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)

Enzymes concerned with neurotransmitter metabolism were measured postmortem in 50 regions from the brains of 11 chronic schizophrenics, 2 patients with senile dementia, 1 depressive, and 18 controls. Enzymes studied were tyrosine hydroxylase, dopa decarboxylase, glutamic decarboxylase, choline acetyltransferase (CAT), and acetylcholinesterase. The schizophrenic group had high CAT activities in the hippocampus, caudate, putamen, and nucleus accumbens; the other patients from the same hospital did not. A compensatory response to long- or short-term drug usage is considered, but correlations are hard to establish in the group studied. An alternative hypothesis proposes that the high levels are a compensatory response to defective cholinergic receptors in the affected areas. On this hypothesis, and by analogy with chorea, dopaminergic antagonists would act in schizophrenia by helping to reestablish cholinergic-dopaminergic balance.
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PMID:Possible changes in striatal and limbic cholinergic systems in schizophrenia. 4 82

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

Chemical and morphological changes in cholinergic marker enzymes, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT) of striatum, hippocampus, and cerebral cortex were studied following haloperidol treatment of rats. After short-term (7-21 days) haloperidol treatment, the levels of both enzymes (AChE and ChAT) were increased in striatum and hippocampus (greater than 25%), but not in cortex. After long-term (+40 days) haloperidol treatment, the level of AChE activity returned to control levels in all brain areas, whereas the levels of striatal and hippocampal ChAT decreased by 26% and 29%, respectively. No change in levels of both enzymes was detected after acute treatment (single dose) of haloperidol or chronic treatment with either clozapine or imipramine. Morphological analysis of cholinergic neurons and their processes using monoclonal antibody to ChAT showed two types of changes following 40 days of haloperidol treatment. First, parallel to the observed decrease in the levels of ChAT activity there was a visual decrease in the immunoreactivity in neurons as well as in their processes in striatum and hippocampus. Second, there was an apparent reduction in the size and number of stained neurons and their processes. No changes were seen in immunoreactivity after an acute treatment with haloperidol. These results indicate that the chronic haloperidol treatment in rats causes changes in central cholinergic systems that may be relevant to the pathophysiology of schizophrenia and its treatment.
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PMID:Haloperidol alters rat CNS cholinergic system: enzymatic and morphological analyses. 329 56

Five vervet monkeys were administered increasing doses (4--12 mg/kg/day) of d-amphetamine over a period of 35 days. Three phases od behavioural change were discerned: phase 1 during which animals exhibited repetitive stereotyped action sequences with rapid head movements, occasional abnormal grooming, picking at the cage, hand-staring and snatching; phase 2 in which behaviour became progressively more restricted and animals became markedly unresponsive to auditory, visual and tactile stimuli; phase 3 was characterised by the abrupt development of gross over-responsiveness to environmental stimuli, ataxia and tremor. At post-mortem, by comparison with controls, amphetamine-treated monkeys showed marked depletions of the monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in corpus striatum and cerebral cortex and reductions in the activities of tyrosine hydroxylase and dopa decarboxylase in striatum. Turnover of these monoamines, assessed by high-performance liquid chromatography determinations of their respective metabolites, was also reduced. These findings are interpreted as evidence of monoamine neurone destruction, most severely in the case of DA neurones. Though there was a non-significant reduction in 3H-spiperone binding (reaching almost 50% in nucleus accumbens), numbers of receptors for the monoamines nA and 5-HT were not significantly changed, and the activities of the enzymes choline acetyltransferase and glutamine decarboxylase were similar in experimental and control animals. The contrast of these findings with those seen in post-mortem brains in schizophrenia is discussed.
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PMID:Behavioural and biochemical effects of chronic amphetamine treatment in the vervet monkey. 613 May 56

Ornithine aminotransferase (Orn-T) activities in Huntington's disease (HD) brains were found to be reduced, when compared to age-matched control brains, by 34-49% in the frontal cortex, parietal cortex, caudate nucleus and putamen. Such changes were not observed in senile dementia of Alzheimer type or schizophrenia. Alterations in choline acetyltransferase activities were consistent with previous findings for these disorders. If Orn-T is involved in the synthesis of neurotransmitter glutamate, the reported losses of Orn-T activity may reflect deterioration of the corticostriatal glutamatergic neurons in HD.
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PMID:Ornithine aminotransferase in Huntington's disease. 645 16

It is well known that the regulation of choline acetyltransferase (ChAT) activity under physiological and pathological conditions is important for the development and neuronal activities of cholinergic systems involved in many fundamental brain functions. This review focuses on recent progress in understanding the regulation of ChAT at the levels of both the protein and the mRNA. A deficiency in ChAT activity has been reported for neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, and schizophrenia. Although a major feature of ChAT regulation is likely to involve the spatial and temporal control of transcription, regulation of expression can also be at the level of RNA processing, transport/translocation, turnover, or translation. In addition, there is increasing evidence that ChAT might be regulated at the posttranslational level by compartmentation and/or covalent modification, i.e., phosphorylation, as well as noncovalent modification (protein-protein interaction, etc.). Synaptic activity and the state of neuronal transmission may also involve the regulation of ChAT at different levels via both positive and negative feedback loops, as was demonstrated in the characterization of two ChAT mutant Drosophila strains. Clearly, identification of cholinergic-specific elements and the characterization of the trans-acting factors that bind to them represent an important area of future research. Equally important is research on the mechanisms governing ChAT as an enzymatic entity. The future should be an exciting time during which we look forward to the elucidation of the cholinergic signal and its regulation as well as the determination of the three-dimensional structure of the enzyme.
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PMID:Choline acetyltransferase: celebrating its fiftieth year. 815 17

The objective was to replicate a reported decrease of choline acetyltransferase (ChAT) in the mesopontine tegmentum of deceased schizophrenics and to see if such a decrease is related to their cognitive status as measured during life. Rigorous antemortem psychiatric evaluations were performed on our large population of schizophrenic patients. Mesopontine tissue was collected promptly following death from eight of these patients, from an additional five schizophrenics without systematic premortem psychiatric evaluation, and from control subjects. ChAT content of this brain tissue was determined using Western immunoblot analysis. There were 13 schizophrenic patients and 8 control subjects. The mean age of subjects in the two groups was similar (64 +/- 9 yr vs 63 +/- 10 yr). Even in the face of reduced post mortem intervals in the patients with schizophrenia, mesopontine tegmental ChAT concentrations were depressed by 70% in schizophrenic patients (1.28 +/- 1.74 vs 4.39 +/- 3.20 ng ChAT/micrograms tissue protein, P < 0.01), and correlated with orientation and reasoning (rs = 0.90 and 0.98, respectively) in those subjects assessed antemortem. Mesopontine ChAT concentrations are depressed in schizophrenia and correlate significantly with measures of cognitive performance in patients with this disorder.
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PMID:Decreased mesopontine choline acetyltransferase levels in schizophrenia. Correlations with cognitive functions. 897 95

The past decade has seen renewed interest in the neuropathology of schizophrenia. The advent of new postmortem techniques and functional imaging, along with a greater understanding of the neuropsychology of schizophrenia, have provided many new clues to the nature of the underlying brain dysfunction in this disorder. There has also been a greater understanding of the presence of severe cognitive dysfunction among many elderly persons with schizophrenia. In this article, a series of investigations are described that seek to answer basic questions about the neuropathology of schizophrenia, in particular as it pertains to cognitive impairment. The first study describes neuropathological findings in 100 consecutively autopsied persons with schizophrenia, the majority of whom had had detailed antemortem assessments. Results from this first study prompted the conclusion that schizophrenia is not characterized by classical, histologically identifiable neuropathology. Moreover, most cases of dementia in schizophrenia are probably not the result of neuropathologically identifiable dementing illnesses. The next four studies examined chemical markers that are altered in Alzheimer's disease and some other dementing conditions and have also been suggested to be abnormal in schizophrenia: choline acetyltransferase, catecholamines and indolamines, neuropeptides, and synaptic proteins. Schizophrenia cases as a group did not show a cholinergic deficit; nor did they differ from elderly comparison cases with respect to cortical catecholamines and indolamines. Among the schizophrenia cases, however, cognitive impairment was negatively correlated with choline acetyltransferase activity. Those with cognitive impairment showed evidence of cortical noradrenergic and serotonergic deficits. Neuropeptide deficits were also present in schizophrenia, but their pattern differed from that seen in Alzheimer's disease. Increased synaptic protein activity was found in the cingulate cortex of persons with schizophrenia, and this activity was correlated with schizophrenia symptoms. From this second series of studies, it was concluded that some biological measures in schizophrenia may be related to cognitive impairment (e.g., cortical amines), whereas others may be related to diagnosis (e.g., neuropeptide deficits). In addition, synaptic organization may correlate with schizophrenia symptoms.
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PMID:Postmortem studies in schizophrenia. 971 27

The pars compacta and pars dissipata of the pedunculopontine nucleus contain cholinergic cell group Ch5, and the laterodorsal tegmental nucleus contains cholinergic cell group Ch6. The pedunculopontine nucleus has been implicated in a variety of functions, including mediation of rapid eye movement sleep and in extrapyramidal motor function, although the role of cholinergic and non-cholinergic neurons is unclear. Quantitative neuroanatomical techniques were used to map the distribution of cholinergic neurons in the mesopontine nuclei of the adult human brain. In addition, the number and distribution of comparably sized non-cholinergic neurons at selected anatomical levels were compared. An antibody raised against human choline acetyltransferase was used to stain immunohistochemically the mesopontine neurons in six brains, ranging in age from 28 to 60 years. The rostrocaudal length of the Cb5/Ch6 cell complex was approximately 10 mm. The estimated total number of cells was similar for all brains, and varied by less than 7%. The estimated average number of cholinergic cells in the combined pedunculopontine and laterodorsal tegmental nuclei was approximately 20,000, with 30% of the cells in the pedunculopontine nucleus pars compacta, 57% in the pedunculopontine nucleus pars dissipata and 13% in the laterodorsal tegmental nucleus. There was no correlation between cell number and age. Within areas of mesopontine tegmentum occupied by the Ch5 cholinergic neurons, there were often more noncholinergic neurons than comparably sized cholinergic neurons. The present study provides detailed maps of the distribution and number of mesopontine cholinergic neurons in the normal human brain. Many non-cholinergic neurons are intermixed with the cholinergic pedunculopontine neurons. One region of the pedunculopontine nucleus pars dissipata containing few cholinergic neurons, located adjacent to the ventral border of the pedunculopontine nucleus pars compacta, may correspond to the midbrain-extrapyramidal area as defined previously in rodent and in non-human primate. These data will be useful for quantitative neuropathological studies concerning the role of both cholinergic and non-cholinergic mesopontine neurons in diseases proposed to affect these neurons, including Parkinson's disease, schizophrenia and progressive supranuclear palsy.
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PMID:Quantification of cholinergic and select non-cholinergic mesopontine neuronal populations in the human brain. 1019 11

Neurochemical and functional abnormalities of the striatum have been reported in schizophrenic brains, but the cellular substrates of these changes are not known. We hypothesized that schizophrenia may involve an abnormality in one of the key modulators of striatal output, the cholinergic interneuron. We measured the densities of cholinergic neurons in the striatum in schizophrenic and control brains in a blind analysis, using as a marker of this cell population immunoreactivity for choline acetyltransferase, the synthetic enzyme of acetylcholine. As an independent marker, we used immunoreactivity for calretinin, a protein which is co-localized with choline acetyltransferase in virtually all of the cholinergic interneurons of the striatum. A significant decrease in choline acetyltransferase-positive and calretinin-positive cell densities was found in the schizophrenic cases compared with controls in the striatum as a whole [for the choline acetyltransferase-positive cells: controls: 3.21 +/- 0.48 cells/mm2 (mean +/- S.D.), schizophrenics: 2.43 +/- 0.68 cells(mm2; P < 0.02]. The decrease was patchy in nature and most prominent in the ventral striatum (for the choline acetyltransferase-positive cells: controls: 3.47 +/- 0.59 cells/mm2, schizophrenics: 2.52 +/- 0.64 cells/ mm2; P < 0.005) which included the ventral caudate nucleus and nucleus accumbens region. Three of the schizophrenic cases with the lowest densities of cholinergic neurons had not been treated with neuroleptics for periods from more than a month to more than 20 years. A decrease in the number or function of the cholinergic interneurons of the striatum may disrupt activity in the ventral striatal-pallidal-thalamic-prefrontal cortex pathway and thereby contribute to abnormalities in function of the prefrontal cortex in schizophrenia.
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PMID:Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia. 1061 93


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