Dopamine Imbalance Research Articles

Cimetidine is critical in CNS disorders

There are many CNS disorders with imbalance of dopamine in brain. Cimetidine adversely increases serum level of the prolactin and leads to activate feedback control to decrease prolactin release and intensifies synthesis and secretion of dopamine. Thus, cimetidine can be critical in CNS disorders.

Computational Systems Analysis of Dopamine Metabolism

A prominent feature of Parkinson's disease (PD) is the loss of dopamine in the striatum, and many therapeutic interventions for the disease are aimed at restoring dopamine signaling. Dopamine signaling includes the synthesis, storage, release, and recycling of dopamine in the presynaptic terminal and activation of pre- and post-synaptic receptors and various downstream signaling cascades. As an aid that might facilitate our understanding of dopamine dynamics in the pathogenesis and treatment in PD, we have begun to merge currently available information and expert knowledge regarding presynaptic dopamine homeostasis into a computational model, following the guidelines of biochemical systems theory. After subjecting our model to mathematical diagnosis and analysis, we made direct comparisons between model predictions and experimental observations and found that the model exhibited a high degree of predictive capacity with respect to genetic and pharmacological changes in gene expression or function. Our results suggest potential approaches to restoring the dopamine imbalance and the associated generation of oxidative stress. While the proposed model of dopamine metabolism is preliminary, future extensions and refinements may eventually serve as an in silico platform for prescreening potential therapeutics, identifying immediate side effects, screening for biomarkers, and assessing the impact of risk factors of the disease.

Elevated dopamine levels during gestation produce region-specific decreases in neurogenesis and subtle deficits in neuronal numbers

Dopamine levels in the fetal brain were increased by administering the dopamine precursor 3,4-dihydroxy-l-phenylalanine (l-DOPA) to pregnant mice in drinking water. The l-DOPA exposure decreased bromodeoxyuridine (BrdU) labeling in the lateral ganglionic eminence and frontal cortical neuroepithelium but not medial or caudal ganglionic eminences. The regional differences appear to reflect heterogeneity in precursor cells' responses to dopamine receptor activation. Relative numbers of E15-generated neurons were decreased at postnatal day 21 (P21) in the caudate-putamen, nucleus accumbens and frontal cortex but not globus pallidus in the l-DOPA group. TUNEL labeling did not show significant differences on P0, P7 or P14 in the caudate-putamen or frontal cortex, suggesting that cell death was not altered. Although virtually all cells in the P21 brains that were labeled with the E15 BrdU injection were NeuN-positive, stereological analyses showed no significant changes in total numbers of NeuN-positive or NeuN-negative cells in the P21 caudate-putamen or frontal cortex. Thus persisting deficits in neuronal numbers were evident in the l-DOPA group only by birth-dating analyses and not upon gross histological examination of brain sections or analysis of total numbers of neurons or glia. One explanation for this apparent discrepancy is that l-DOPA exposure decreased cell proliferation at E15 but not at E13. By E15, expansion of the neuroepithelial precursor pool is complete and any decrease in cell proliferation likely produces only marginal decreases in the total numbers of cells generated. Our l-DOPA exposure model may be pertinent to investigations of neurological dysfunction produced by developmental dopamine imbalance.

Peptide hormone exendin‐4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of parkinson's disease

We investigated the effects of exendin-4 on neural stem/progenitor cells in the subventricular zone of the adult rodent brain and its functional effects in an animal model of Parkinson's disease. Our results showed expression of GLP-1 receptor mRNA or protein in the subventricular zone and cultured neural stem/progenitor cells isolated from this region. In vitro, exendin-4 increased the number of neural stem/progenitor cells, and the number of cells expressing the neuronal markers microtubule-associated protein 2, beta-III-tubulin, and neuron-specific enolase. When exendin-4 was given intraperitoneally to naïve rodents together with bromodeoxyuridine, a marker for DNA synthesis, both the number of bromodeoxyuridine-positive cells and the number of neuronal precursor cells expressing doublecortin were increased. Exendin-4 was tested in the 6-hydroxydopamine model of Parkinson's disease to investigate its possible functional effects in an animal model with neuronal loss. After unilateral lesion and a 5-week stabilization period, the rats were treated for 3 weeks with exendin-4. We found a reduction of amphetamine-induced rotations in animals receiving exendin-4 that persisted for several weeks after drug administration had been terminated. Histological analysis showed that exendin-4 significantly increased the number of both tyrosine hydroxylase- and vesicular monoamine transporter 2-positive neurons in the substantia nigra. In conclusion, our results show that exendin-4 is able to promote adult neurogenesis in vitro and in vivo, normalize dopamine imbalance, and increase the number of cells positive for markers of dopaminergic neurons in the substantia nigra in a model of Parkinson's disease.

Dopamine Receptor Activation Modulates GABA Neuron Migration from the Basal Forebrain to the Cerebral Cortex

GABA neurons of the cerebral cortex and other telencephalic structures are produced in the basal forebrain and migrate to their final destinations during the embryonic period. The embryonic basal forebrain is enriched in dopamine and its receptors, creating a favorable environment for dopamine to influence GABA neuron migration. However, whether dopamine receptor activation can influence GABA neuron migration is not known. We show that dopamine D1 receptor activation promotes and D2 receptor activation decreases GABA neuron migration from the medial and caudal ganglionic eminences to the cerebral cortex in slice preparations of embryonic mouse forebrain. Slice preparations from D1 or D2 receptor knock-out mouse embryos confirm the findings. In addition, D1 receptor electroporation into cells of the basal forebrain and pharmacological activation of the receptor promote migration of the electroporated cells to the cerebral cortex. Analysis of GABA neuron numbers in the cerebral wall of the dopamine receptor knock-out mouse embryos further confirmed the effects of dopamine receptor activation on GABA neuron migration. Finally, dopamine receptor activation mobilizes striatal neuronal cytoskeleton in a manner consistent with the effects on neuronal migration. These data show that impairing the physiological balance between D1 and D2 receptors can alter GABA neuron migration from the basal forebrain to the cerebral cortex. The intimate relationship between dopamine and GABA neuron development revealed here may offer novel insights into developmental disorders such as schizophrenia, attention deficit or autism, and fetal cocaine exposure, all of which are associated with dopamine and GABA imbalance.

Dopamine in the Pathophysiology and Treatment of Schizophrenia: New Findings

Back to table of contents Previous article Next article Book Forum: SCHIZOPHRENIAFull AccessDopamine in the Pathophysiology and Treatment of Schizophrenia: New FindingsFÉLIX-ANTOINE BÉRUBÉ, M.D., and MARC-ANDRÉ ROY, M.D., M.Sc., F.R.C.P., FÉLIX-ANTOINE BÉRUBÉSearch for more papers by this author, M.D., and MARC-ANDRÉ ROYSearch for more papers by this author, M.D., M.Sc., F.R.C.P., Beauport, Quebec, CanadaPublished Online:1 Nov 2005https://doi.org/10.1176/ajp.162.11.2204-aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Few paradigms in psychiatry have shown the resilience of the dopamine hypothesis of schizophrenia. Thirty years after the demonstration that the blockade of dopamine receptors is the common denominator underlying the effects of antipsychotic drugs, this neurotransmitter system remains at the heart of current research. In 2002, on the 50th anniversary of the introduction of antipsychotics, a meeting was held in Montreal, gathering European and North American leaders in the field of dopamine and schizophrenia research, who shared and updated current knowledge on the subject. The results of this enterprise are embodied in pages of this attractive yet dense book.The 12 chapters, each by different authors, offer a comprehensive picture of the present state of research. A number of different topics and points of view are brought up, sometimes stirring controversy between the authors. This book provides, among other material, a summary of the historical background of the dopamine hypothesis and its successive formulations, showing that we are a long way from the first formulations, which implied, somewhat naively, that schizophrenia can be reduced to dopamine mesolimbic hypersecretion. The chapter authors caution against such a monolithic view, and the content of the book reflects this concern.Plausible models of interaction between dopamine and glutamatergic systems are described in chapters 1 and 2, and the importance of other neurotransmitter systems and receptors, especially serotonin, is detailed in chapter 9. Abi-Dargham reviews the recent evidence from brain imaging studies pointing toward a dopamine imbalance at a limbic level and once more confirming the role of dopamine in schizophrenia. As one would expect, the current hypotheses about the neurobiological basis of atypicality are explored, especially the apparent paradox of amisulpride, which has a strong and almost exclusive affinity to dopamine receptors while behaving clinically like an atypical antipsychotic. The authors posit that amisulpride, which is widely used in Europe but unavailable in North America, could offer some advantage in the treatment of negative symptoms in maintenance therapy. Furthermore, an inspiring reflection about a probable genetic mechanism of risk for schizophrenia, involving variations in the COMT gene, is put forward by Weinberger in chapter 7.The dopamine hypothesis may also offer an understanding of clinical phenomena, as outlined by Kapur and, albeit in a wider frame, Spitzer. The dopamine system plays a central role in the attribution of salience, a psychological mechanism by which the brain filters and labels important information. Chapter authors stress the idea that dopamine dysfunction, for this reason, could constitute a primary mechanism for the elaboration of delusions and delusional perceptions, eloquently bridging the apparent gap between neuroscience and psychology. Stahl provides an inspiring conclusion that reviews the unmet needs in the treatment of schizophrenia.Overall, this is a very instructive piece of work, successfully depicting the current state of knowledge regarding the dopamine hypothesis and opening avenues of research and reflection. Exhaustiveness has been preferred to uniformity, making it a heterogeneous work. However, one could argue that it is representative of our relative ignorance on the matter, where there is ample space for controversy and generation of new hypotheses eliciting original and diversified angles of approach. Although some chapters may seem at first glance tedious to the neophyte, this book is undoubtedly a must-read for clinicians and researchers alike who want to better their knowledge of dopamine’s role in schizophrenia.Edited by Shitij Kapur and Ives Lecrubier. London, Martin Dunitz (Independence, Ky., Taylor & Francis, distributor), 2003, 260 pp., $59.95 (paper). FiguresReferencesCited byDetailsCited ByNone Volume 162Issue 11 November 2005Pages 2204-a-2205 Metrics PDF download History Published online 1 November 2005 Published in print 1 November 2005

Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment.

The fundamental pathological process(es) associated with schizophrenia remain(s) uncertain, but multiple lines of evidence suggest that this condition is associated with (1) excessive stimulation of striatal dopamine (DA) D2 receptors, (2) deficient stimulation of prefrontal DA D1 receptors and, (3) alterations in prefrontal connectivity involving glutamate (GLU) transmission at N-methyl-d-aspartate (NMDA) receptors. This chapter first briefly discusses the current knowledge status for these abnormalities, with emphasis on results derived from clinical molecular imaging studies. The evidence for hyperstimulation of striatal D2 receptors rests on strong pharmacological evidence and has recently received support from brain imaging studies. The hypothesis of deficient prefrontal cortex (PFC) D1 receptor stimulation is almost entirely derived from preclinical studies. Preliminary imaging data compatible with this hypothesis have recently emerged. The NMDA hypofunction hypothesis originates mainly from indirect pharmacological data. The interactions between DA and GLU systems relevant to schizophrenia are then reviewed. Animal and imaging data supporting the general model that the putative DA imbalance in schizophrenia (striatal excess and cortical deficiency) might be secondary to NMDA hypofunction in the PFC and its connections are presented. Equally important are the potential consequences of this DA imbalance for NMDA function in the striatum and the cortex, which are subsequently discussed. In conclusion, it is proposed that schizophrenia is associated with strongly interconnected abnormalities of GLU and DA transmission: NMDA hypofunction in the PFC and its connections might generate a pattern of dysregulation of DA systems that, in turn, further weakens NMDA-mediated connectivity and plasticity.

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Differential effects of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire an attentional set.

Evidence from both human and animal studies indicates that catecholamine (dopamine and noradrenaline) imbalances in the fronto-striatal circuitry are associated with deficits in higher- order cognitive functions. The present study examined how catecholamines within this circuitry modulate attentional function, specifically the ability to develop, maintain, and shift an attentional set. Catecholamine depletions within the frontal cortex of the common marmoset impaired the ability to acquire an attentional set, and increased susceptibility to distraction from task-irrelevant stimuli. Analysis of set-shifting performance with stimulus dimensions of varying salience suggested that frontal catecholamine depletion selectively disrupts "top-down", but not "bottom-up" attentional processing. In contrast, the ability to acquire and shift an attentional set remained intact following dopaminergic depletion from the caudate nucleus. However, the reduced susceptibility to distraction from task-irrelevant stimuli displayed by monkeys with dopaminergic depletions of the caudate nucleus suggests that responding was under more rigid control by the currently rewarded stimulus. The results demonstrate opposite behavioural effects of 6-hydroxydopamine (6-OHDA) lesions in the frontal cortex and caudate nucleus in tasks requiring selective attention. Frontal catecholamine depletion caused an increase in distractibility while caudate dopamine loss induced greater focusing of responding.

Overview of restless legs syndrome.

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.

Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice.

Two uptake systems that control the extracellular concentrations of released monoamine neurotransmitters such as noradrenaline and adrenaline have been described. Uptake-1 is present at presynaptic nerve endings, whereas uptake-2 is extraneuronal and has been identified in myocardium and vascular and nonvascular smooth muscle cells. The gene encoding the uptake-2 transporter has recently been identified in humans (EMT), rats (OCT3), and mice (Orct3/Slc22a3). To generate an in vivo model for uptake-2, we have inactivated the mouse Orct3 gene. Homozygous mutant mice are viable and fertile with no obvious physiological defect and also show no significant imbalance of noradrenaline or dopamine. However, Orct3-null mice show an impaired uptake-2 activity as measured by accumulation of intravenously administered [(3)H]MPP(+) (1-methyl-4-phenylpyridinium). A 72% reduction in MPP(+) levels was measured in hearts of both male and female Orct3 mutant mice. No significant differences between wild-type and mutant mice were found in any other adult organ or in plasma. When [(3)H]MPP(+) was injected into pregnant females, a threefold-reduced MPP(+) accumulation was observed in homozygous mutant embryos but not in their placentas or amniotic fluid. These data show that Orct3 is the principal component for uptake-2 function in the adult heart and identify the placenta as a novel site of action of uptake-2 that acts at the fetoplacental interface.

Dopamine and serotonin imbalances in the left anterior cingulate and pyriform cortices following the repeated intermittent administration of cocaine

Studies on the neurobiology of cocaine abuse suggest that cocaine directly modifies the activity of dopamine neurons projecting from the dopamine-synthesizing cells of the ventral tegmental area to the nucleus accumbens. The repeated use of cocaine produces persistent adaptations within the mesocortico-limbic system and the resulting changes in monoamine neurotransmission may lead to behavioral sensitization. The present series of experiments sought to determine the effects of the repeated, intermittent administration of cocaine for five days on (i) the expression of locomotor activity in response to a cocaine challenge that took place two days after discontinuation of the pretreatment regimen; (ii) the ex vivo levels of biogenic monoamines, choline and acetylcholine in the nucleus accumbens, the dorsolateral caudate nucleus, as well as the anterior cingulate, frontal motor, frontal somatosensory and pyriform cortices; and (iii) the degree of neurochemical relationship between the left and right hemispheres. The repeated administration of cocaine produced sensitized behavioral responses to a subsequent challenge. Neurochemical correlates of repeated cocaine administration were observed at the cortical level and included a significant decrease in serotonin levels in the left anterior cingulate and pyriform cortices and an increase in dopamine metabolism in the left pyriform cortex. Furthermore, a shift in the interhemispheric coupling coefficient matrix for dopamine neurotransmission was observed in both the pyriform cortex and nucleus accumbens of cocaine-sensitized animals suggesting that, in these structures, the two hemispheres are operating independently. These results demonstrate that cocaine produces alterations in specific dopaminergic and serotonergic pathways that arise from the mesencephalon and project towards both the anterior cingulate and pyriform cortices.

Age-related alteration of the adenosine/dopamine balance in the rat striatum

An antagonistic interaction between adenosine A 2A- and dopamine D 2-receptors has been described. Radioligand binding experiments showed a predominant reduction in the number of D 2 vs. A 2A-receptors in the striatum of aged compared to young rats. The A 2A-receptor-mediated antagonistic modulation of D 2-receptor binding remained unchanged in aged animals. In striatal homogenates a significant increase in adenosine and no change in dopamine content was found in aged vs. young rats. These results reveal the existence of an age-dependent imbalance of adenosine vs. dopamine in favor of adenosine, which involves both presynaptic and postsynaptic mechanisms.

Dopamine differentiation factors produce partial motor recovery in 6-hydroxydopamine lesioned rats

Two-week infusion of muscle-derived differentiation factor (MDF), or human recombinant acidic fibroblast growth factor (aFGF) and/or its muscle-derived activating substance into the striatum of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats caused a significant and long lasting (40 days) reduction (48–100%) in amphetamine-induced rotational asymmetry. In parallel with behavioural recovery, striatal tyrosine hydroxylase (TH) activity, dopamine (DA) and dihydroxy-phenyl-acetic acid (DOPAC) levels recovered in a dose-dependent manner in all treated rats when compared to controls. The greatest increments were observed in rats infused with aFGF and its activator. Increases in biochemical indices were not reflected in trophic changes of the dopamine system; thus, the number of TH-immunoreactive neurones and their striatal innervation were unmodified by treatment with MDF. In contrast with the lesioned brain, infusion of these agents into the intact brain produced no change in nigrostriatal dopamine biochemistry. Our results suggest that dopamine differentiation factors may be important in regulating the production of dopamine in the injured brain and, therefore, may be useful in the treatment of DA imbalances associated with certain neurological disorders such as Parkinson's disease.

Does unilateral dopamine deficit contribute to depression?

A system of emotional control of behavior is believed to be lateralized to the right hemisphere. Given that dopaminergic pathways are involved in affective behavior, depression, which is recognized as an integral part of Parkinson's disease, may be associated with a dopamine imbalance. The present study examined this hypothesis in patients with unilateral symptomatology indicating either left hemisphere parkinsonism (LHP) or right hemisphere parkinsonism (RHP). Sixteen patients were tested on a battery of neuropsychological tests and several scales for evaluating mood. The two groups did not differ significantly on either cognitive or emotional measures. However, RHP patients rated themselves higher on the Present Scale of Cantril, and showed some neglect of the left visual field, as compared to LHP patients.

The rotating rodent: A two component system?

The hypothesis that the rotating rat requires both nigro-striatal and mesolimbic dopaminergic components for activity has been tested. 6-Hydroxydopamine lesions were induced unilaterally in either or both the ascending nigrostriatal and mesolimbic dopamine pathways. In one group of rat the nucleus accumbens was destroyed bilaterally with electrolesions. Circling behavior was only recorded when there was both on imbalance in striatal dopamine concentrations concomitant with stimulation of the limbic dopamine regions. Lesions of the mesolimbic dopamine pathway resulted in changes in drug-induced motor activity but postural asymmetry or circling behaviour was not observed. The results support the hypothesis that the rotating rodent requires two functional dopamine components: striatal dopamine imbalance causing a postural asymmetry and stimulation of mesolimbic dopamine systems providing a locomotor component. The relevance of these components in this animal model is discussed with reference to dopaminergic agonist and antagonist drugs.