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kainate receptors
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rat, bovine and human brain. The aim of our study was to investigate the levels and the nature of the peptides chromogranin(CgA) and secretoneurin (SN) in the CSF of drug naive first episode schizophrenic patients (n=21) in comparison to controls (n=40). Radioimmunoassay revealed measurable immunoreactivities (IR) in all samples of CSF from controls and schizophrenic patients. A statistical comparison showed significant group differences concerning SN. We did not find any differences between groups in CgA immunoreactivity. Schizophrenics showed lower SN levels (1200fmol/ml) than controls (1500fmol/ml). To further characterize CgAand SN immunoreactivities gel chromatography was performed. CgA-IR was found to consist of 3 peaks, corresponding to CgA and two intermediate peptide fragments. SN-IR was found to be a single peak coeluting with synthetic SN. In conclusion we have found significant changes in SN and CgA/SN ratio in drug free first episode schizophrenic patients. These peptides may contribute to the pathophysiology of schizophrenia and may be of diagnostic value.
STIMULATORY EFFECTS OF SUBANAESTHETIC DOSES OF KETAMINE ON DOPAMINE AND GLUTAMATE LEVELS IN THE PREFRONTAL CORTEX. IMPLICATIONS FOR GLUTAMATERGIC MODULATION OF CORTICAL DOPAMINE RELEASE THROUGH AMPA/KAINATE RECEPTORS Bita Moghaddam*
Department of Psychiatry, Yale University School of Medicine and West Haven VA Medical Center, 116A/2, West Haven, CT06516, USA Sub-anaesthetic doses of ketamine cause several schizophrenia-like deficits in non-schizophrenics including impaired performance on frontal lobe sensitive tests. In this study, intracerebral microdialysis in conscious rats was used to assess the effect of ketamine on the extracellular levels of dopamine and glutamate in the prefrontal cortex. Sub-anesthetic doses of ketamJne ( 10, 20, and 30 mg/kg, i.p.) increased glutamate levels while the anesthetic dose of 100 mg/kg decreased these levels. An intermediate dose of 50mg/kg was without effect. Administration of 30 mg/kg ketamine also increased the release of dopamine in the prefrontal cortex. Local infusion of the AMPA/kainate receptor antagonist, CNQX, blocked the stimulatory effect of ketamine on dopamine release. This finding is similar to our previous report that the increase in the release of dopamine following stress (a treatment which also effectively increases cortical glutamate release) is blocked by CNQX, and indicates that dopamine release in the prefrontal cortex is modulated by AMPA/kainate receptors. Furthermore, these findings suggest that ketamine may exert some of its behavioral effect by increasing the levels of endogenous excitatory amino acids, thus causing a stimulation of post synaptic (non-MDA)
excitatory amino acid receptors. Ongoing behavioral studies in the laboratory are assessing this notion.
BENZODIAZEPRINE RECEPTORS IN HUMAN POSTMORTEM BRAIN: EFFECT OF SCHIZOPHRENIA, SUICIDE, AND NEUROLEPTIC DRUG TREATMENT G.N. Pandey, S.C. Pandey, R.R. Conley, R. Roberts, C.A. Tamminga
The Psychiatric Institute, Department of Psychiatry, University of Illinois, College of Medicine, 1601 West Taylor Street, Chicago, IL 60612, USA There is some evidence to suggest that abnormalities in benzodiazepine receptors may be associated with schizophrenia. Furthermore, benzodiazepine receptors appear to be a part of the GABA-benzodiazepine receptor complex, and GABA has also been implicated in schizophrenia. We have therefore determined the benzodiazepine receptors in postmortem brain of 18 schizophrenic patients, 6 non-schizophrenic suicide victims, and 10 normal controls using [3H]-ROI5-1788 as the ligand. We observed that the mean B,~x of the central benzodiazepine receptor binding sites in the frontal cortex (Brodmann Area 10) of suicidal subjects (non-schizophrenics) were significantly higher than that of control subjects. The mean Bmax in brain of schizophrenics were not significantly different than those of control subjects; however, the mean Bm,~ in brain of schizophrenics treated with neuroleptics were lower than in those patients who were free of neuroleptics. The mean Br~ in the frontal cortex of drug-free suicidal schizophrenics were higher than of control subjects. There were no significant differences in the Ko values of benzodiazepine receptor binding sites between the various groups. These results thus suggest that neuroleptic drug treatment may decrease benzodiazepine receptor binding in postmortem brain of schizophrenic patients and that benzodiazepine receptors are increased in both suicidal schizophrenic and non-schizophrenic subjects.
SELECTIVE MODULATION OF STRIATAL NMDA CURRENTS BY COCAINE J.R. Plant*, B.A. MacVicar
Neuroscience Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1 Cocaine is a powerful CNS stimulant which can produce psychotic states resembling those of schizophrenia. High levels of cocaine binding are found in the striatum and nucleus accumbens, and its actions there are thought to underlie its psychoactive properties. While inhibition of dopamine and 5-HT uptake have been suggested to mediate cocaine's psychogenic properties, cocaine also binds to 6 receptors, the site of action of many antipsychotic drugs. Since 6 receptor activation
rat, bovine and human brain. The aim of our study was to investigate the levels and the nature of the peptides chromogranin(CgA) and secretoneurin (SN) in the CSF of drug naive first episode schizophrenic patients (n=21) in comparison to controls (n=40). Radioimmunoassay revealed measurable immunoreactivities (IR) in all samples of CSF from controls and schizophrenic patients. A statistical comparison showed significant group differences concerning SN. We did not find any differences between groups in CgA immunoreactivity. Schizophrenics showed lower SN levels (1200fmol/ml) than controls (1500fmol/ml). To further characterize CgAand SN immunoreactivities gel chromatography was performed. CgA-IR was found to consist of 3 peaks, corresponding to CgA and two intermediate peptide fragments. SN-IR was found to be a single peak coeluting with synthetic SN. In conclusion we have found significant changes in SN and CgA/SN ratio in drug free first episode schizophrenic patients. These peptides may contribute to the pathophysiology of schizophrenia and may be of diagnostic value.
STIMULATORY EFFECTS OF SUBANAESTHETIC DOSES OF KETAMINE ON DOPAMINE AND GLUTAMATE LEVELS IN THE PREFRONTAL CORTEX. IMPLICATIONS FOR GLUTAMATERGIC MODULATION OF CORTICAL DOPAMINE RELEASE THROUGH AMPA/KAINATE RECEPTORS Bita Moghaddam*
Department of Psychiatry, Yale University School of Medicine and West Haven VA Medical Center, 116A/2, West Haven, CT06516, USA Sub-anaesthetic doses of ketamine cause several schizophrenia-like deficits in non-schizophrenics including impaired performance on frontal lobe sensitive tests. In this study, intracerebral microdialysis in conscious rats was used to assess the effect of ketamine on the extracellular levels of dopamine and glutamate in the prefrontal cortex. Sub-anesthetic doses of ketamJne ( 10, 20, and 30 mg/kg, i.p.) increased glutamate levels while the anesthetic dose of 100 mg/kg decreased these levels. An intermediate dose of 50mg/kg was without effect. Administration of 30 mg/kg ketamine also increased the release of dopamine in the prefrontal cortex. Local infusion of the AMPA/kainate receptor antagonist, CNQX, blocked the stimulatory effect of ketamine on dopamine release. This finding is similar to our previous report that the increase in the release of dopamine following stress (a treatment which also effectively increases cortical glutamate release) is blocked by CNQX, and indicates that dopamine release in the prefrontal cortex is modulated by AMPA/kainate receptors. Furthermore, these findings suggest that ketamine may exert some of its behavioral effect by increasing the levels of endogenous excitatory amino acids, thus causing a stimulation of post synaptic (non-MDA)
excitatory amino acid receptors. Ongoing behavioral studies in the laboratory are assessing this notion.
BENZODIAZEPRINE RECEPTORS IN HUMAN POSTMORTEM BRAIN: EFFECT OF SCHIZOPHRENIA, SUICIDE, AND NEUROLEPTIC DRUG TREATMENT G.N. Pandey, S.C. Pandey, R.R. Conley, R. Roberts, C.A. Tamminga
The Psychiatric Institute, Department of Psychiatry, University of Illinois, College of Medicine, 1601 West Taylor Street, Chicago, IL 60612, USA There is some evidence to suggest that abnormalities in benzodiazepine receptors may be associated with schizophrenia. Furthermore, benzodiazepine receptors appear to be a part of the GABA-benzodiazepine receptor complex, and GABA has also been implicated in schizophrenia. We have therefore determined the benzodiazepine receptors in postmortem brain of 18 schizophrenic patients, 6 non-schizophrenic suicide victims, and 10 normal controls using [3H]-ROI5-1788 as the ligand. We observed that the mean B,~x of the central benzodiazepine receptor binding sites in the frontal cortex (Brodmann Area 10) of suicidal subjects (non-schizophrenics) were significantly higher than that of control subjects. The mean Bmax in brain of schizophrenics were not significantly different than those of control subjects; however, the mean Bm,~ in brain of schizophrenics treated with neuroleptics were lower than in those patients who were free of neuroleptics. The mean Br~ in the frontal cortex of drug-free suicidal schizophrenics were higher than of control subjects. There were no significant differences in the Ko values of benzodiazepine receptor binding sites between the various groups. These results thus suggest that neuroleptic drug treatment may decrease benzodiazepine receptor binding in postmortem brain of schizophrenic patients and that benzodiazepine receptors are increased in both suicidal schizophrenic and non-schizophrenic subjects.
SELECTIVE MODULATION OF STRIATAL NMDA CURRENTS BY COCAINE J.R. Plant*, B.A. MacVicar
Neuroscience Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1 Cocaine is a powerful CNS stimulant which can produce psychotic states resembling those of schizophrenia. High levels of cocaine binding are found in the striatum and nucleus accumbens, and its actions there are thought to underlie its psychoactive properties. While inhibition of dopamine and 5-HT uptake have been suggested to mediate cocaine's psychogenic properties, cocaine also binds to 6 receptors, the site of action of many antipsychotic drugs. Since 6 receptor activation