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Neurochemical abnormalities of the cerebral cortex in schizophrenia
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
134 Table VIII.A.4 Schizophrenic
Control
Specific binding (fmol/mg). Mean f SEM
ASP NIP ASP KA ASP NIP TCP
Polar temporal: medical lateral Orbital frontal cortex: Putamen, body:
Left
Right
Left
Right
2988+223 680f72 730*55 16.650.9 991&114 280+23 130* 15
3742k322 456+41 521&52 2O.OkO.8 1175~103 316k28 11227
2679+ 189 578 + 74 702 f 58 19.5+ 1.4 1312& 172 373*37 148k24
2950+258 528 + 53 637k56 19.4_+1.1 1584+242 366k35 141+13
dense glutamatergic innervation’. We have now examined the anatomical distribution of these abnormalities in a series of brains (12 schizophrenics vs 19 controls) in which we had previously established the presence of cerebral atrophy4. Radioligand binding-site assays were conducted on dissected tissue from up to 14 anatomical locations. Glutamate and GABA uptake sites were examined using [3H]D-aspartate (ASP) and [aH]nipecotic acid (NIP) respectively. Glutamate receptors were examined using [3H]kainate (KA) and [3H]TCP. The major disease-related differences determined in the study are shown in the Table. The results are generally compatible with our previous data. Schizophrenia was associated with localised deficits in glutamate and GABA uptake sites in polar temporal cortex (BA38), whereas in orbital frontal cortex (BAI I) a lateralised increase in the binding of both ASP and KA was apparent. However, there were also increases in the binding of ASP, NIP and TCP in the body of the putamen, in contradiction with our earlier findings. The results provide further support for abnormal cortical amino acid neurotransmitter function in schizophrenia: temporal lobe deficits which may be related to structural pathology; increases in glutamatergic markers suggesting hyperinnervation of orbital frontal cortex. I. Deakin, J.F.W. et al. (1989) J. Neurochem. 52, 781-786. 2. Simpson, M.D.C. et al. (1989) Neurosci. Lett. 107,21 I-215. 3. Simpson, M.D.C. et al. (1990) Eur. J. Neurosci. Suppl. 3, 2171. 4. Royston, M.C. et al. (1991) Biol. Psychiatry (in press).
Some patients with schizophrenic illness benefit from lithium, but it is unclear how. Lithium’s benefits may be related to its effects on the inositol phospholipid system. Brain membrane phospholipid metabolism can be noninvasively studied using in vivo 3’P NMR spectroscopy. Renshaw et al. (Biol. Psychiatry, 21, 691-694, 1986) have shown that in therapeutic concentrations, lithium increases the phosphomonoestor (PME) peak in 31P MRS in cats, and such increases probably reflect inositol phosphates. We hypothesized that similar increases may predict lithium response. We carried out 3’P MRS in 18 patients with schizophrenia before and after treatment with lithium for I and 2 weeks. There were 13 nonresponders and 5 responders to lithium treatment (mean dose Il81.7* 336.5 mg; mean lithium level 0.89+0.14 mg Eq/l). In the responder group, PMEs increased at week 1 (~‘0.03; one tailed r-test) and had declined at week 2 (n.s.). A trend for the opposite was observed with the nonresponders. The degree of increase in PME at week I correlated significantly with improvements in positive psychotic symptoms (r = 0.63; p = 0.04). The week I increase in PME could be related to accumulation of inositol phosphates due to the lithium induced inhibition of inositol phosphatase. The week 2 decline could be related to the fact that over time, the enzymatic block results in a lack of replenishing of the inositol phosphates. 3’P MRS may thus be useful in in vivo prediction of lithium response. These preliminary findings need to be confirmed in a larger sample of patients with schizophrenic and bipolar disorders. Supported by Scottish Rite Grant 5-37100.
VII1.B. PHOSPHOLIPIDS VII1.B. 1 MEMBRANE PHOSPHOLIPIDS AND LITHIUM RESPONSE IN SCHIZOPHRENIA: A 31P MRS STUDY
VIII.B.2 INCREASED LYSOPHOSPHATIDYLCHOLINE IN PLATELET MEMBRANE OF SCHIZOPHRENICS
CONTENT
A.M. Pangerl, A. Stuedle, H.W. Jaroni and W.F. Gattaz
M.S. Keshavan,
J.W. Pettegrew,
K. Panchalingam
Department of Psychiatry, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, U.S.A.
Zentralinstitut fir Seelische Gesundheit. Arbeitsgruppe Meurobiologie der FunktioneNen Psychosen, Pos!fach 12 21 20. D-6800 Mannheim. Germany
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
134 Table VIII.A.4 Schizophrenic
Control
Specific binding (fmol/mg). Mean f SEM
ASP NIP ASP KA ASP NIP TCP
Polar temporal: medical lateral Orbital frontal cortex: Putamen, body:
Left
Right
Left
Right
2988+223 680f72 730*55 16.650.9 991&114 280+23 130* 15
3742k322 456+41 521&52 2O.OkO.8 1175~103 316k28 11227
2679+ 189 578 + 74 702 f 58 19.5+ 1.4 1312& 172 373*37 148k24
2950+258 528 + 53 637k56 19.4_+1.1 1584+242 366k35 141+13
dense glutamatergic innervation’. We have now examined the anatomical distribution of these abnormalities in a series of brains (12 schizophrenics vs 19 controls) in which we had previously established the presence of cerebral atrophy4. Radioligand binding-site assays were conducted on dissected tissue from up to 14 anatomical locations. Glutamate and GABA uptake sites were examined using [3H]D-aspartate (ASP) and [aH]nipecotic acid (NIP) respectively. Glutamate receptors were examined using [3H]kainate (KA) and [3H]TCP. The major disease-related differences determined in the study are shown in the Table. The results are generally compatible with our previous data. Schizophrenia was associated with localised deficits in glutamate and GABA uptake sites in polar temporal cortex (BA38), whereas in orbital frontal cortex (BAI I) a lateralised increase in the binding of both ASP and KA was apparent. However, there were also increases in the binding of ASP, NIP and TCP in the body of the putamen, in contradiction with our earlier findings. The results provide further support for abnormal cortical amino acid neurotransmitter function in schizophrenia: temporal lobe deficits which may be related to structural pathology; increases in glutamatergic markers suggesting hyperinnervation of orbital frontal cortex. I. Deakin, J.F.W. et al. (1989) J. Neurochem. 52, 781-786. 2. Simpson, M.D.C. et al. (1989) Neurosci. Lett. 107,21 I-215. 3. Simpson, M.D.C. et al. (1990) Eur. J. Neurosci. Suppl. 3, 2171. 4. Royston, M.C. et al. (1991) Biol. Psychiatry (in press).
Some patients with schizophrenic illness benefit from lithium, but it is unclear how. Lithium’s benefits may be related to its effects on the inositol phospholipid system. Brain membrane phospholipid metabolism can be noninvasively studied using in vivo 3’P NMR spectroscopy. Renshaw et al. (Biol. Psychiatry, 21, 691-694, 1986) have shown that in therapeutic concentrations, lithium increases the phosphomonoestor (PME) peak in 31P MRS in cats, and such increases probably reflect inositol phosphates. We hypothesized that similar increases may predict lithium response. We carried out 3’P MRS in 18 patients with schizophrenia before and after treatment with lithium for I and 2 weeks. There were 13 nonresponders and 5 responders to lithium treatment (mean dose Il81.7* 336.5 mg; mean lithium level 0.89+0.14 mg Eq/l). In the responder group, PMEs increased at week 1 (~‘0.03; one tailed r-test) and had declined at week 2 (n.s.). A trend for the opposite was observed with the nonresponders. The degree of increase in PME at week I correlated significantly with improvements in positive psychotic symptoms (r = 0.63; p = 0.04). The week I increase in PME could be related to accumulation of inositol phosphates due to the lithium induced inhibition of inositol phosphatase. The week 2 decline could be related to the fact that over time, the enzymatic block results in a lack of replenishing of the inositol phosphates. 3’P MRS may thus be useful in in vivo prediction of lithium response. These preliminary findings need to be confirmed in a larger sample of patients with schizophrenic and bipolar disorders. Supported by Scottish Rite Grant 5-37100.
VII1.B. PHOSPHOLIPIDS VII1.B. 1 MEMBRANE PHOSPHOLIPIDS AND LITHIUM RESPONSE IN SCHIZOPHRENIA: A 31P MRS STUDY
VIII.B.2 INCREASED LYSOPHOSPHATIDYLCHOLINE IN PLATELET MEMBRANE OF SCHIZOPHRENICS
CONTENT
A.M. Pangerl, A. Stuedle, H.W. Jaroni and W.F. Gattaz
M.S. Keshavan,
J.W. Pettegrew,
K. Panchalingam
Department of Psychiatry, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, U.S.A.
Zentralinstitut fir Seelische Gesundheit. Arbeitsgruppe Meurobiologie der FunktioneNen Psychosen, Pos!fach 12 21 20. D-6800 Mannheim. Germany