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)

Two catecholamine-containing pathways, the locus ceruleus system and the dopamine neurons arising from the ventral mid-brain, may be involved in reward. Dopamine neurons function as a system for energizing the organism's responses and directing them toward significant environmental stimuli, but the functions of the locus ceruleus system remain obscure. It appears increasingly likely that neuroleptic drugs exert their anti-psychotic effects in acute schizophrenia by blocking dopamine receptors, although the time course of the effect suggests that the mechanism is more complex than a simple reversal of a neurohumoral imbalance. Evidence from postmortem studies suggests that, at least in the chronic state, dopamine turnover is not increased, but that there may be an increase in postsynaptic receptor density in some cases, including some patients who apparently had not received medication in the year before death. The evidence is consistent with Olds and Travis' conjecture that "counteraction of positive feedback processes subserving positive reinforcement mechanisms may be a key to control of certain psychotic episodes".
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PMID:Catecholamine reward pathways and schizophrenia: the mechanism of the antipsychotic effect and the site of the primary disturbance. 3 90

Dopamine and its metabolites homovanillic acid and dihydroxyphenylacetic acid, noradrenaline, serotonin and its metabolite 5-hydroxyindoleacetic acid, and tryptophan and its metabolite kynurenine have been assayed in 9 schizophrenic and 10 control brains, together with the monoamine-related enzymes tyrosine hydroxylase monoamine oxidase, dopamine-beta-hydroxylase, and catechol-o-methyl-transferase. In schizophrenic brains dopamine, noradrenaline and serotonin were significantly increased in some areas of corpus striatum, but there were no significant changes in enzyme activity or monoamine metabolite concentrations in any of the brain areas examined. The findings are not consistent with theories that serotonin or noradrenaline stores are grossly depleted or noradrenaline neurones have degenerated, or that monoamine oxidase activity is abnormal, in schizophrenia, and provide no direct support for the hypothesis that dopamine neurones are overactive.
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PMID:Monoamine mechanisms in chronic schizophrenia: post-mortem neurochemical findings. 4 9

Dopamine, glutamic acid decarboxylase (G.A.D.) and choline acetyltransferase (C.A.T.) were measured in four regions of post-mortem brains. 41 patients with the hospital diagnosis of schizophrenia (psychotic group) were compared with a control grout normal in the putamen. G.A.D. activity was significantly reduced in the psychotic group, by about 50% in the nucleus accumbens, amygdala and hippocampus, and by about 30% in the putamen. C.A.T. activity was significantly lower in nucleus accumbens from the psychotic group, but normal in other brain regions. From an assessment of case notes, "schizophrenia" was distinguished from "schizophrenia-like psychosis". The biochemical findings for these subgroups were essentially similar, although C.A.T. activity in nucleus accumbens and hippocampus from the schizophrenic group was significantly lower than in controls. It is of brain are associated with schizophrenia and schizophrenia-like psychoses, although whether such neurochemical abnormalities are related to the illness or are a consequence of prolonged treatment with neuroleptic drugs remains unclear.
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PMID:Increased brain dopamine and reduced glutamic acid decarboxylase and choline acetyl transferase activity in schizophrenia and related psychoses. 7 64

Dopaminergic mechanisms have been investigated in post-mortem brain specimens from nineteen patients with schizophrenia and nineteen controls. Dopamine turnover was not increased in schizophrenic patients but, as assessed by the spiroperidol-binding technique, there was a significant increase in postsynaptic receptor sensitivity. The change in the dopamine receptor occurred in nucleus accumbens, putamen, and caudate nucleus. Increased dopamine-receptor sensitivity was present in five patients who had been free of neuroleptic medication for at least 1 year before death, and therefore may be related to the disease process.
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PMID:Increased dopamine-receptor sensitivity in schizophrenia. 7 25

Dopamine and its specific receptors are widely distributed in man. Body regions where dopaminergic activity is of special pharmacologic interest include the basal ganglions, hypothalamus, chemoreceptor trigger zone, other less well defined areas in the central nervous system, and the renal and cardiovascular systems. The search for dopaminergic agents to modify these systems in disease states has depended heavily on in vitro and in vivo bioassays. These assays involving receptor binding, enzyme activation, smooth muscle and neuronal excitation, and modification of animal behavior have provided physicians with important therapeutic tools. Indeed, the introduction of levodopa for the treatment of Parkinson's disease and of the phenothiazines and related drugs for schizophrenia and psychosis has been a hallmark of neuropharmacologic research. However, the maximal benefits that these drugs may afford have not yet been realized due to an inadequate understanding of disease processes and a relative lack of specificity of drug action.
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PMID:Clinical aspects of dopamine agonists and antagonists. 35 76

Dopamine, noradrenaline, glutamate decarboxylase (GAD) and choline acetyl-transferase (CAT) were measured in post-mortem brain samples from more than 50 patients dying with a hospital diagnosis of schizophrenia and an equal number of controls. GAD was measured in 14 different brain regions, and was significantly lower in both control and schizophrenia patients who died following a protracted illness. If GAD values from patients who died suddenly were compared, no significant differences were observed between the control and schizophrenia groups. There was also no differences between the CAT values measured in 13 different brain regions in the two groups. Noradrenaline values were not different in the two groups in most limbic areas or in the caudate nucleus, but were elevated in the schizophrenic group in nucleus accumbens and in anterior perforated substance. These differences were not, however, statistically significant. On the other hand dopamine concentrations in nucleus accumbens and in anterior perforated substance were significantly elevated (by 34 and 95 per cent, respectively) in the schizophrenia group as compared with controls, although dopamine values were not different in caudate nucleus, putamen, septal nuclei or amygdala. The finding of elevated concentrations of dopamine in certain areas of the limbic forebrain in schizophrenia is discussed in relation to current hypotheses of the involvement of dopamine in this illness, and the difficulties of determining whether the observed changes are related to chronic treatment with antischizophrenic drugs.
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PMID:Increased dopamine concentration in limbic areas of brain from patients dying with schizophrenia. 45 44

Dopamine-containing neurons of the mammalian midbrain are required for normal behavior and movements. In vivo they fire action potentials in bursts, but in vitro they discharge regularly spaced action potentials. Burst firing in vitro has now been shown to be robustly induced by the glutamate agonist N-methyl-D-aspartate (NMDA) although not by the non-NMDA agonists kainate or quisqualate. The hyperpolarization between bursts of action potentials results from electrogenic sodium ion extrusion by a ouabain-sensitive pump. This mechanism of burst generation in mammalian neurons may be important in the pathophysiology of schizophrenia and Parkinson's disease.
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PMID:Burst firing in dopamine neurons induced by N-methyl-D-aspartate: role of electrogenic sodium pump. 132 9

Dopamine (DA) D2, D3, and D4 receptors are targets for antipsychotic drugs. The recent cloning, deoxyribonucleic acid sequencing, and brain location of these receptors provide new insight on the DA hypothesis of schizophrenia, particularly for the basis of antipsychotic therapy of schizophrenia. In schizophrenia brain tissue, D2 receptors are elevated and have lost the link to D1 receptors. Brain positron-emission tomography studies of patients may also reveal elevated D2, depending on the method used. Hallucinations and positive symptoms are blocked when about 70% of the D2 receptors are occupied by neuroleptic drugs. An analysis of the literature indicates that therapeutic concentrations of antipsychotic drugs (in the patient's cerebrospinal fluid or plasma water) act primarily at D2 receptors, with the exception of clozapine, which acts at D4 receptors.
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PMID:Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. 136 57

Dopamine autoreceptor agonists reduce the firing rate, synthesis, and release of dopamine in dopaminergic neurons by means of a negative feedback mechanism via stimulation of autoreceptors. Moreover, dopamine autoreceptor agonists are able to stimulate supersensitive but not normosensitive postsynaptic receptors. For dopamine autoreceptor agonists, therapeutic effects by readjustment of excessive or deficient dopaminergic function have been postulated for positive and negative schizophrenic symptomatology as well as for subtypes of depressive disorders. Investigations on the therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia or depression have yielded inconsistent results. In order to reduce the excess of central dopaminergic activity postulated by the dopamine hypothesis of schizophrenia, dopamine autoreceptor agonists have been tested in open clinical trials in positive schizophrenic symptomatology. However, administration of selective dopamine autoreceptor agonists like talipexole or roxindole did not result in a significant improvement of positive psychotic symptoms. In negative schizophrenic symptomatology, a dopamine deficit rather than an excess has been hypothesized. Current evidence from pilot studies suggests that dopamine autoreceptor agonists like roxindole may produce a minor to moderate improvement of symptoms like affective flattening, depressed mood, alogia, and avolition, possibly by stimulation of supersensitive postsynaptic dopamine receptors. For certain subgroups of depression, a reduction of functional dopamine activity has been postulated. In an open pilot study in patients with a major depression, roxindole demonstrated antidepressive properties comparable to those of standard antidepressants, justifying further double-blind controlled trials against reference drugs.
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PMID:Dopamine autoreceptor agonists in the treatment of schizophrenia and major depression. 136 97

Two major pharmacological classes of dopamine receptors exist in the central nervous system. These receptors have been designated as D1 or D2 based upon their differing pharmacology and influence on the cyclic AMP second messenger system. Different genes for the D1 and D2 dopamine receptors have been isolated and are found to be expressed in high abundance. Within the neostriatum, however the cellular distribution of the dopamine receptors is equivocal. Dopamine receptors are the targets for drugs used to treat neurological dysfunctions such as Parkinson's disease and schizophrenia, and thus knowledge of their specific cellular location is important for devising future therapeutic manipulations. Using retrograde labeling methods combined with immunofluorescence of various receptor amino acid sequences, this study has examined the postsynaptic distribution of striatal D2 dopamine receptors. We have found that the D2 dopamine receptor can be visualized on a minimum of 60% of the neurons projecting from the neostriatum to the substantia nigra. However, some 65% of all D2 receptor positive cells are represented by other intrinsic neurons of this basal ganglia nucleus.
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PMID:D2 dopamine receptor localization on striatonigral neurons. 143 5


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