Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormal dopaminergic transmission is implicated in schizophrenia, attention deficit hyperactivity disorder, and drug addiction. In an attempt to model aspects of these disorders, we have generated hyperdopaminergic mutant mice by reducing expression of the dopamine transporter (DAT) to 10% of wild-type levels (DAT knockdown). Fast-scan cyclic voltammetry and in vivo microdialysis revealed that released dopamine was cleared at a slow rate in knockdown mice, which resulted in a higher extracellular dopamine concentration. Unlike the DAT knockout mice, the DAT knockdown mice do not display a growth retardation phenotype. They have normal home cage activity but display hyperactivity and impaired response habituation in novel environments. In addition, we show that both the indirect dopamine receptor agonist amphetamine and the direct agonists apomorphine and quinpirole inhibit locomotor activity in the DAT knockdown mice, leading to the hypothesis that a shift in the balance between dopamine auto and heteroreceptor function may contribute to the therapeutic effect of psychostimulants in attention deficit hyperactivity disorder.
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PMID:Hyperactivity and impaired response habituation in hyperdopaminergic mice. 1117 62

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal.
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PMID:BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. 1133 82

Substantial evidence suggests that the functional status of the mesocorticolimbic dopamine (DA) system originating in the ventral tegmental area is under a phasic and tonic inhibitory control by the 5-HT system that acts by stimulating 5-HT(2C) receptor subtypes. Indeed, electrophysiological and biochemical data demonstrate that 5-HT(2C) receptor agonists decrease, whereas 5-HT(2C) receptor antagonists enhance, mesocorticolimbic DA function. However, 5-HT(2C) receptors do not appear to play a relevant role in the control of the nigrostriatal DA system originating in the substantia nigra pars compacta. In this article, the role of 5-HT(2C) receptors in the control of brain DA function will be reviewed, and the search for new therapies for neuropsychiatric disorders, such as depression, schizophrenia and drug addiction, based on these findings will be discussed.
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PMID:Role of 5-HT(2C) receptors in the control of central dopamine function. 1133 73

Dopamine is implicated in movement, learning, and motivation, and in illnesses such as Parkinson's disease, schizophrenia, and drug addiction. Little is known about the control of dopamine release in humans, but research in experimental animals suggests that the prefrontal cortex plays an important role in regulating the release of dopamine in subcortical structures. Here we used [(11)C]raclopride and positron emission tomography to measure changes in extracellular dopamine concentration in vivo after repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in healthy human subjects. Repetitive TMS of the left dorsolateral prefrontal cortex caused a reduction in [(11)C]raclopride binding in the left dorsal caudate nucleus compared with rTMS of the left occipital cortex. There were no changes in binding in the putamen, nucleus accumbens, or right caudate. This shows that rTMS of the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus. This finding has implications for the therapeutic and research use of rTMS in neurological and psychiatric disorders.
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PMID:Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. 1145 78

Dopamine projections from the midbrain to the striatum and frontal cortex are involved in behavioral reactions controlled by rewards, as inferred from deficits in parkinsonism, schizophrenia, and drug addiction. Recent experiments have shown that dopamine neurons are not directly modulated in relation to movements. Rather, they appear to code the rewarding aspects of environmental stimuli. They show short, phasic increases of activity following primary food and liquid rewards ("unconditioned stimuli") and conditioned, reward-predicting stimuli of visual, auditory, and somatosensory modalities. They also display smaller activation-depression sequences after stimuli resembling rewards and after novel or particularly intense stimuli. Rewards are only reported as far as they occur differently than predicted. According to learning theories, a "prediction error" message may constitute a powerful teaching signal for behavior and learning. The phasic reward message is different from the more tonic enabling function of dopamine that is deficient in Parkinson's disease, indicating that dopamine neurons subserve different functions at different time scales. Neurons in other brain structures, such as the striatum, orbitofrontal cortex, and amygdala, code the quality, quantity, and preference of rewards. The dopamine reward prediction error signal may cooperate with these reward perception signals during the learning and performance of behavioral reactions to motivating environmental stimuli.
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PMID:Reward signaling by dopamine neurons. 1148 95

Monoamine transporters include plasma membrane and vesicular monoamine transporters(VMAT). The former selectively and Na+/Cl(-)-dependently transport dopamine, noradrenaline and serotonin into the cytoplasma, and the latter non-selectively carries monoamine into the vesicle. These transporters are composed of amino acid groups containing 12 folds more transmembrane components. Cytoplasmic transporters are a target site of certain drugs. Antiepileptic drugs such as SSRI and tricyclic antidepressants bind with serotonin transporter(SERT), noradrenaline transporter(NET) and/or dopamine transporters(DAT) to inhibit transport of monoamines into the cytoplasma, thereby increasing monoamine levels within the synaptic cleft. However, amphetamine, known to induce drug dependence, is transported by DAT and inhibit VMAT to induce reverse-transport of monoamines into the synaptic area, thereby producing psychiatric and behavioral alterations. Thus, monoamine transporters are target sites of drugs, and functional changes in the transporters may be involved in the pathogenesis of affective diseases, schizophrenia and/or personality disorders including neurogenerative diseases such as Parkinson's disease.
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PMID:[Function of monoamine neurotransmitter transporters]. 1151 42

Repeated administration of psychomotor stimulants produces an enduring and progressively enhanced behavioral response known as behavioral sensitization, which has been implicated as a model for psychiatric disorders such as mania, schizophrenia, and drug addiction. The objective of the study was to determine whether lithium chloride (LiCl), an anti-manic agent, is effective in blocking the development and/or the expression of behavioral sensitization to methylphenidate. Male Sprague-Dawley rats (n=64) weighing 170-190 g were randomly divided into seven treatment groups. A computerized animal activity monitor system continuously recorded locomotor activity for 16 days. Effects of LiCl on induction of methylphenidate sensitization were studied by giving LiCl before or during six daily methylphenidate administrations. Effects of LiCl on the expression of methylphenidate sensitization were studied by injecting LiCl after sensitization to methylphenidate was induced. It was shown that LiCl treatment modulated the acute methylphenidate effects by transiently attenuating the locomotor response to methylphenidate during the six daily methylphenidate administrations but neither single nor multiple treatments with LiCl blocked the development or the expression of behavioral sensitization.
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PMID:Effects of lithium chloride on induction and expression of methylphenidate sensitization. 1152 72

There is substantial evidence that the functional status of mesocorticolimbic dopaminergic (DA) system originating in the ventral tegmental area (VTA) is under a phasic and tonic inhibitory control by the serotonergic system, which acts by stimulating serotonin(2C) (5-HT(2C)) receptor subtypes. This assertion is based upon a number of electrophysiological and biochemical data showing that 5-HT(2C) receptor agonists decrease, while 5-HT(2C) receptor antagonists enhance mesocorticolimbic DA function. On the other hand, it does not seem that 5-HT(2C) receptors play a relevant role in the control of nigrostriatal DA system originating in the substantia nigra pars compacta (SNc). The authors of this article review the most relevant data regarding the role of 5-HT(2C) receptors in the control of brain DA function and underline the importance of this subject in the search of new therapies for neuropsychiatric disorders such as depression, schizophrenia, drug addiction, and Parkinson's disease.
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PMID:Role of serotonin(2C) receptors in the control of brain dopaminergic function. 1188 64

The article summarizes the 3-year (1998-2000) consulting and treatment experience of a psychotherapeutic unit in one Moscow general hospital. Psychiatrists realized emergent and planned consultations of the mentally-ill patients in all hospital departments, conducted, in addition to general treatment, psychopharmacotherapy and psychotherapy or directed them, on demand, to psychiatric hospitals. For the 3-year period, the psychiatrists have consulted 4685 somatic patients with comorbid mental diseases (5% of the total amount of the patients admitted to the hospital at that period), 1360 patients (29%) being affected with psychotic disorders. One hundred eighty two patients were diagnosed to have schizophrenia, 784--arteriosclerosis and old-age psychosis and dementia, 45--reactive psychosis, 16--epilepsy (disphoria and psychotic episodes), 67--mental retardation with inadequate behavior, 266--delirium of alcoholic and drug addiction genesis. In some cases, usage of psychotropics, in combination with psychotherapy, has resulted in recovery or considerable psychic state improvement in 9.1% of the patients, improvement in 52% ones, insignificant improvement in 36%. In 2.9% of the cases, the effect of treatment has not been achieved.
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PMID:[Psychiatric service in general hospital]. 1191 10

Considerable evidence suggests that a dysfunction of the dopamine and serotonin (5-hydroxytryptamine or 5-HT) neurotransmitter systems contributes to a diverse range of pathological conditions including schizophrenia, depression and drug abuse. Recent electrophysiological and behavioral studies suggest that 5-HT modulates dopaminergic neurons in the ventral tegmental area via activation of 5-HT(2A) receptors. It is currently unknown if 5-HT(2A) receptors mediate their actions on dopaminergic neurons in the ventral tegmental area via direct or indirect mechanisms. This study investigated whether 5-HT(2A) receptors were localized on dopamine cells within the A10 dopamine subnuclei of the rat, including the ventral tegmental area. We discovered that 5-HT(2A) receptor-like immunoreactivity colocalized with tyrosine hydroxylase, a marker for dopamine neurons, throughout the A10 dopamine cell population. Colocalization was most prominent in rostral and mid A10 regions, including the paranigral, parabrachial, and interfascicular subnuclei. Though more rare, non-dopaminergic neurons also expressed 5-HT(2A) receptor immunoreactivity in the ventral tegmental area. Additionally, although a dense population of 5-HT(2A) immunoreactive cells was observed in the rostral dorsal raphe nucleus, rarely were these cells immunoreactive for tyrosine hydroxylase. The linear raphe A10 dopamine subdivisions also displayed a low degree of 5-HT(2A) receptor and tyrosine hydroxylase colocalization. These findings provide an anatomical basis for the physiological modulation of dopamine neurons in the rostral ventral tegmental area either directly, by 5-HT(2A) receptors localized on dopamine cells, or indirectly, through a non-dopaminergic mechanism. Interestingly, 5-HT(2A) receptors were expressed on dopamine neurons in several A10 subnuclei that project to mesolimbic forebrain regions implicated in drug addiction, and recent evidence indicates that ventral tegmental area 5-HT(2A) receptor activation may modulate reward-related behavior in rodents. 5-HT(2A) receptors were also expressed on dopamine cells in A10 subnuclei that project to forebrain areas that have been implicated in schizophrenia, and atypical antipsychotic drugs have high affinities for 5-HT(2A) receptors. Thus, findings in this study could have important implications for understanding 5-HT and dopamine circuitry dysfunction in schizophrenia.
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PMID:Localization of 5-HT(2A) receptors on dopamine cells in subnuclei of the midbrain A10 cell group. 1195 20


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