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)

Interest in the role of monoaminergic mechanisms in schizophrenia has stimulated the development of specific radioligands that allow PET analysis of quantitative aspects of monoamine receptor subtypes in the living human brain. Clinical studies with such ligands have not consistently demonstrated specific alterations of the total populations of D1 and D2 dopamine receptors in the caudate putamen complex of drug-naive schizophrenic patients. However, recent studies using [11C]SCH 23390, a specific D1 dopamine receptor ligand, disclosed a highly significant reduction of ligand binding in pixel elements of the basal ganglia that normally contain high activity. This finding may be related to reduced D1 dopamine regulated transmission in subsets of neuronal pathways within the basal ganglia. D3, D4, and D5 receptor subtypes constitute minor fractions of the total number of dopamine receptors in the human brain. However, efforts to find selective ligands for D3 and D4 subtypes also show promise. Radioligands for monoamine receptors have also been used to follow drug effects on receptor subtypes in schizophrenic patients treated with different types of antipsychotic drugs. Such studies have allowed the analysis of relationships between occupancy of dopamine receptor subtypes and some clinical manifestations of drug treatment. Such studies with the selective D2 antagonist raclopride indicated quantitative relationships between the degree of D2 dopamine receptor occupancy in the basal ganglia and the extrapyramidal manifestations, as well as the antipsychotic action. Some of the currently available antipsychotic drugs also induced significant occupancy of D1 dopamine receptors. However, the selective D1 antagonist SCH 39166 in doses inducing a more than 70% occupancy of D1 dopamine receptors in the caudate putamen failed to induce an antipsychotic action. This indicates that, in contrast to D2 blockade, selective antagonism of D1-regulated pathways does not mediate antipsychotic action in schizophrenia. Some but not all antipsychotic drugs also induced high occupancy of neocortical 5HT2A receptors. Because selective 5HT2A antagonism does not appear to be an efficient treatment for schizophrenia, it seems most likely that 5HT2A receptors and, perhaps, D1 receptors act in concert to modify aspects of the mandatory D2 blockade to induce antipsychotic actions. Computer graphic methods for image analysis add new dimensions to brain imaging research, allowing three-dimensional visualization of receptor populations computed from molecular PET data. This will make possible further exploration of the detailed molecular compartmentalization of the human brain using radioligand binding.
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PMID:Utilization of radioligands in schizophrenia research. 758 17

The present study was aimed at clarifying to what extent the hypermotility induced by the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 depends on dopamine (DA) D-1 compared to D-2 receptor tone. The D-1 receptor antagonist SCH 23390 was found to reduce locomotion to a greater extent in MK-801-treated than in vehicle-treated mice, whereas the reverse appeared to be the case for the DA D-2 receptor antagonist raclopride. In other words, MK-801-induced hyperactivity was more readily antagonized by SCH 23390 than by raclopride and, thus, DA D-1 receptors seem to be more important than D-2 receptors for MK-801-induced hyperactivity. These results are in line with our previous observation that MK-801 generally interacts synergistically with a DA D-1 but not with a D-2 receptor agonist in monoamine-depleted mice. In view of the possible role of deficient glutamatergic neurotransmission in schizophrenia, our findings underline the importance of investigating the efficacy of selective DA D-1 antagonists in this disorder.
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PMID:On the roles of dopamine D-1 vs. D-2 receptors for the hyperactivity response elicited by MK-801. 786 66

According to the view that N-methyl-D-aspartate (NMDA) agonists could be seen as putative therapeutic agents in schizophrenia, the present study was aimed at investigating whether the NMDA positive modulator D-cycloserine (DCS) could show neuroleptic activity. When given alone, DCS (1.5, 3, 6, 12 mg/kg) failed to affect the stereotyped behavior induced by 0.5 mg/kg SC apomorphine, a test routinely used to detect neuroleptic activity. Nevertheless, the administration of different doses of DCS (1.5, 3, 6 mg/kg) in combination with the D1 dopamine receptor blocker SCH 23390 or the D2 antagonist YM 09151-2, both given in doses which by themselves were ineffective in blocking apomorphine elicited behavior, induced a dose- dependent neuroleptic effect. Furthermore the positive NMDA modulator allowed (-)-sulpiride, which given alone never antagonized the apomorphine-induced stereotypy, to exhibit a full neuroleptic activity. The lower dose of DCS effective in potentiating antipsychotic effect of dopaminergic blockers also counteracted the behavioral response (hypermotility) induced by the NMDA negative modulator MK-801 (0.25 mg/kg), thus indicating the specificity of DCS effect. The results strengthen the view that drugs which increase NMDA receptor function could be a useful supplement in the therapy of psychotic disorders.
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PMID:The NMDA positive modulator D-cycloserine potentiates the neuroleptic activity of D1 and D2 dopamine receptor blockers in the rat. 787 Aug 78

Because glutamate is an important modulator of subcortical dopamine (DA) function, and abnormal glutamate/DA interactions may be involved in the pathophysiology of schizophrenia, we examined the effect of chronically administered antipsychotic drugs (APDs) on the levels of specific glutamate receptor subunits in the terminal fields of nigrostriatal and mesocorticolimbic DA systems. By immunoblotting procedures using antibodies specific for the NMDAR1, GluR1, and GluR2 subunits, we found that haloperidol (predominantly a D2-like antagonist) increased NMDAR1 subunit immunoreactivity (and mRNA levels) in the striatum, while the D1-like antagonist SCH 23390 had the opposite effect. No effect was seen on GluR1 or GluR2 levels. The result that D1-like and D2-like receptor antagonism can reciprocally regulate NMDAR1 expression is consistent with our observation that complete unilateral destruction of the nigrostriatal DA pathway with 6-hydroxy-dopamine had no effect on striatal NMDAR1 subunit levels. Further examination of these striatal effects revealed that chronic treatment with the D2-like receptor antagonist raclopride significantly increased NMDAR1 levels in the striatum, while the 5-HT2a/2c antagonist mianserin tended to produce an increase that did not achieve statistical significance. These findings indicate that the dopaminergic antagonist properties of haloperidol are likely most responsible for its regulation of this subunit. In contrast, the atypical APD clozapine had no effect on striatal NMDAR1 levels, consistent with the relatively weaker influence of this drug on nigrostriatal DA function. The second major finding of the present study was the ability of haloperidol and clozapine to increase GluR1 levels in the medial prefrontal cortex (PFC), whereas chronic SCH 23390 treatment decreased GluR1 levels.
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PMID:Regulation of cortical and subcortical glutamate receptor subunit expression by antipsychotic drugs. 789 Nov 80

A number of previously published homogenate receptor binding studies have postulated that dopaminergic dysfunction in schizophrenia may be related to abnormalities in dopamine receptors. In this study, postmortem striatal specimens from patients with schizophrenia, normal controls, and psychiatric controls that had received neuroleptics were studied with quantitative autoradiography for dopamine receptors. Autoradiography with single concentrations of [3H]-SCH 23390 for D1 receptors, [3H]-raclopride for D2 receptors, and [3H]-CFT for dopamine uptake sites failed to define significant differences between the study groups. [3H]-CFT bound in a patchy distribution in the striatum that is believed to correspond to striosomal and matrix striatal compartments. There were no differences between groups when [3H]-CFT binding density was examined in the striosomal and matrix compartments. There were also no differences between groups in the percentage of striatal area occupied by striosomal or matrix compartments as defined by [3H]-CFT binding. We conclude that abnormalities of these dopamine receptor subtypes are probably not primary features of the schizophrenic syndrome in the brain collection examined. Previous reports of elevated D2 receptor binding in schizophrenia may have been related to drug treatment effects. Alternatively, the relatively high affinity of ligands used in previous studies for D4 receptors may explain the discrepancy in our findings. Unchanged [3H]-CFT binding in the schizophrenic group also suggests that the density of mesostriatal neuronal terminals is not altered in schizophrenia.
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PMID:Quantitative autoradiography of dopamine-D1 receptors, D2 receptors, and dopamine uptake sites in postmortem striatal specimens from schizophrenic patients. 789 46

We have studied the interactions between dopamine and glutamate-mediated transmission in the entorhinal cortex using intracellular recording in a slice preparation from the rat brain. High concentrations (0.1-1 mM) of dopamine had weak, direct effects on the membrane potential with predominantly hyperpolarizing responses in layer II neurons and depolarizing responses in layer V. Studies with the dopamine antagonists sulpiride (D2 antagonist, 10-50 microM) and SCH-23390 (D1 antagonist, 50 microM) indicated that the hyperpolarization by dopamine could be mediated by D2 receptors, although the pharmacology was not clear-cut. The depolarizing response was not affected by either D1 or D2 antagonists. Synaptic responses of layer II and layer V cells were complex, consisting of both inhibitory and excitatory potentials. In untreated slices, dopamine reduced all components of the synaptic responses. However, when components of the responses were pharmacologically isolated, only the excitatory, glutamate-mediated potentials were consistently affected and the GABAergic inhibitory potentials were more resistant to reduction by dopamine. Excitatory potentials mediated by both N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-isoxazolepropionic acid receptors were reduced by dopamine, but the former were more strongly affected. Studies with antagonists suggested that the D1 receptor is more likely to be involved in the decrement of glutamate transmission. Thus, dopamine appears to modulate glutamate-mediated synaptic transmission in the entorhinal cortex, and it is conceivable that a disturbance in this interaction could be involved in the aetiology of schizophrenia.
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PMID:Interactions of dopamine with glutamate- and GABA-mediated synaptic transmission in the rat entorhinal cortex in vitro. 790 91

In the present study we have investigated, using radioligand binding techniques and the dopamine receptor antagonist [3H]SCH 23390 as a ligand, the existence of specific dopamine D1-like receptors in human peripheral blood lymphocytes. [3H]SCH 23390 binding to human peripheral blood lymphocytes was time-, temperature-, concentration-dependent and of high affinity with a dissociation constant value (Kd) of 0.58 +/- 0.05 nM and a maximum binding density (Bmax) of 11.02 +/- 0.3 fmol/5 x 10(6) cells. The binding was also reversible. Pharmacological analysis displacement curves of [3H]SCH 23390 binding with dopamine competing with the radioligand in the submicromolar range suggests that peripheral blood lymphocytes express dopamine D5 receptors rather than dopamine D1 receptors. These results, which are consistent with studies performed with molecular biology techniques, suggest that dopamine may modulate peripheral blood lymphocyte activity. Radioligand binding techniques, applied to lymphocyte receptor studies for their feasibility and flexibility may be used to investigate the possible relationship between the immune and dopaminergic systems. Moreover, they could be employed as a tool in Parkinson's disease, migraine, schizophrenia and hypertension research.
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PMID:Dopamine D5 receptors in human peripheral blood lymphocytes: a radioligand binding study. 805 Dec 91

Vulnerability to relapse is a central issue in the biology of schizophrenia. The common neural mechanisms underlying such vulnerability can be studied using the experimental model of behavioral sensitization induced by repeated administration of low doses of methamphetamine (MAP) to rodents. This review summarizes a series of behavioral and neurochemical studies on MAP-induced behavioral sensitization from the viewpoint that the mechanisms involved in initiation (or development) of psychotic symptoms and their expression differ. The initiation of behavioral sensitization to MAP in rats requires stimulation of dopaminergic neurons, and can be blocked by SCH 23390 (a dopamine D1-receptor antagonist) and BMY 14802 (a sigma-receptor antagonist). The expression of behavioral sensitization induced by subchronic MAP pretreatment takes several forms. First, dopamine release from the cerebral dopaminergic neuron terminal containing areas in response to either to rechallenge with MAP or cocaine, or evoked by intrastriatal ouabain infusion is enhanced. Second, the behavioral responses to dopamine D2- and sigma-receptor agonists are augmented. A third form involves changes indicative of transsynaptic neural circuits, such as increased numbers of D1 receptors in the substantia nigra pars reticulata, enhanced electrophysiological responses to D1 receptor activation, the putative role of excitatory amino acid receptors and interchangeability of MAP and stress. Although MAP-induced behavioral sensitization in rodents serves as a useful animal model, the elucidation of the mechanisms involved in the vulnerability of patients with schizophrenia to relapse of psychotic episodes requires further study.
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PMID:Methamphetamine-induced behavioral sensitization and its implications for relapse of schizophrenia. 805 17

To study whether it was possible to modify mesolimbic dopaminergic activity by intermittent electrical stimulations (IES), 44 rats were either electrically stimulated or sham-stimulated in the ventral tegmental area (VTA) once daily for 70 days. This was done through chronically implanted intracranial electrodes. The intensity of electrical stimulation was determined by the lowest current that elicited a definite motor response. Stimulated rats demonstrated a significantly potentiated behavioral response after 70 stimulations. Seven months after IES rats still demonstrated an increased sensitivity to electrical stimulations in the VTA. A new stimulation period only resulted in a modest additional fall in threshold values. There was a highly significant difference between the current needed to provoke a given response in sensitized rats and in sham-stimulated rats. The behavioral response to stimulation was suppressed both by the dopamine (DA) D2 receptor antagonists haloperidol and raclopride and by the DA D1 receptor antagonist SCH 23390. Furthermore, stimulated rats showed an enhanced response to stimulation with amphetamine and to a lesser extent with apomorphine. Between stimulation periods sensitized animals demonstrated a reduced social interaction. In conclusion intermittent electrical stimulations of the VTA resulted in a syndrome characterized by a hypersensitive response to electrical and pharmacological DA provocation combined with abnormal social interaction. This animal model has points of resemblance with recent interpretations of the DA hypothesis for schizophrenia.
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PMID:Electrical sensitization of the meso-limbic dopaminergic system in rats: a pathogenetic model for schizophrenia. 837 92

Using SKF-38393/[3H]SCH-23390 dopamine D1 receptor agonist/antagonist competition binding technique, we showed that schizophrenics distinguished from the neuro-psychiatric and normal controls by exhibiting a significant increase in the density of the low-affinity state, and a concomitant enhancement in the binding affinity of the high-affinity state of D1 dopamine receptors in caudate nucleus. The results suggest that perturbation in dynamic equilibrium of high- and low-affinity states of D1 receptors underlies the pathogenesis of schizophrenia.
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PMID:High- and low-affinity states of dopamine D1 receptors in schizophrenia. 847 45


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