primaquine, flurazepam and citalopram. Moreover, the knowledge of the involvement of MAOs in the metabolism of a drug may suggest possible, although not obligatory, interactions with tyramine-containing food or drink, with over the counter medicines sold to relieve the symptoms of coughs and colds (generally containing the indirectly-acting sympathomimetic amine phenylpropanolamine) or with phenylephrine-containing preparations. Finally, biotransformation by amine oxidases, as by CYP, does not always lead to detoxication but can produce toxic compounds.

Benes, F. M. and S. Berretta (2001). "GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder." Neuropsychopharmacology 25(1): 1-27.
A core component to corticolimbic circuitry is the GABAergic interneuron. Neuroanatomic studies conducted over the past century have demonstrated several subtypes of interneuron defined by characteristic morphological appearances in Golgi-stained preparations. More recently, both cytochemical and electrophysiological techniques have defined various subtypes of GABA neuron according to synaptic connections, electrophysiological properties and neuropeptide content. These cells provide both inhibitory and disinhibitory modulation of cortical and hippocampal circuits and contribute to the generation of oscillatory rhythms, discriminative information processing and gating of sensory information within the corticolimbic system. All of these functions are abnormal in schizophrenia. Recent postmortem studies have provided consistent evidence that a defect of GABAergic neurotransmission probably plays a role in both schizophrenia and bipolar disorder. Many now believe that such a disturbance may be related to a perturbation of early development, one that may result in a disturbance of cell migration and the formation of normal lamination. The ingrowth of extrinsic afferents, such as the mesocortical dopamine projections, may "trigger" the appearance of a defective GABA system, particularly under stressful conditions when the modulation of the dopamine system is likely to be altered. Based on the regional and subregional distribution of changes in GABA cells in schizophrenia and bipolar disorder, it has been postulated that the basolateral nucleus of the amygdala may contribute to these abnormalities through an increased flow of excitatory activity. By using "partial" modeling, changes in the GABA system remarkably similar to those seen in schizophrenia and bipolar disorder have been induced in rat hippocampus. In the years to come, continued investigations of the GABA system in rodent, primate and human brain and the characterization of changes in specific phenotypic subclasses of interneurons in schizophrenia and bipolar disorder will undoubtedly provide important new insights into how the integration of this transmitter system may be altered in neuropsychiatric disease.

Ben-Jonathan, N. and R. Hnasko (2001). "Dopamine as a prolactin (PRL) inhibitor." Endocr Rev 22(6): 724-63.
Dopamine is a small and relatively simple molecule that fulfills diverse functions. Within the brain, it acts as a classical neurotransmitter whose attenuation or overactivity can result in disorders such as Parkinson's disease and schizophrenia. Major advances in the cloning and characterization of biosynthetic enzymes, transporters, and receptors have increased our knowledge regarding the metabolism, release, reuptake, and mechanism of action of dopamine. Dopamine reaches the pituitary via hypophysial portal blood from several hypothalamic nerve tracts that are regulated by PRL itself, estrogens, and several neuropeptides and neurotransmitters. Dopamine binds to type-2 dopamine receptors that are functionally linked to membrane channels and G proteins and suppresses the high intrinsic secretory activity of the pituitary lactotrophs. In addition to inhibiting PRL release by controlling calcium fluxes, dopamine activates several interacting intracellular signaling pathways and suppresses PRL gene expression and lactotroph proliferation. Thus, PRL homeostasis should be viewed in the context of a fine balance between the action of dopamine as an inhibitor and the many hypothalamic, systemic, and local factors acting as stimulators, none of which has yet emerged as a primary PRL releasing factor. The generation of transgenic animals with overexpressed or mutated genes expanded our understanding of dopamine-PRL interactions and the physiological consequences of their perturbations. PRL release in humans, which differs in many respects from that in laboratory animals, is affected by several drugs used in clinical practice. Hyperprolactinemia is a major neuroendocrine-related cause of reproductive disturbances in both men and women. The treatment of hyperprolactinemia has greatly benefited from the generation of progressively more effective and selective dopaminergic drugs.

Berger, F. and S. S. Gambhir (2001). "Recent advances in imaging endogenous or transferred gene expression utilizing radionuclide technologies in living subjects: applications to breast cancer." Breast Cancer Res 3(1): 28-35.
A variety of imaging technologies is being investigated as tools for studying gene expression in living subjects. Two technologies that use radiolabeled isotopes are single photon emission computed tomography (SPECT) and positron emission tomography (PET). A relatively high sensitivity, a full quantitative tomographic capability, and the ability to extend small animal imaging assays directly into human applications characterize radionuclide approaches. Various radiolabeled probes (tracers) can be synthesized to target specific molecules present in breast cancer cells. These include antibodies or ligands to target cell surface receptors, substrates for intracellular enzymes, antisense oligodeoxynucleotide probes for targeting mRNA, probes for targeting intracellular receptors, and probes for genes transferred into the cell. We briefly discuss each of these imaging approaches and focus in detail on imaging reporter genes. In a PET reporter gene system for in vivo reporter gene imaging, the protein products of the reporter genes sequester positron emitting reporter probes. PET subsequently measures the PET reporter gene dependent sequestration of the PET reporter probe in living animals. We describe and review reporter gene approaches using the herpes simplex type 1 virus thymidine kinase and the dopamine type 2 receptor genes. Application of the reporter gene approach to animal models for breast cancer is discussed. Prospects for future applications of the transgene imaging technology in human gene therapy are also discussed. Both SPECT and PET provide unique opportunities to study animal models of breast cancer with direct application to human imaging. Continued development of new technology, probes and assays should help in the better understanding of basic breast cancer biology and in the improved management of breast cancer patients.

Bergstrom, K. A., E. Tupala, et al. (2001). "Dopamine transporter in vitro binding and in vivo imaging in the brain." Pharmacol Toxicol 88(6): 287-93.
Much research interest has lately been focused on the dopamine transporter function in brain. Recent findings indicate that dopamine reuptake is more like a highly regulated than a constitutive determinant of dopamine clearance. Positron emission tomography (PET) and single-photon emission tomography (SPET) offer unique methods to study dopamine transporter function. Results from in vivo PET and SPET studies correspond well with in vitro studies performed on post mortem human brain tissue. Considering some of the variances between in vitro and in vivo receptor binding phenomena it may be that the role of a compound to alter binding to monoamine uptake sites in vitro does not indicate its potential to affect monoamine transporters after administration in vivo. This discrepancy may be better understood taking into account recent studies indicating the possibility of a rapid regulation of transporter function and surface expression. Furthermore, the dopamine transporter is a fruitful target for CNS drug discovery. Fundamental nature of drug actions in vivo may be studied using demonstrated in vitro and in vivo imaging methods.

Berner, P. (2001). "[New concepts of schizophrenic sub-syndromes - consequences for treatment]." Fortschr Neurol Psychiatr 69 Suppl 2: S101-3.
Etiopathogenetic research gives rise to the suspicion that the classifications on hand pool heterogeneous disturbances under the heading of schizophrenia. This has drawn increasing attention to the necessity of identifying schizophrenic subsyndromes. Investigations using factor analysis revealed convincingly three major groups of schizophrenic symptoms: 1. a "negative factor", 2. a "psychoticism factor", comprising delusions and hallucinations and 3. a "disorganization syndrome" whose cardinal item is formal thought disorder. These studies have not yet furnished final results, but already opened insights enabling the conceptualization of syndrom-oriented therapies. The observation that the psychoticism symptomatology occurs in the frame of a "dynamic instability", based on a thymopsychic hyperreactivity, is in this regard especially important. In schizophrenic patients this hyperreactivity may be caused by secondary biological compensation mechanisms - such as perhaps an "up-regulation" of postsynaptic dopamine receptors. "Classic" neuroleptics can only correct the dynamic instability and thus eliminate psychoticism symptoms and reduce the accentuation of disorganization symptoms. They have, however, no influence upon negative symptomatology and can moreover aggravate "secondary" negative symptoms and especially impede cognitive functions. New "atypical" neuroleptics do not produce these side effects. They seem to have a reducing influence on negative symptoms and to improve cognitive functions. In each neuroleptic therapy a stepwise drug withdrawal should make clear whether or not a continous treatment is necessary. In the first case the needed efficacious dosis must be identified. The patients must learn to recognize relapse prodromes and to prevent the appearance of acute episodes through appropriate modifications of the medication. This strategy requires the combination with adequate psychotherapeutic methods enabling the patient to master persistent negative and disorganization symptoms in the best possible way.

Bezard, E., J. M. Brotchie, et al. (2001). "Pathophysiology of levodopa-induced dyskinesia: potential for new therapies." Nat Rev Neurosci 2(8): 577-88.
Involuntary movements--or dyskinesias--are a debilitating complication of levodopa therapy for Parkinson's disease, and is experienced in most patients. Despite the importance of this problem, little was known about the cause of dyskinesia until recently; however, this situation has changed significantly in the past few years. Our increased understanding of levodopa-induced dyskinesia is not only valuable for improving patient care, but also in providing us with new insights into the functional organization of the basal ganglia and motor systems.

Bezzi, P. and A. Volterra (2001). "A neuron-glia signalling network in the active brain." Curr Opin Neurobiol 11(3): 387-94.
Glial cells are active partners of neurons in processing information and synaptic integration. They receive coded signals from synapses and elaborate modulatory responses. The active properties of glia, including long-range signalling and regulated transmitter release, are beginning to be elucidated. Recent insights suggest that the active brain should no longer be regarded as a circuitry of neuronal contacts, but as an integrated network of interactive neurons and glia.

Bhana, N., R. H. Foster, et al. (2001). "Olanzapine: an updated review of its use in the management of schizophrenia." Drugs 61(1): 111-61.
Olanzapine, a thienobenzodiazepine derivative, is a second generation (atypical) antipsychotic agent which has proven efficacy against the positive and negative symptoms of schizophrenia. Compared with conventional antipsychotics, it has greater affinity for serotonin 5-HT2A than for dopamine D2 receptors. In large, well controlled trials in patients with schizophrenia or related psychoses, olanzapine 5 to 20 mg/day was significantly superior to haloperidol 5 to 20 mg/day in overall improvements in psychopathology rating scales and in the treatment of depressive and negative symptoms, and was comparable in effects on positive psychotic symptoms. The 1-year risk of relapse (rehospitalisation) was significantly lower with olanzapine than with haloperidol treatment. In the first double-blind comparative study (28-week) of olanzapine and risperidone, olanzapine 10 to 20 mg/day proved to be significantly more effective than risperidone 4 to 12 mg/day in the treatment of negative and depressive symptoms but not on overall psychopathology symptoms. In contrast, preliminary results from an 8-week controlled study suggested risperidone 2 to 6 mg/day was superior to olanzapine 5 to 20 mg/day against positive and anxiety/depressive symptoms (p < 0.05), although consistent with the first study, both agents demonstrated similar efficacy on measures of overall psychopathology. Improvements in general cognitive function seen with olanzapine treatment in a 1-year controlled study of patients with early-phase schizophrenia, were significantly greater than changes seen with either risperidone or haloperidol. However, preliminary results from an 8-week trial showed comparable cognitive enhancing effects of olanzapine and risperidone treatment in patients with schizophrenia or schizoaffective disorder. Several studies indicate that olanzapine has benefits against symptoms of aggression and agitation, while other studies strongly support the effectiveness of olanzapine in the treatment of depressive symptomatology. Olanzapine is associated with significantly fewer extrapyramidal symptoms than haloperidol and risperidone. In addition, olanzapine is not associated with a risk of agranulocytosis as seen with clozapine or clinically significant hyperprolactinaemia as seen with risperidone or prolongation of the QT interval. The most common adverse effects reported with olanzapine are bodyweight gain, somnolence, dizziness, anticholinergic effects (constipation and dry mouth) and transient asymptomatic liver enzyme elevations. In comparison with haloperidol, the adverse events reported significantly more frequently with olanzapine in > or = 3.5% of patients were dry mouth, bodyweight gain and increased appetite and compared with risperidone, only bodyweight gain occurred significantly more frequently with olanzapine. The high acquisition cost of olanzapine is offset by reductions in other treatment costs (inpatient and/or outpatient services) of schizophrenia. Pharmacoeconomic analyses indicate that olanzapine does not significantly increase, and may even decrease, the overall direct treatment costs of schizophrenia, compared with haloperidol. Compared with risperidone, olanzapine has also been reported to decrease overall treatment costs, despite the several-fold higher daily acquisition cost of the drug. Olanzapine treatment improves quality of life in patients with schizophrenia and related psychoses to a greater extent than haloperidol, and to broadly the same extent as risperidone. CONCLUSIONS: Olanzapine demonstrated superior antipsychotic efficacy compared with haloperidol in the treatment of acute phase schizophrenia, and in the treatment of some patients with first-episode or treatment-resistant schizophrenia. The reduced risk of adverse events and therapeutic superiority compared with haloperidol and risperidone in the treatment of negative and depressive symptoms support the choice of olanzapine as a first-line option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.

Bhana, N. and C. M. Perry (2001). "Olanzapine: a review of its use in the treatment of bipolar I disorder." CNS Drugs 15(11): 871-904.
Olanzapine, a thienobenzodiazepine derivative, is a psychotropic agent that has shown efficacy in the treatment of patients with bipolar I disorder. Olanzapine has a multireceptorial binding profile including a greater affinity for serotonin 5-HT(2A) than for dopamine D(2) receptors. Olanzapine 5 to 20 mg/day demonstrated significantly greater antimanic efficacy than placebo in two double-blind, randomised 3- or 4-week trials of patients with bipolar I disorder of either manic or mixed episodes, with or without psychotic features. Additionally, in one of these trials, improvements in cognitive function and hostility were superior with olanzapine. In cohorts of severely depressed and rapid cycling patients, improvements in manic and depressive symptoms and in manic symptoms only, were superior with olanzapine compared with placebo. Significant improvements from baseline in symptoms of mania, depression, cognitive functioning and hostility were seen with olanzapine in a 49-week extension phase study. In double-blind trials, olanzapine 10 mg/day appeared to have similar antimanic efficacy to oral lithium 400mg twice daily in the treatment of patients with pure mania (4-week small study). In patients with acute manic or mixed episodes olanzapine 5 to 20 mg/day appeared to be more effective than oral valproate semisodium (divalproex sodium) 500 to 2500 mg/day (3-week study) and at least as effective as oral haloperidol 3 to 15 mg/day (12-week study). Preliminary results from a large 6-week placebo-controlled study suggest that olanzapine 5 to 20 mg/day in combination with mood stabilisers (lithium or valproate semisodium) provides effective augmentation of antimanic treatment of patients with bipolar I disorder, with benefits seen in the first week. Adverse events reported significantly more often with olanzapine than with placebo were somnolence, dry mouth, dizziness and bodyweight gain, and in comparison with valproate semisodium were somnolence, dry mouth, increased appetite and bodyweight gain. Olanzapine was generally well tolerated with no clinically relevant abnormalities in laboratory tests, vital signs or electrocardiogram results. CONCLUSION: Olanzapine demonstrated superior efficacy compared with placebo in the short-term treatment of patients with bipolar I disorder with manic or mixed episodes, with or without psychotic features, and was generally well tolerated. According to preliminary data the antimanic efficacy of olanzapine appears similar to that of haloperidol and better than that of valproate semisodium in patients with bipolar I disorder experiencing a manic or mixed episode; among nonpsychotic patients with manic or mixed episodes olanzapine appears to be superior to haloperidol. Available data support the choice of olanzapine as an option in the short-term management of mania in patients with bipolar I disorder with manic or mixed episodes, with or without psychotic features.

Bhatia, K., D. J. Brooks, et al. (2001). "Updated guidelines for the management of Parkinson's disease." Hosp Med 62(8): 456-70.
New data on diagnosis, drug therapy, surgery and psychosocial concerns have emerged since the publication of the 1998 Guidelines for the Management of Parkinson's Disease. This article reviews new data and addresses issues left unanswered in the previous guidelines.

Biglan, K. and R. G. Holloway (2001). "Initial treatment of early Parkinson's disease: a review of recent, randomized controlled trials." Curr Neurol Neurosci Rep 1(4): 329-36.
Many studies have shown dopamine agonists to significantly improve parkinsonian symptoms compared with placebo in early Parkinson's disease (PD), but how do agonists compare with the standard treatment of levodopa? Recently, three large, multicenter, randomized controlled studies directly comparing a dopamine agonist with levodopa as initial therapy in early PD have been published. These studies suggest that although both agents effectively ameliorate parkinsonian symptoms, levodopa was superior to dopamine agonists as measured by improvement in Unified Parkinson's Disease Rating Scale (UPDRS) scores. However, levodopa was more frequently associated with dopaminergic motor complications, and the dopamine agonists were more commonly associated with adverse events. Until further studies clearly demonstrate the beneficial effects of one therapeutic strategy over another, the decision to initiate treatment in early PD with either an agonist or levodopa will be based on the favorable motor complication profile of agonists versus the more potent antiparkinsonian effects and the favorable side-effect profile of levodopa.

Binder, E. B., B. Kinkead, et al. (2001). "The role of neurotensin in the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs." Biol Psychiatry 50(11): 856-72.
It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather pathologic alterations of several interacting systems. Targeting of neuropeptide neuromodulator systems, capable of concomitantly regulating several transmitter systems, represents a promising approach for the development of increasingly effective and side effect-free antipsychotic drugs. Neurotensin (NT) is a neuropeptide implicated in the pathophysiology of schizophrenia that specifically modulates neurotransmitter systems previously demonstrated to be dysregulated in this disorder. Clinical studies in which cerebrospinal fluid (CSF) NT concentrations have been measured revealed a subset of schizophrenic patients with decreased CSF NT concentrations that are restored by effective antipsychotic drug treatment. Considerable evidence also exists concordant with the involvement of NT systems in the mechanism of action of antipsychotic drugs. The behavioral and biochemical effects of centrally administered NT remarkably resemble those of systemically administered antipsychotic drugs, and antipsychotic drugs increase NT neurotransmission. This concatenation of findings led to the hypothesis that NT functions as an endogenous antipsychotic. Moreover, typical and atypical antipsychotic drugs differentially alter NT neurotransmission in nigrostriatal and mesolimbic dopamine (DA) terminal regions, and these effects are predictive of side effect liability and efficacy, respectively. This review summarizes the evidence in support of a role for the NT system in both the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs.

Binder, E. B., B. Kinkead, et al. (2001). "Neurotensin and dopamine interactions." Pharmacol Rev 53(4): 453-86.
Interactions between the classical monoamine neurotransmitter dopamine (DA) and the peptide neurotransmitter neurotensin (NT) in the central nervous system (CNS) have now been investigated for over two decades. Interest in this topic has been sustained, primarily because of the potential clinical relevance of these interactions to schizophrenia and drug abuse. In the past five years, important new discoveries in the NT field have markedly expanded our previous database. Additional NT receptors have been cloned, and novel and refined techniques have contributed to a more detailed description of the anatomy of the CNS NT system. Additionally, lipophilic NT receptor antagonists, active in the CNS after peripheral administration, have rendered more facile the investigation of the physiologic importance of endogenous NT at electrophysiologic, neurochemical, and behavioral levels. In the present review, the discussion of NT/DA interactions will progress from a discussion of the anatomical interactions between these two systems, to electrophysiologic and neurochemical interactions, and finally to behavioral implications-always with focus toward the potential clinical relevance of the data. The discussion of interactions between NT and DA systems will be limited to those occurring within the CNS. Moreover, because the DA projections from the midbrain to the striatum account for the bulk of the DA innervation in the CNS, we will focus on NT/DA interactions within these brain regions. Last, because of the extensive literature on NT/DA interactions available in the rat, our discussion will be based primarily on studies using this species.

Blenau, W. and A. Baumann (2001). "Molecular and pharmacological properties of insect biogenic amine receptors: lessons from Drosophila melanogaster and Apis mellifera." Arch Insect Biochem Physiol 48(1): 13-38.
In the central nervous system (CNS) of both vertebrates and invertebrates, biogenic amines are important neuroactive molecules. Physiologically, they can act as neurotransmitters, neuromodulators, or neurohormones. Biogenic amines control and regulate various vital functions including circadian rhythms, endocrine secretion, cardiovascular control, emotions, as well as learning and memory. In insects, amines like dopamine, tyramine, octopamine, serotonin, and histamine exert their effects by binding to specific membrane proteins that primarily belong to the superfamily of G protein-coupled receptors. Especially in Drosophila melanogaster and Apis mellifera considerable progress has been achieved during the last few years towards the understanding of the functional role of these receptors and their intracellular signaling systems. In this review, the present knowledge on the biochemical, molecular, and pharmacological properties of biogenic amine receptors from Drosophila and Apis will be summarized. Arch.

Blier, P. (2001). "Crosstalk between the norepinephrine and serotonin systems and its role in the antidepressant response." J Psychiatry Neurosci 26 Suppl: S3-10.
Many behavioural overlaps exist in the effects of norepinephrine (NE), serotonin (5-HT) and dopamine, and it is now thought that complex behaviour patterns may reflect interactions among these neurotransmitters. There is a wide variety of evidence for the pivotal role of the NE system in the pathogenesis and treatment of major depression. This paper discusses the functioning of the NE system, specifically the regulation of neuronal firing and the postsynaptic responses to NE, which can be controlled by norepinephrine reuptake inhibitors and other drugs. In addition, interactions between NE neurons and 5-HT neurons have implications for the treatment of depression and anxiety disorders. Specifically, the projections of 5-HT neurons have an inhibitory effect on NE neurons, which means that selective serotonin reuptake inhibitors also affect the NE system. Further experiments and long-term studies will increase knowledge of the mechanisms of action of various psychopharmacologic agents and may eventually lead to better therapeutic choices.

Blodgett, D. J. (2001). "Fescue toxicosis." Vet Clin North Am Equine Pract 17(3): 567-77.
Most of the tall fescue pastures in the United States are infected by an endophyte, N. coenophialum. The fungus derives nutrients from the plant while supplying the plant with toxins for defense. The most detrimental toxins for animals in tall fescue are ergopeptine alkaloids, especially ergovaline. Ergovaline functions as a dopamine D2 agonist and alters prolactin and several other hormones in the body. Pregnant mares are most susceptible during their last month of gestation. Clinical signs include prolonged gestation, dystocia, retained placentas, agalactia, and dysmature foals that are either stillborn or weak.

Blum, D., S. Torch, et al. (2001). "Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease." Prog Neurobiol 65(2): 135-72.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a preferential loss of the dopaminergic neurons of the substantia nigra pars compacta. Although the etiology of PD is unknown, major biochemical processes such as oxidative stress and mitochondrial inhibition are largely described. However, despite these findings, the actual therapeutics are essentially symptomatical and are not able to block the degenerative process. Recent histological studies performed on brains from PD patients suggest that nigral cell death could be apoptotic. However, since post-mortem studies do not allow precise determination of the sequence of events leading to this apoptotic cell death, the molecular pathways involved in this process have been essentially studied on experimental models reproducing the human disease. These latter are created by using neurotoxic compounds such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or dopamine (DA). Extensive study of these models have shown that they mimick, in vitro and in vivo, the histological and/or the biochemical characteristics of PD and thus help to define important cellular actors of cell death presumably critical for the nigral degeneration. This review reports recent data concerning the biochemical and molecular apoptotic mechanisms underlying the experimental models of PD and correlates them to the phenomena occurring in human disease.

Boening, J. A., O. M. Lesch, et al. (2001). "Pharmacological relapse prevention in alcohol dependence: from animal models to clinical trials." Alcohol Clin Exp Res 25(5 Suppl ISBRA): 127S-131S.
This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Jobst August-Ludwig Boening and Otto Michel Lesch. The presentations were (1) Pharmacological validation of a new animal model of alcoholism, by Rainer Spanagel; (2) Persisting loss of control as main criterion for alcohol addiction in rats and mice, by Jochen Wolffgramm; (3) Role of NMDA receptor subunits associated with protein kinase C in the prevention of alcohol dependence, by Minoru Narita; (4) Long-term follow up of continued naltrexone treatment, by David Sinclair; (5) Pharmacological treatment trials with dopaminergic and serotonergic substances: Myths or facts? by Gerhard A. Wiesbeck; and (6) Methodology and behavioral therapy of the U.S. acamprosate study, by Barbara J. Mason.

Borbely, K. (2001). "[Functional neuroimaging in movement disorders]." Orv Hetil 142(43): 2347-55.
Positron Emission Tomography (PET) and Single Photon Emission. Computed Tomography (SPECT) highly contribute to the management of patients with movement disorders by measuring regional cerebral metabolism/blood flow and dopamine receptors. Imaging of the dopaminergic system is a powerful tool for distinguishing patients with neurodegenerative disorders, such as Parkinson's disease. Parkinsonism is most of the time caused by idiopathic Parkinson's disease. Considering the differences in therapeutic response and prognosis, differentiation between Parkinson's disease and "parkinsonism-plus syndromes" is important. Visualisation of pre- and post-synaptic D2 dopamine receptors by using receptor ligands helps to discriminate between Parkinson's disease and "parkinsonism-plus syndromes" as Parkinson's disease is a presynaptic disease. Early disease detection in subjects suspected at risk for developing Parkinson's disease has become possible using ligands for the dopamine transporter. Functional imaging modalities are useful in the management of patients with movement disorders, are able to monitor in an objective way the efficacy of new pharmacological therapies, can document the effect of neuronal grafting for Parkinson's disease, and delineate the progression of these diseases.

Bouvier, M. (2001). "Oligomerization of G-protein-coupled transmitter receptors." Nat Rev Neurosci 2(4): 274-86.
Examples of G-protein-coupled receptors that can be biochemically detected in homo- or heteromeric complexes are emerging at an accelerated rate. Biophysical approaches have confirmed the existence of several such complexes in living cells and there is strong evidence to support the idea that dimerization is important in different aspects of receptor biogenesis and function. While the existence of G-protein-coupled-receptor homodimers raises fundamental questions about the molecular mechanisms involved in transmitter recognition and signal transduction, the formation of heterodimers raises fascinating combinatorial possibilities that could underlie an unexpected level of pharmacological diversity, and contribute to cross-talk regulation between transmission systems. Because G-protein-coupled receptors are major pharmacological targets, the existence of dimers could have important implications for the development and screening of new drugs. Here, we review the evidence supporting the existence of G-protein-coupled-receptor dimerization and discuss its functional importance.

Bracero, N. and H. A. Zacur (2001). "Polycystic ovary syndrome and hyperprolactinemia." Obstet Gynecol Clin North Am 28(1): 77-84.
Analysis of the evidence linking PCOS and hyperprolactinemia suggests that these conditions have independent origins. Elevated prolactin serum levels are documented in the early studies of patients with polycystic ovaries. However, recent investigators using serial serum sampling have excluded transient elevations of prolactin and have shown a less frequent association of these disorders. Treatment of individuals with both PCOS and hyperprolactinemia is distinct from the management of the individual with only one of these conditions. Upon evaluating the therapeutic alternatives for dysfunctional uterine bleeding and hirsutism in these patients, the effect of exogenous estrogen and progesterone on the secretion of prolactin must be considered. The addition of a dopamine agonist (e.g., bromocriptine or cabergoline) to a regimen of clomiphene citrate must also be considered as ovulation induction options for these women. Finally, future discoveries about the relationship between PCOS and hyperprolactinemia will require a better understanding of how the hypothalamus regulates the pituitary secretion of LH and prolactin.

Braff, D. L., M. A. Geyer, et al. (2001). "Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies." Psychopharmacology (Berl) 156(2-3): 234-58.
RATIONALE: Since the mid-1970s, cross-species translational studies of prepulse inhibition (PPI) have increased at an astounding pace as the value of this neurobiologically informative measure has been optimized. PPI occurs when a relatively weak sensory event (the prepulse) is presented 30-500 ms before a strong startle-inducing stimulus, and reduces the magnitude of the startle response. In humans, PPI occurs in a robust, predictable manner when the prepulse and startling stimuli occur in either the same or different modalities (acoustic, visual, or cutaneous). OBJECTIVE: This review covers three areas of interest in human PPI studies. First, we review the normal influences on PPI related to the underlying construct of sensori- (prepulse) motor (startle reflex) gating. Second, we review PPI studies in psychopathological disorders that form a family of gating disorders. Third, we review the relatively limited but interesting and rapidly expanding literature on pharmacological influences on PPI in humans. METHODS: All studies identified by a computerized literature search that addressed the three topics of this review were compiled and evaluated. The principal studies were summarized in appropriate tables. RESULTS: The major influences on PPI as a measure of sensorimotor gating can be grouped into 11 domains. Most of these domains are similar across species, supporting the value of PPI studies in translational comparisons across species. The most prominent literature describing deficits in PPI in psychiatrically defined groups features schizophrenia-spectrum patients and their clinically unaffected relatives. These findings support the use of PPI as an endophenotype in genetic studies. Additional groups of psychopathologically disordered patients with neuropathology involving cortico-striato-pallido-pontine circuits exhibit poor gating of motor, sensory, or cognitive information and corresponding PPI deficits. These groups include patients with obsessive compulsive disorder, Tourette's syndrome, blepharospasm, temporal lobe epilepsy with psychosis, enuresis, and perhaps posttraumatic stress disorder (PTSD). Several pharmacological manipulations have been examined for their effects on PPI in healthy human subjects. In some cases, the alterations in PPI produced by these drugs in animals correspond to similar effects in humans. Specifically, dopamine agonists disrupt and nicotine increases PPI in at least some human studies. With some other compounds, however, the effects seen in humans appear to differ from those reported in animals. For example, the PPI-increasing effects of the glutamate antagonist ketamine and the serotonin releaser MDMA in humans are opposite to the PPI-disruptive effects of these compounds in rodents. CONCLUSIONS: Considerable evidence supports a high degree of homology between measures of PPI in rodents and humans, consistent with the use of PPI as a cross-species measure of sensorimotor gating. Multiple investigations of PPI using a variety of methods and parameters confirm that deficits in PPI are evident in schizophrenia-spectrum patients and in certain other disorders in which gating mechanisms are disturbed. In contrast to the extensive literature on clinical populations, much more work is required to clarify the degree of correspondence between pharmacological effects on PPI in healthy humans and those reported in animals.

Brambilla, F. (2001). "Aetiopathogenesis and pathophysiology of bulimia nervosa: biological bases and implications for treatment." CNS Drugs 15(2): 119-36.
Bulimia nervosa is an eating disorder characterised by recurrent episodes of binge eating and associated efforts to purge the ingested calories through self-induced vomiting, laxative or diuretic abuse, fasting or intensive exercise. The aetiopathogenesis and pathophysiology of the disorder are currently unclear. Biological bases have been proposed repeatedly, based on several lines of evidence: hunger, satiety and food choice are regulated by neurotransmitters and neuropeptides, and impairment of eating habits may be related to alterations in the secretion of these chemicals; genetic studies suggest that these neurotransmitter systems are dysfunctional in individuals with bulimia nervosa; and the frequent comorbidity of bulimia nervosa with major depressive and obsessive-compulsive disorders, conditions in which multiple alterations of brain biochemical functions have been demonstrated. Data in the literature suggest that levels of noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) are lower in individuals with bulimia nervosa than in healthy controls. Levels of dopamine are similar to, or lower than, those in controls. After remission of the disorder, noradrenergic function returns to that seen in controls, whereas dopaminergic and serotonergic function rebound to levels higher than in controls. Among the neuropeptides, alterations in the levels of neuropeptide Y, peptide YY, beta-endorphin, corticotrophin-releasing hormone, somatostatin, cholecystokinin and vasopressin have been found in the symptomatic phase of bulimia nervosa, with a return to levels seen in controls after remission. Pharmacological treatment of bulimia nervosa that is directed at correction of the neurochemical alterations observed is difficult because of the complexity of the impairments. However, such treatment is necessary and should be continued long after symptomatic remission to ensure reinstitution of cerebral biochemical homeostasis.

Buckland, P. R. (2001). "Genetic association studies of alcoholism--problems with the candidate gene approach." Alcohol Alcohol 36(2): 99-103.
In recent years, progress has been made in the identification of causative factors in most single gene disorders and those with genes of major effect. In comparison, no genes contributing to a complex disorder have been unambiguously identified. A number of reasons for this have been previously presented in theoretical papers. Alcoholism is such a complex illness and genetic studies into its underlying genetic causes have suffered from lack of power due to small subject numbers, poor selection of control subjects, and over-emphasis on markers with low prior probability of involvement.

Bukofzer, S. and N. Livesey (2001). "Safety and tolerability of apomorphine SL (Uprima)." Int J Impot Res 13 Suppl 3: S40-4.
The side effect profile of apomorphine SL (2-6 mg) has been determined in clinical studies of over 5000 patients using over 120 000 doses. Apomorphine, 2 and 3 mg, has been shown to have an excellent safety profile. The most commonly occurring side effects (<7%), nausea, headache and dizziness, tend to be mild and not compliance limiting. Neither the incidence nor the nature of the side effects is significantly affected by common co-morbidites or by the use of many concurrent medications. Over this dose range there is little evidence of vasoactivity; there is little change in haemodynamic baseline and there is no synergistic effect with nitrates. Although syncope can occur at higher doses, it is rarely observed at approved doses (<0.2%).

Burnside, B. (2001). "Light and circadian regulation of retinomotor movement." Prog Brain Res 131: 477-85.

Buvat, J. and F. Montorsi (2001). "Safety and tolerability of apomorphine SL in patients with erectile dysfunction." BJU Int 88 Suppl 3: 30-5.

Byerly, M. J., M. T. Weber, et al. (2001). "Antipsychotic medications and the elderly: effects on cognition and implications for use." Drugs Aging 18(1): 45-61.
Despite being frequently prescribed in the elderly, antipsychotic medications are commonly associated with adverse effects in this population, including sedative, orthostatic and extrapyramidal adverse effects. Growing evidence suggests that antipsychotics can also cause deleterious cognitive effects in some elderly patients. Preclinical and growing clinical evidence indicates that inhibitory effects on dopaminergic, cholinergic and histaminergic neurochemical systems may account for antipsychotic-associated cognitive impairment in the elderly. A review of published reports of the cognitive effects of antipsychotics in the elderly suggests that newer antipsychotic medications may possess a more favourable cognitive profile than that of traditional agents in this population. The cognitive effect that a specific antipsychotic will have in the elderly, however, is likely better predicted by considering the pharmacodynamic action of an individual agent in combination with the pathophysiology of the condition being treated. Agents with relatively weak dopamine inhibiting effects (e.g. clozapine and quetiapine), for example, would theoretically have a cognitive profile superior to that of agents with higher degrees of dopaminergic inhibition (all traditional agents, risperidone, olanzapine and ziprasidone) when used for conditions associated with diminished dopamine function (e.g. idiopathic Parkinson's disease). Drugs with weak anticholinergic effects (high-potency traditional agents, risperidone, quetiapine and ziprasidone) would theoretically be less likely to cause cognitive impairment than agents with high degrees of cholinergic receptor blocking actions (clozapine and olanzapine) when treating patients with impaired cholinergic function (e.g. Alzheimer's disease). Cholinergic agonist effects of clozapine and olanzapine may, however, mitigate potential adverse cognitive effects associated with the cholinergic blocking actions of these agents. Large, rigorous trials comparing the cognitive effects of antipsychotics with diverse pharmacodynamic actions are lacking in the elderly and are needed.

Calabrese, E. J. (2001). "Dopamine: biphasic dose responses." Crit Rev Toxicol 31(4-5): 563-83.
The present article indicates that dopamine and/or its agonists induce biphasic dose-response relationships for numerous endpoints. These include locomotion, pain sensitivity, blood pressure, prolactin secretion, oxytocin release, heart rate, memory, and neuronal adenylate cyclase activity. Biphasic responses were reported predominantly with male Sprague-Dawley rats, but also with mice, dogs, monkeys, and humans. Regardless of the model or endpoint the maximum changes from the control were always modest being within the 10 to 80% range. The range of stimulatory responses was quite variable, extending from slightly greater than a factor of 10 for the endpoints such as memory, pain-vocalization, and diastolic blood pressure to the 10(6) range for prolactin release and the 10(8) range for oxytocin release. Mechanistic studies suggested that the stimulatory and inhibitory effects of dopamine are mediated by different receptors or receptor subtypes having opposite actions and different ligand affinities.

Carey, R. M. (2001). "Theodore Cooper Lecture: Renal dopamine system: paracrine regulator of sodium homeostasis and blood pressure." Hypertension 38(3): 297-302.
All of the components of a complete dopamine system are present within the kidney, where dopamine acts as a paracrine substance in the control of sodium excretion. Dopamine receptors can be divided into D(1)-like (D(1) and D(5)) receptors that stimulate adenylyl cyclase and D(2)-like (D(2), D(3), and D(4)) receptors that inhibit adenylyl cyclase. All 5 receptor subtypes are expressed in the kidney, albeit in low copy. Dopamine is synthesized extraneuronally in proximal tubule cells, exported from these cells largely into the tubule lumen, and interacts with D(1)-like receptors to inhibit the Na(+)-H(+) exchanger and Na(+),K(+)-ATPase, decreasing tubule sodium reabsorption. During moderate sodium surfeit, dopamine tone at D(1)-like receptors accounts for approximately 50% of sodium excretion. In experimental and human hypertension, 2 renal dopaminergic defects have been described: (1) decreased renal generation of dopamine and (2) a D(1) receptor-G protein coupling defect. Both defects lead to renal sodium retention, and each may play an important role in the pathophysiology of essential hypertension.

Carlsson, A. (2001). "A paradigm shift in brain research." Science 294(5544): 1021-4.
As late as the 1950s, it was assumed that communication between nerve cells in the brain occurred predominantly, if not entirely, by electrical impulses. A decade later, the theory of chemical transmission, which until then had been thought to occur only in the peripheral nervous system, had gained strong entrance for the central nervous system. This paradigm shift opened up an enormous new perspective in brain research, not least by facilitating the study of brain function by means of chemical tools, which in different ways could modify the chemical signaling between nerve cells. Moreover, such tools sometimes turned out to be useful as therapeutic agents. Thus for the first time, a variety of disorders in the central nervous system could be treated effectively.

Carlsson, A., N. Waters, et al. (2001). "Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence." Annu Rev Pharmacol Toxicol 41: 237-60.
In spite of its proven heuristic value, the dopamine hypothesis of schizophrenia is now yielding to a multifactorial view, in which the other monoamines as well as glutamate and GABA are included, with a focus on neurotransmitter interactions in complex neurocircuits. The primary lesion(s) in schizophrenia does not necessarily involve any of these neurotransmitters directly but could deal with a more general defect, such as a faulty connectivity of developmental origin. Nevertheless, a precise identification of neurotransmitter aberrations in schizophrenia will probably provide clues for a better understanding of the disease and for the development of new treatment and prevention strategies.

Carlsson, M. L. (2001). "On the role of prefrontal cortex glutamate for the antithetical phenomenology of obsessive compulsive disorder and attention deficit hyperactivity disorder." Prog Neuropsychopharmacol Biol Psychiatry 25(1): 5-26.
1. The objective of the present study was to compare the phenomenology and pathophysiology of obsessive compulsive disorder (OCD) and attention deficit hyperactivity disorder/deficits in attention, motor control and perception (ADHD/DAMP). 2. Through detailed studies of the literature on OCD and ADHD/DAMP, the phenomenology of these two conditions is compared, and possible underlying pathophysiological mechanisms involving interactions between glutamate, dopamine, serotonin and acetylcholine are discussed, with emphasis on OCD. The present paper also discusses possible mechanisms of action for current pharmacological treatments of OCD and ADHD, as well as possible future treatment strategies for these disorders. 3. OCD and ADHD/DAMP are common neuropsychiatric conditions which in many regards appear to be each other's antipodes with respect to clinical manifestations, associated personality traits and brain biochemistry, notably prefrontal cortical glutamate activity. Future pharmacological treatments of these disorders may involve manipulations with glutamate, dopamine D , serotonin 2A and nicotine receptors. 4. It appears that OCD is a hyperglutamatergic and ADHD a hypoglutamatergic condition, with prefrontal brain regions being especially affected.

Catafau, A. M. (2001). "Brain SPECT of dopaminergic neurotransmission: a new tool with proved clinical impact." Nucl Med Commun 22(10): 1059-60.

Centonze, D., B. Picconi, et al. (2001). "Dopaminergic control of synaptic plasticity in the dorsal striatum." Eur J Neurosci 13(6): 1071-7.
Cortical glutamatergic and nigral dopaminergic afferents impinge on projection spiny neurons of the striatum, providing the most significant inputs to this structure. Isolated activation of glutamate or dopamine (DA) receptors produces short-term effects on striatal neurons, whereas the combined stimulation of both glutamate and DA receptors is able to induce long-lasting modifications of synaptic excitability. Repetitive stimulation of corticostriatal fibres causes a massive release of both glutamate and DA in the striatum and, depending on the glutamate receptor subtype preferentially activated, produces either long-term depression (LTD) or long-term potentiation (LTP) of excitatory synaptic transmission. D1-like and D2-like DA receptors interact synergistically to allow LTD formation, while they operate in opposition during the induction phase of LTP. Corticostriatal synaptic plasticity is severely impaired after chronic DA denervation and requires the stimulation of DARPP-32, a small protein expressed in dopaminoceptive spiny neurons which acts as a potent inhibitor of protein phosphatase-1. In addition, the formation of LTD and LTP requires the activation of PKG and PKA, respectively, in striatal projection neurons. These kinases appear to be stimulated by the activation of D1-like receptors in distinct neuronal populations.

Cerqueira-Gomes, M., J. Polonia, et al. (2001). "[Neuro-hormonal mechanisms in heart failure -- from physiopathology to treatment]." Rev Port Cardiol 20 Suppl 5: V-99-122; discussion V-123-5.
This review updates some recent advances of a new and exciting developments in basic and clinical cardiology: a) the role, in the congestive heart failure (CHF), of the neurohumoral systems (NHS) which act to maintain circulatory homeostatic equilibrium, and b) the therapeutic implications of such a role. Six NHS, acting in CHF, have presently been identified: three of them induce vasoconstriction and sodium retention (sympathetic nervous systems, renin-angiotensin-aldosterone system and arginine-vasopressine system); the remaining three offset or balance the former ones, acting, therefore as "counterregulators" (prostaglandins--PGE2 and PGI2--, dopaminergic system and atrial natriuretic factor). Each one of these NHS influences the "compensatory" mechanisms of heart failure, acting on the target-organs both by direct effects and by interaction with other NHS; consequently, in heart failure, all the NHS are stimulated with the respective increase in the plasma levels of their active agents. In asymptomatic stages of ventricular dysfunction the stimulation of the vasodilator-and-natriuretic systems appears to be predominant and able to maintain circulatory equilibrium. However, as the heart dysfunction increases and becomes symptomatic, the vasoconstrictor and sodium-retaining forces appear to predominate; this phenomenon becomes increasingly apparent as the functional class becomes more advanced. The hyperstimulation of these last systems has an extremely important role in the pathophysiology and clinical manifestations of congestive heart failure, as well as in its prognosis. Therefore, the attempts to correct these neurohormonal imbalance in patients with heart failure has a sound rational basis, not only to improve the symptoms and the exercise capacity but also to increase the survival of these patients. At the present time, amongst the potential pharmacological interventions acting on NHS in CHF, the blockade of the RAA system with ACE-inhibitors is generally accepted as the most feasible, the safest and the most effective therapeutic tool. In fact, its application has broadened from an earlier use in severe CHF to other symptomatic stages of cardiac failure, including the milder forms. In addition, preliminary data strongly suggest its unique usefulness in asymptomatic phase of ventricular dysfunction. Looking back at the medical therapy of heart failure, in can be concluded that we are starting a new era. Throughout 200 years (since the introduction of digitalis) the therapeutic goal in CHF has been the improvement of symptoms. With the developments of the present decade, a new and exciting goal is being offered to these patients, called by Packer "the second frontier", that is, the prolongation of their lives.

Chambers, R. A., J. H. Krystal, et al. (2001). "A neurobiological basis for substance abuse comorbidity in schizophrenia." Biol Psychiatry 50(2): 71-83.
It is commonly held that substance use comorbidity in schizophrenia represents self-medication, an attempt by patients to alleviate adverse positive and negative symptoms, cognitive impairment, or medication side effects. However, recent advances suggest that increased vulnerability to addictive behavior may reflect the impact of the neuropathology of schizophrenia on the neural circuitry mediating drug reward and reinforcement. We hypothesize that abnormalities in the hippocampal formation and frontal cortex facilitate the positive reinforcing effects of drug reward and reduce inhibitory control over drug-seeking behavior. In this model, disturbances in drug reward are mediated, in part, by dysregulated neural integration of dopamine and glutamate signaling in the nucleus accumbens resulting form frontal cortical and hippocampal dysfunction. Altered integration of these signals would produce neural and motivational changes similar to long-term substance abuse but without the necessity of prior drug exposure. Thus, schizophrenic patients may have a predilection for addictive behavior as a primary disease symptom in parallel to, and in many, cases independent from, their other symptoms.

Chase, T. N., S. Konitsiotis, et al. (2001). "Striatal molecular mechanisms and motor dysfunction in Parkinson's disease." Adv Neurol 86: 355-60.

Chevalier, R. L. (2001). "The moth and the aspen tree: sodium in early postnatal development." Kidney Int 59(5): 1617-25.
Over the past 25 years, our perception of the neonatal kidney has changed markedly from its being a "limited" organ compared with that of the adult to being extraordinarily well adapted in its role in maintaining homeostasis and making possible the rapid somatic growth necessary during this critical period of life. The present review focuses on the physiologic adaptations by the neonatal kidney in the maintenance of a positive sodium balance, which is necessary for normal growth not only in mammals but also in moths. There is a fine interplay between the developing brain, heart, thyroid, adrenals, and sympathetic nervous system, all converging on the kidney to conserve sodium, which is limited in the diet. The renin-angiotensin system plays a central role in this response and is balanced by developmental changes in the renal response to atrial natriuretic peptide, all of which contribute to sodium conservation. Over the next 25 years, advances in molecular genetics will doubtless elucidate many more facets of the mechanisms underlying neonatal sodium homeostasis. This will be particularly important as the survival of ever smaller preterm infants improves steadily.

Chiueh, C. C. (2001). "Iron overload, oxidative stress, and axonal dystrophy in brain disorders." Pediatr Neurol 25(2): 138-47.
Hallervorden-Spatz syndrome is an autosomal-recessive brain disorder with signs of extrapyramidal dysfunction and mental deterioration, which associate with iron accumulation in globus pallidus and substantia nigra pars reticulata. Studies of oxidant stress in parkinsonian animal models suggest a linkage of iron overload to axonal dystrophy. Redox cycling of iron complexes (i.e., ferrous citrate and hemoglobin) increases hydroxyl radicals, lipid peroxidation, axonal dystrophy, and necrotic or apoptotic cell death. An increase of oxidative stress in the basal ganglia because of redox cycling of iron complexes leads to dopamine overflow and psychomotor dysfunction. Iron overload-induced axonal dystrophy has been demonstrated consistently using in vitro and in vivo models with a prominent feature of lipid peroxidation. This iron-induced oxidative stress is often accentuated by ascorbate and oxidized glutathione, although it is suppressed by the following antioxidants: S-nitrosoglutathione or nitric oxide, MnSOD mimics, manganese, U-78517F, Trolox, and deferoxamine. Preconditioning induction of stress proteins (i.e., hemeoxygenase-1 and neuronal nitric oxide synthase) and hypothermia therapy suppress the generation of toxic reactive oxygen, lipid, and thiol species evoked by bioactive iron complexes in the brain. Finally, combined antioxidative therapeutics and gene induction procedures may prove to be useful for slowing progressive neurodegeneration caused by iron overload in the brain.

Chu, V. L. and J. W. Cheng (2001). "Fenoldopam in the prevention of contrast media-induced acute renal failure." Ann Pharmacother 35(10): 1278-82.
OBJECTIVE: To examine the role of fenoldopam in prevention of contrast media-induced acute renal failure (ARF). DATA SOURCES: A literature search of MEDLINE (from 1966 to October 2000) was performed using the following title search terms: fenoldopam, contrast, and renal failure. STUDY SELECTlON: English-language human studies, abstracts, and pertinent animal data were reviewed. DATA SYNTHESIS: Small trials using animals with artificially induced ARF receiving fenoldopam demonstrated improvement in renal function. Preliminary trials in healthy humans have also demonstrated similar results using doses not affecting systemic blood pressure. CONCLUSIONS: Fenoldopam may have a role in the management of ARF induced by contrast dye. However, due to the lack of a large-scale study it cannot be routinely recommended.

Clarke, C. E. and K. D. Deane (2001). "Cabergoline versus bromocriptine for levodopa-induced complications in Parkinson's disease." Cochrane Database Syst Rev(1): CD001519.
BACKGROUND: Long term levodopa therapy in Parkinson's disease is associated with the development of motor complications including abnormal involuntary movements and a shortening response to each dose (wearing off phenomenon). It is thought that dopamine agonists can reduce the duration of immobile off periods and the need for levodopa therapy whilst maintaining or improving motor impairments and only minimally increasing dopaminergic adverse events. OBJECTIVES: To compare the efficacy and safety of adjuvant cabergoline therapy versus bromocriptine in patients with Parkinson's disease, already established on levodopa and suffering from motor complications. SEARCH STRATEGY: Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Pharmacia Upjohn Limited. SELECTION CRITERIA: Randomised controlled trials of cabergoline versus bromocriptine in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, off time measurements and the frequency of withdrawals and adverse events. MAIN RESULTS: Cabergoline has been compared with bromocriptine in five randomised, double-blind, parallel group studies including 1071 patients. Only one of the phase II studies was medium term (36 weeks), the others all being short term (12 -15 weeks). The non-significant difference in off time reduction produced by cabergoline compared with bromocriptine was 0.29 hours/day in favour of the former (weighted mean difference; 95% CI -0.10, 0.68; p = 0.15). Dyskinesia reported as an adverse event was significantly increased with cabergoline compared with bromocriptine (Peto odds ratio 1.57; 95% CI 1.05, 2.35; p = 0.03). Motor impairment and disability were measured in four of the studies using the UPDRS rating scale but the small differences in UPDRS ADL (part II) and motor (part III) scores were not statistically significant in any study. Similarly, no significant difference in Schwab and England score was seen. The number of patients rated as much or very much improved on a clinician's global impression scale was similar with both agonists. Levodopa dose reduction was no different between cabergoline and bromocriptine. There was more confusion with cabergoline (Peto odds ratio 2.02; 95% CI 1.09, 3.76; p = 0.03). Otherwise, dopaminergic adverse events were comparable with these agonists and no significant difference in all cause withdrawal rate was found. REVIEWER'S CONCLUSIONS: Cabergoline produces similar benefits to bromocriptine in off time reduction, motor impairment and disability ratings, and levodopa dose reduction over the first three months of therapy. Dyskinesia and confusion were increased with cabergoline but otherwise the frequency of adverse events and withdrawals from treatment were similar with the two agonists.

Clarke, C. E. and K. H. Deane (2001). "Cabergoline for levodopa-induced complications in Parkinson's disease." Cochrane Database Syst Rev(1): CD001518.
BACKGROUND: Long term levodopa therapy in Parkinson's disease is associated with the development of motor complications including abnormal involuntary movements and a shortening response to each dose (wearing off phenomenon). It is thought that dopamine agonists can reduce the duration of immobile off periods and the need for levodopa therapy whilst maintaining or improving motor impairments and only minimally increasing dopaminergic adverse events. OBJECTIVES: To compare the efficacy and safety of adjuvant cabergoline therapy versus placebo in patients with Parkinson's disease, already established on levodopa and suffering from motor complications. SEARCH STRATEGY: Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Pharmacia Upjohn Limited. SELECTION CRITERIA: Randomised controlled trials of cabergoline versus placebo in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, off time measurements and the frequency of withdrawals and adverse events. MAIN RESULTS: Cabergoline has been compared with placebo in two phase II (6 - 12 weeks) and one phase III randomised controlled trials (24 weeks). These were double-blind, parallel group, multicentre studies including 268 patients with Parkinson's disease and motor complications. The reduction of 1.14 hours (WMD; 95% CI -0.06, 2.33; p = 0.06) in off time in favour of cabergoline was not statistically significant. Inadequate data on dyskinesia was collected either on rating scales or as adverse event reporting to allow a conclusion to be drawn. A small but statistically significant advantage of cabergoline over placebo was seen in one study for UPDRS ADL (part II) score and UPDRS motor score. No such advantage was seen in one other study due to small numbers of patients and the comparatively low doses of cabergoline used. No significant differences in Schwab and England scale were seen in two studies. Levodopa dose reduction was significantly greater with cabergoline (WMD 149.6 mg/d; 95% CI 94.1, 205.1; p < 0.00001). There was a trend towards more dopaminergic adverse events with cabergoline but this did not reach statistical significance at the p < 0.01 level. However, there was a trend towards fewer withdrawals from cabergoline. REVIEWER'S CONCLUSIONS: In the management of the motor complications seen in Parkinson's disease, cabergoline can be used to reduce levodopa dose and modestly improve motor impairment and disability with an acceptable adverse event profile. These conclusions are based on, at best, medium term evidence.

Clarke, C. E. and K. H. Deane (2001). "Ropinirole versus bromocriptine for levodopa-induced complications in Parkinson's disease." Cochran