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Compelling evidence for orbito-frontal glutamatergic dysfunction in schizophrenic brain
133
VIII. Neurochemistry and Neuropharmacology VII1.A. EXCITATORY
AMINO ACIDS
VIII.A.3 DIFFERENT CAPABILITY OF NMDA ANTAGONISTS TO ELICIT PHENCYCLIDINE-LIKE EEG AND BEHAVIOURAL EFFECTS IN RATS S. Sagratella,
WIlA. 1 COMPELLING EVIDENCE FOR ORBITOFRONTAL GLUTAMATERGIC DYSFUNCTION IN SCHIZOPHRENIC BRAIN J.F.W. Deakin, M.D.C. Simpson, P. Slater and MC. Royston Department of Psychiatry, Manchester Royal Infirmary. Ml3 9 WL Manchester, U.K.
One in twenty comparisons of a neurochemical parameter in areas of schizophrenic versus control post mortem brain will be ‘significant’ (~~0.05) by chance. However, the probability of the same comparison achieving significance in a second series is 0.0025: replication is compelling. We now report, in a new series of brains, a replication of our original finding (Deakin et al., 1989) that radioligand binding to pre and post synaptic markers for glutamatergic markers are increased selectively in orbito-frontal cortex (OFC) in schizophrenics (n = 13) compared with controls (n = 18). [‘H]o-aspartate binds to glutamate uptake sites and marks presynaptic glutamate neurones. ANOVAR revealed significant increases in right schizophrenic OFC in this study (see Simpson’s abstract, VIII.A.4), and bilateral in the published study. t3H]kainate binds to postsynaptic receptors and was increased on the left in schizophrenics and bilaterally in the earlier study. Other markers for glutamatergic elements are increased in OFC and not other areas of brain: glutamate content (Reynolds), kainate binding (Nishikawa), I-OHDPAT binding to 5-HT,, receptors on pyramidal cortical cells (Hashimoto). Increases in frontal muscarinic (Hanada) and LSD (Whitaker) binding to uncertain neuronal elements have also been reported. In contrast, markers for non-glutamatergic elements are unchanged (GABA uptake, Reynolds, Simpson; GABA content Reynolds) or reduced (5HT, binding to interneurones). Schizophrenia clearly involves disturbances in the basolateral circuit which we suggest directly relate to pathogenesis because they interfere with mechanisms of social signalling.
P. Popoli and A. Scotti de Carobs
Pharmacology Department, Istituto Superiore di Sanita’, Roma, Italy
Phenciclidine (PCP), a psychotomimetic drug inducing schizophrenia-like symptoms in humans, is reported to be a non competitive antagonist at the N-methyl-D-aspdrtate receptor (NMDA), a subtype of excitatory aminoacid receptors. PCP produces typical behavioural and EEG effects in experimental animals. The drug induces three dose-dependent EEG patterns in the rat: (I) increase of the cortical desynchronization; (2) increase of the amplitude of the fast (20-30 Hz) low voltage (30-50 uV) cortical waves; (3) appearance of 2-3 Hz slow wave-sharp wave complexes. These EEG changes are accompanied by stimulatory-depressive effects such as head weaving and ataxia. The aim of the present study was to evaluate the EEG and behavioural effects induced by some competitive and non-competitive NMDA antagonists after systemic administration in rats. The results demonstrated that both competitive and non-competitive NMDA antagonists induce all the PCP-like behavioural and EEG effects. The rank of potency is MK 801 (from 0.5 mg/kg i.p.) >CGS 19755 ‘(from 20-25 mg/kg i.p.)> CPP (from 30-50 mg/kg i.p.). On the contrary, dextromethorphan and SL 82.0715 are devoid of PCP-like behavioural and EEG effects up to the high dose tested of 100 mg/kg i.p. The data strongly promote an involvement of the NMDA neurotransmission in the behavioural and EEG effects of PCP.
VIII.A.4 NEUROCHEMICAL ABNORMALITIES THE CEREBRAL CORTEX IN SCHIZOPHRENIA
OF
M.D.C. Simpson, M.C. Roy&on, P. Slater and J.F.W. Deakin Department of Physiological Sciences. University of Manchester, Manchester, Ml3 9PT. U.K.
We previously suggested that deficits in markers of amino acid (glutamate, GABA) synapses in schizophrenic temporal cortex were the consequence of structural abnormalities of the temporal lobe’*‘. Subcortical areas were also affected, deficits being particularly marked within the putamen”. In contrast, in orbital frontal cortex both pre and postsynaptic glutamate markers were bilaterally increased, implying an abnormally
VIII. Neurochemistry and Neuropharmacology VII1.A. EXCITATORY
AMINO ACIDS
VIII.A.3 DIFFERENT CAPABILITY OF NMDA ANTAGONISTS TO ELICIT PHENCYCLIDINE-LIKE EEG AND BEHAVIOURAL EFFECTS IN RATS S. Sagratella,
WIlA. 1 COMPELLING EVIDENCE FOR ORBITOFRONTAL GLUTAMATERGIC DYSFUNCTION IN SCHIZOPHRENIC BRAIN J.F.W. Deakin, M.D.C. Simpson, P. Slater and MC. Royston Department of Psychiatry, Manchester Royal Infirmary. Ml3 9 WL Manchester, U.K.
One in twenty comparisons of a neurochemical parameter in areas of schizophrenic versus control post mortem brain will be ‘significant’ (~~0.05) by chance. However, the probability of the same comparison achieving significance in a second series is 0.0025: replication is compelling. We now report, in a new series of brains, a replication of our original finding (Deakin et al., 1989) that radioligand binding to pre and post synaptic markers for glutamatergic markers are increased selectively in orbito-frontal cortex (OFC) in schizophrenics (n = 13) compared with controls (n = 18). [‘H]o-aspartate binds to glutamate uptake sites and marks presynaptic glutamate neurones. ANOVAR revealed significant increases in right schizophrenic OFC in this study (see Simpson’s abstract, VIII.A.4), and bilateral in the published study. t3H]kainate binds to postsynaptic receptors and was increased on the left in schizophrenics and bilaterally in the earlier study. Other markers for glutamatergic elements are increased in OFC and not other areas of brain: glutamate content (Reynolds), kainate binding (Nishikawa), I-OHDPAT binding to 5-HT,, receptors on pyramidal cortical cells (Hashimoto). Increases in frontal muscarinic (Hanada) and LSD (Whitaker) binding to uncertain neuronal elements have also been reported. In contrast, markers for non-glutamatergic elements are unchanged (GABA uptake, Reynolds, Simpson; GABA content Reynolds) or reduced (5HT, binding to interneurones). Schizophrenia clearly involves disturbances in the basolateral circuit which we suggest directly relate to pathogenesis because they interfere with mechanisms of social signalling.
P. Popoli and A. Scotti de Carobs
Pharmacology Department, Istituto Superiore di Sanita’, Roma, Italy
Phenciclidine (PCP), a psychotomimetic drug inducing schizophrenia-like symptoms in humans, is reported to be a non competitive antagonist at the N-methyl-D-aspdrtate receptor (NMDA), a subtype of excitatory aminoacid receptors. PCP produces typical behavioural and EEG effects in experimental animals. The drug induces three dose-dependent EEG patterns in the rat: (I) increase of the cortical desynchronization; (2) increase of the amplitude of the fast (20-30 Hz) low voltage (30-50 uV) cortical waves; (3) appearance of 2-3 Hz slow wave-sharp wave complexes. These EEG changes are accompanied by stimulatory-depressive effects such as head weaving and ataxia. The aim of the present study was to evaluate the EEG and behavioural effects induced by some competitive and non-competitive NMDA antagonists after systemic administration in rats. The results demonstrated that both competitive and non-competitive NMDA antagonists induce all the PCP-like behavioural and EEG effects. The rank of potency is MK 801 (from 0.5 mg/kg i.p.) >CGS 19755 ‘(from 20-25 mg/kg i.p.)> CPP (from 30-50 mg/kg i.p.). On the contrary, dextromethorphan and SL 82.0715 are devoid of PCP-like behavioural and EEG effects up to the high dose tested of 100 mg/kg i.p. The data strongly promote an involvement of the NMDA neurotransmission in the behavioural and EEG effects of PCP.
VIII.A.4 NEUROCHEMICAL ABNORMALITIES THE CEREBRAL CORTEX IN SCHIZOPHRENIA
OF
M.D.C. Simpson, M.C. Roy&on, P. Slater and J.F.W. Deakin Department of Physiological Sciences. University of Manchester, Manchester, Ml3 9PT. U.K.
We previously suggested that deficits in markers of amino acid (glutamate, GABA) synapses in schizophrenic temporal cortex were the consequence of structural abnormalities of the temporal lobe’*‘. Subcortical areas were also affected, deficits being particularly marked within the putamen”. In contrast, in orbital frontal cortex both pre and postsynaptic glutamate markers were bilaterally increased, implying an abnormally