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)

Several pieces of evidence support the view that GABA neurons inhibit the DA system both in extrapyramidal and limbic regions. This inhibition is exerted on cell bodies and terminals of DA neurons and is involved in the regulation of their activity. A recently synthesized GABAmimetic compound SL 76.002 has considerably helped in elucidating the role of GABA in this regulation as well as the therapeutic implication of changes of GABAergic transmission in human brain. Thus, impairment of dopaminergic transmission by SL 76.002 has been shown to be effective in iatrogenic extrapyramidal syndromes such as L-DOPA-induced involuntary movements in parkinsonian patients and neuroleptic-induced tardive dyskinesias: the first attributed to an exaggerated formation and liberation of DA, the second to supersensitivity of target cells of DA neurons. Furthermore, GABAergic medication has been confirmed to be useful in Huntington's chorea in which some symptoms originate from degeneration of striatal GABAergic neurons. Finally, GABAergic inhibition on cellular excitability has been proved to ameliorate epilepsy. However, SL 76.002, contrary to the expectation, was not effective in schizophrenia suggesting that GABA does not play a major role in the pathogenesis of this disorder.
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PMID:[Potential therapeutic activity of GABA-mimetic drugs in neuropsychiatry]. 4 43

In order to investigate possible disturbances of the blood-brain transport mechanisms of monoamine precursors in manic-depressive illness and schizophrenia, we have measured the brain arterio-venous difference of DOPA, or 5-HTP, or tyrosine and tryptophan in 36 patients, during the infusion of either L-DOPA or L-5-HTP. The infusion lasted for 30 min, and blood was sampled during and immediately after the infusion, simultaneously in the femoral artery, the jugular vein and a vein of the arm. During the infusion of L-DOPA, manic patients have a higher extraction of L-DOPA than depressive patients and controls. During the infusion of L-5-HTP, pdpressive patients have a higher brain extraction of 5-HTP than manic or schizophrenic patients. In depressive patients, a small uptake of tryptophan correlated with a large outflow of tyrosine was observed. The opposite was seen in manic patients, with an outflow of tryptophan correlated with an uptake of tyrosine. In schizophrenics, there was an outflow of tryptophan and random variations of tyrosine. These brain arterio-venous differences were not correlated with arterio-venous differences for peripheral tissues. Taken together, these results are compatible with a disturbance of the blood-brain transport of amino acids precursors of monoamines in manic-depressive illness and schizophrenia.
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PMID:Blood-brain movements of tryptophan and tyrosine in manic-depressive illness and schizophrenia. 29 Jul 57

1 The roles of catecholamine and 5-hydroxytryptamine (5-HT) release in mediating backward walking and circling were studied in rats. 2 These behaviours occurred in animals given 15 mg/kg intraperitoneally of (+)-amphetamine (which predominantly releases catecholamines) or either p-chloroamphetamine or fenfluramine (which predominantly release 5-HT). They also occurred when smaller doses of (+)-amphetamine (5 mg/kg) and either p-chloroamphetamine (2--5 mg/kg) or fenfluramine (5 mg/kg) were given together. 3 Characteristic dopamine-dependent behaviours (rearing, licking, gnawing) resulting from (+)-amphetamine injection were greatly reduced by p-chloroamphetamine or fenfluramine. 4 Characteristic 5-HT-dependent behaviours (wet dog shake, hind limb abduction) resulting from injection of either p-chloroamphetamine or fenfluramine were unaffected by (+)-amphetamine. 5 Fragmentary backward walking and circling resulting from levallorphan injection (50 mg/kg s.c.) were decreased by (+)-amphetamine at low dosage. 6 Results in general strengthen previous evidence that backward walking and circling are mediated by simultaneous dopamine and 5-HT release. 7 The possible relevance of the above findings to hallucinogenic activity, amphetamine psychosis, schizophrenia and abnormal movements due to L-DOPA treatment is discussed.
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PMID:Backward walking and circling: behavioural responses induced by drug treatments which cause simultaneous release of catecholamines and 5-hydroxytryptamine. 46 94

Methylphenidate hydrochloride dextroamphetamine sulfate, and levamfetamine succinate have potential as pharmacologic tools for the indirect evaluation of the role of neurotransmitters in schizophrenia. In actively ill schizophrenic patients, methylphenidate administered intravenously causes a brief but clear intensification of preexisting psychotic symptoms, such as hallucinations and delusions. In our study, methylphenidate, dextroamphetamine, and levamfetamine were administered in equimolar doses to schizophrenic patients. Methylphenidate was a more effective activator of symptoms than dextroamphetamine, which in turn was more effective than levamfetamine. Levodopa (L-dopa) given orally also reportedly produces a temporary worsening of schizophrenic symptoms. While these findings augment a body of information suggesting that dopamine and norepinephrine may play a role in the activation of schizophrenic symptoms, our findings with methylphenidate (reportedly weak in eliciting stereotyped behaviour in rat) and our review of the literature indicate complexities that remain to be resolved. There is some utility of the procedure for differential diagnosis and selective therapy, but this is still of occasional and limited potential.
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PMID:Methylphenidate, dextroamphetamine, and levamfetamine. Effects on schizophrenic symptoms. 76 22

L-Dopa (in a dose of 300-400 mg daily) was used concomitantly with conventional antipsychotic drugs in four patients with long-standing schizophrenia (of more than 10 years' duration). In two of these four patients marked symptomatic improvement was observed, while in the other two symptoms remained unchanged. Symptoms that were found most responsive included disturbance of contact with others and emotional poverty.
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PMID:Behavioral effects of L-dopa and thyrotropin-releasing hormone in schizophrenic patients: a preliminary report. 81 71

Growth hormone (hGH) responses to centrally acting dopamine agonists were used as indices of CNS dopaminergic function in order to test hypotheses implicating dopaminergic alteration in the etiopathology of schizophrenia. Apomorphine, a direct acting dopamine receptor agonist, and L-Dopa, an indirect agonist dependent upon presynaptic conversion to dopamine for its action, both elicited elevations in plasma hGH in most young male schizophrenic- and control-subjects. A highly significant difference was seen between the distribution of hGH responses to apomorphine for schizophrenics and that for controls. Unusually high hGH response to apomorphine was seen in schizophrenics who subsequently failed to respond to neuroleptic therapy; intermediate hGH response was seen in controls; and low hGH response was seen in subsequent neuroleptic responders; differences in hGH response were statistically significant for all intergroup comparisons. No such differences were seen between responses of individuals to L-Dopa and to apomorphine. The findings suggest that the variability of hGH response to apomorphine is a reflection of dopamine receptor sensitivity, and that this variability may be an index of non-endocrine related dopaminergic sensitivity. They are consistent with hypotheses relating schizophrenia to alteration in dopamine receptors, although the type of receptor and the direction of alteration may be complex.
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PMID:Dopamine receptor alteration in schizophrenia: neuroendocrine evidence. 82 70

The importance of amino acid transport across the blood-brain barrier as the limiting factor in the metabolism of monoamines has been emphasized by many recent publications. Particularly critical is the transport of tryptophan, since tryptophan hydroxylase is not saturated. This transport is regulated by complex mechanisms, both at the periphery (total and free plasmatic levels and levels of the other essential amino acids) and centraly (by feedback mechanism initiated at the pre- and post-synaptic levels). The hydroxylated derivatives of tryptophan and tyrosine, i.e. 5-HTP and L-DOPA, most probably share the same transport mechanism as these amino acids themselves. In manic-depressive patients, the uptake of L-5-HTP is increased during the depressive phase, while the uptake of L-DOPA, is increased during the manic phase. We suggest that an increase in the uptake of tryptophan may set off oscillations in all the monoaminergic systems, thus providing a biochemical model of manic-depressive psychosis. In terms of this model, melancholy would be due to a hyperserotoninergic syndrome together with a relative hypocatecholaminergic syndrome. Mania would be due to a homogeneous hypercatecholaminergic syndrome together with a relative hyposerotoninergic syndrome. Such a model is compatible with present knowledge of the physiology of monoamines, of the semeiology and biological disturbances of manic-depressive psychosis, and of the treatment of this disease. It reconciles the monoaminergic and ionic theories of the disease better than other existing hypotheses. A reduced transport of tryptophan with a secondary increase in the transport ot tyrosine provides a conceivable model for schizophrenia. Indeed, a serotoninergic hypoactivity coupled with a dopaminergic hyperactivity, with or without a noradrenergic deficiency, would account for the semeiology quite adequately. This model too would be compatible with present knowledge of monoamine physiology, of the biochemical disturbances underlying schizophrenia and of the mode of action of anti-psychotic drugs. This unitarian heuristic concept of the monoaminergic psychoses would be in better agreement with the classic clinical data concerning this disease (typology intermediate syndromes and crossed heredity).
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PMID:[Hypothetical concept: the physiopathological entity of monoaminergic psychoses]. 108 12

Oral administration of ET-495 was found to cause worsening of psychiatric status in 4 out of 7 schizophrenic patients, and to induce a paranoid state and a syndrome of auditory hallucinosis in 2 non-schizophrenics. These observations were compatible with the hypothesized role of dopamine in schizophrenia. However, these psychotogenic effects were far less dramatic than those noted in other studies with amphetamine, methylphenidate or L-Dopa. Possible explanations for this differing psychotogenic potency of receptor stimulators versus presynaptic agonists are presented. Intravenous ET-495 and apomorphine did not show psychotogenic effects.
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PMID:Clinical studies with dopamine-receptor stimulants. 120 62

Dopamine receptors in the brain play an important role in the treatment of schizophrenia and in the development of tardive dyskinesia. In Parkinson's disease the loss of dopamine innervation and the use of chronic administration of L-DOPA or therapy with dopamine agonists also affects the function of dopamine receptors in brain. Subacute administration of neuroleptic drugs to rodents for a few weeks followed by the withdrawal of the drug induces supersensitivity of dopamine receptors in the striatum. However, the long-term administration of neuroleptic drugs to rodents shows that typical neuroleptic drugs can induce functional supersensitivity of dopamine receptors despite continued administration of drug. In contrast, atypical neuroleptics such as sulpiride, do not appear to induce the same changes in the activity of dopamine receptors. The functional supersensitivity of dopamine receptors produced by repeated administration of neuroleptic is reflected in changes in cholinergic, gamma-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT) and peptide neuronal systems. Chronic treatment of parkinsonian patients with drugs may obscure the changes in the function of dopamine receptors caused by the disease process. However, chronic administration of L-DOPA to normal rats and to rats with a unilateral lesions of the nigrostriatal pathway induced with 6-hydroxydopamine does not produce a down-regulation of the number of dopamine receptors. Rather, these experiments indicate the development of a functional supersensitivity of dopamine receptors in the absence of any obvious change in the nature of dopamine receptor populations in brain. In conclusion, while pharmacological manipulation, using neuroleptic drugs, produces the expected development of receptor supersensitivity, studies involving chronic treatment with agonists suggests that dopamine receptors do not always respond as would be predicted. It appears that there are aspects of the regulation of dopamine receptors in brain following pharmacological manipulation which remain to be resolved.
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PMID:Chronic pharmacological manipulation of dopamine receptors in brain. 288 59

Because dopamine D2 receptors are known to be elevated in schizophrenic brain striata, this study examined whether a similar dopamine receptor elevation occurred in other diseases including neuroleptic-treated Alzheimer's and Huntington's diseases. The average D1 density in postmortem striata from Alzheimer's patients was 17.6 +/- 0.1 pmol/g, similar to an age-matched control density of 16.6 +/- 0.4 pmol/g. The average D1 density in schizophrenia patients was 19.0 +/- 0.6 pmol/g, similar to the age-matched control density of 17.9 +/- 0.6 pmol/g. In Parkinson's disease patients, however, the D1 receptor density was elevated, with values of 22.8 +/- 1.2 pmol/g (in patients not receiving L-DOPA) and 19.6 +/- 1.5 pmol/g (in patients receiving L-DOPA) compared to the age-matched control density of 16.0 +/- 0.4 pmol/g. The D2 receptors in Alzheimer's striata averaged 13.4 +/- 0.6 pmol/g (in patients who had not received neuroleptics), almost identical to the control density of 12.7 +/- 0.3 pmol/g. The average D2 density in neuroleptic-treated Alzheimer's striata was 16.7 +/- 0.7 pmol/g, an elevation of 31%, the individual values of which had a normal distribution. In Parkinson's disease patients, the D2 densities were elevated in tissues from patients not receiving L-DOPA (19.9 +/- 1.5 pmol/g in putamen and 14.8 +/- 1.2 pmol/g in striatum) compared to the age-matched control values of 13.0 +/- 0.4 pmol/g and 12.6 +/- 0.3 pmol/g, respectively. In Huntington's disease patients, the D2 density averaged 7.5 +/- 0.4 pmol/g in patients who had not received neuroleptics, but was 10.3 +/- 0.6 pmol/g in those who had. Although all of the D1 and D2 densities in each of the above diseases and subgroups revealed a normal distribution pattern, the D2 densities in schizophrenia displayed a bimodal distribution pattern, with 48 striata having a mode at 14 pmol/g, and the other 44 striata having a mode at 26 pmol/g. Thus, compared to the neuroleptic-induced and unimodal elevations in D2 of 31% in Alzheimer's disease and 37% in Huntington's disease, the schizophrenic striata with a mode of 26 pmol/g (105% above control) appear to contain more D2 receptors than can be accounted for by the neuroleptic administration alone.
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PMID:Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Huntington's diseases. 290 95


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