Research Article| Volume 29, ISSUE 1, P41-54, January 01, 1991

Selective loss of cerebral cortical Sigma, but not PCP binding sites in schizophrenia

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      Drugs such as phencyclidine (PCP) that interact with PCP and sigma binding sites can produce psychotomimetic effects that resemble some symptoms of schizophrenia. Therefore, it has been suggested that PCP and sigma receptors may be important in the clinical manifestations of schizophrenia. Assays of these two binding sites in human postmortem brains showed consistent significant reductions in the density of sigma, but not PCP sites, in schizophrenics as compared with age-matched and postmortem interval-matched normal and suicide controls. Reductions in the density of sigma binding sites in schizophrenia were most prominent in temporal cerebral cortex, and were accompanied by a small increase in affinity for the ligand [3H]haloperidol. These data provide the first evidence for alterations in sigma binding sites in schizophrenia, and suggest that selective sigma ligands may be useful in the treatment of the disorder.
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        • Allen R.M.
        • Young S.J.
        Phencyclidine-induced psychosis.
        Am J Psychiatry. 1978; 135: 1081-1084
        • Beart P.M.
        • O'Shea R.D.
        • Manallack D.T.
        Regulation of σ receptors: High and low affinity agonist states, GTP shifts and up-regulation by rimcazoel and 1,3-Di(2-tolyl)guanidine.
        J Neurochem. 1989; 53: 779-788
        • Bell J.A.
        • Spivak C.E.
        • Su T.-P.
        • London E.D.
        Haloperidol-sensitive, selective electrophysiological effects of sigma lignads on NCB-20 cells (Abstract).
        Soc Neurosci. 1988; 14: 155
        • Bellville J.W.
        • Forrest W.H.
        Respiratory and subjective effects of d and l-pentazocine.
        Clin Pharmacol Ther. 1968; 9: 142-151
        • Bogerts B.
        • Meertz E.
        • Schonfeldt-Bausch R.
        Basal ganglia and limbic system pathology in schizophrenia.
        Arch Gen Psychiatry. 1985; 42: 784-791
        • Bowen W.D.
        • Kirschner B.N.
        • Newman A.H.
        • Rice K.C.
        σ receptors negatively modulate agonist-stimulated phosphoinositol metabolism in rat brain.
        Eur J Pharmacol. 1988; 149: 399-400
        • Brown R.
        • Colter N.
        • Corsellis J.A.W.
        • et al.
        Postmortem evidence of structural brain changes in schizophrenia.
        Arch Gen Psychiatry. 1986; 43: 36-42
        • Buchsbaum M.S.
        • Delisi L.E.
        • Holcomb H.H.
        • Hazlett E.
        • Kessler R.
        Cerebral glucography in schizophrenia.
        in: Greitz T.V.B. Ingvar D.H. Widen L. The Metabolism of the Human Brain Studied with Positron Emission Tomography. Raven Press, New York1985: 471-483
        • Byrd J.C.
        • Bykov V.
        • Rothman R.
        Chronic haloperidol treatment up-regulates rat brain PCP receptors.
        Eur J Pharmacol. 1987; 149: 121-122
        • Ceci A.
        • Smith M.
        • French E.D.
        Activation of the A10 mesolimbic system by the σ receptor agonist (+)SKF 10,047 can be blocked by rimcazole, a novel antipsychotic.
        Eur J Pharmacol. 1988; 154: 53-57
        • Clow D.W.
        • Jhamandas K.
        Characterization of l-glutamate action on the release of endogenous dopamine from the rat caudate-putamen.
        J Pharmacol Exp Ther. 1989; 248: 722-728
        • Contreras P.C.
        • DiMaggio D.A.
        • O'Donohue T.L.
        An endogenous ligand for the sigma opioid binding site.
        Synapse. 1987; 1: 57-61
        • Contreras P.C.
        • Quirion R.
        • Gehlert D.R.
        • Contreras M.L.
        • O'Donohue T.L.
        Autoradiographic distribution of non-dopaminergic binding sites labeled by [3]haloperidol in rat brain.
        Neurosci Lett. 1987; 75: 133-140
        • Della Puppa A.
        • London E.D.
        Cerebral metabolic effects of sigma ligands in the rat.
        Brain Res. 1990; (in press)
        • Freeman A.S.
        • Bunney B.S.
        The effects of phencyclidine and N-allylnormetazocine on midbrain dopamine neuronal activity.
        Eur J Pharmacol. 1984; 104: 287-293
        • Gundlach A.L.
        • Largent B.L.
        • Snyder S.H.
        Autoradiographic localization of sigma receptor binding sites in guinea pig and rat central nervous system with (+)3H-3-(3-hydroxyphenyl)-N-(l-propyl)-piperidine.
        J Neurosci. 1986; 6: 1757-1770
        • Haertzen C.A.
        Subjective effects of narcotic antagonists cyclazocine and nalorphine on the Addiction Research Center Inventory.
        Psychopharmacology (Berlin). 1970; 18: 366-377
        • Heath R.
        • Franklin D.
        • Shraberg D.
        Gross pathology of the cerebellum in patients diagnosed and treated as functional psychiatric disorders.
        J Nerv Ment Dis. 1979; 16: 585-592
        • Itzhak Y.
        • Alerhand S.
        Differential regulation of σ and PCP receptors after chronic administration of haloperidol and phencyclidine in mice.
        FASEB J. 1989; 3: 1868-1872
        • Jakob H.
        • Beckman H.
        Prenatal developmental disturbances in the limbic allocortex in schizophrenics.
        J Neural Transm. 1986; 65: 303-326
        • Javitt D.C.
        Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia.
        Hillside J Clin Psychiatry. 1987; 9: 12-35
        • Johnson R.M.
        • Snell L.D.
        • Morter R.S.
        N-methyl-D-aspartate enhances 3H-TCP binding to rat cortical membranes: Effects of divalent cations and glycine.
        in: Domino E.F. Kamanka J.M. Sigma and Phencyclidine-like Compounds as Molecular Probes in Biology. NPP Books, Ann Arbor, MI1987: 259-268
        • Keats A.S.
        • Telford J.
        Narcotic antagonists as analgesics: Clinical aspects.
        in: Gould R.F. Molecular Modification in Drug Design, Advances in Chemistry. American Chemical Society, Washington DC1964: 170-176 (series 45)
        • Kornhuber J.
        • Mack-Butrkhardt F.
        • Riederer P.
        • et al.
        [3H]MK-801 binding sites in postmortem brain regions of schizophrenic patients.
        Neural Transm. 1989; 77: 231-236
        • Largent B.L.
        • Gundlach A.L.
        • Snyder S.H.
        Pharmacological and autoradiographic discrimination of sigma and phencyclidine receptor binding sites in brain with(+)-[3H]SKF 10,047, (+)-[3H]-3-PPP and [3H]TCP.
        J Pharmacol Exp Ther. 1986; 238: 739-748
        • Largent B.L.
        • Wikstrom H.
        • Snowman A.M.
        • Snyder S.H.
        Novel antipsychotic drugs share a high affinity for σ receptors.
        Eur J Pharmacol. 1988; 155: 345-347
        • London E.D.
        • Dam M.
        • Weissman A.D.
        Different patterns of cerebral glucose utilization produced by phencyclidine and d-N-allynormetazocine.
        in: Domino E.F. Kamanka J.M. Sigma and Phencyclidine-like Compounds as Molecular Probes in Biology. BPP Books, Ann Arbor, MI1987: 197-307
        • Lowry O.H.
        • Rosebrough N.J.
        • Farr A.L.
        • Randall R.J.
        Protein measurements with the Folin phenol reagent.
        J Biol Chem. 1951; 193: 265-275
        • Luby E.D.
        • Cohen B.D.
        • Rosenbaum G.
        • Gottlieb J.S.
        • Kelley R.
        Study of a new schizophrenomimetic drug—Senyl.
        Arch Neurol Psychiatry. 1959; 81: 363-366
        • Luisada P.V.
        • Brown B.I.
        Clinical management of the phencyclidine psychosis.
        Clin Toxicol. 1976; 9: 539-554
        • Maragos W.F.
        • Chu D.C.M.
        • Greenamyne J.T.
        High correlation between the localization of [3H]TCP binding and NMDA receptors.
        Eur J Pharmacol. 1986; 123: 173-174
        • Matthews R.T.
        • McMillen B.A.
        • Sallis R.
        • Blair D.
        Effect of BMY 14802, a potential antipsychotic drug, on rat brain dopaminergic function.
        J Pharmacol Exp Ther. 1986; 239: 124-131
        • Munson P.J.
        • Rodbard D.
        LIGAND: A versatile computerized approach for characterization of ligand-binding systems.
        Anal Biochem. 1980; 107: 220-239
        • Quirion R.R.
        • Hammer Jr., P.
        • Herkenham M.
        • Pert C.B.
        The phencyclidine (angel dust)/sigma ‘opiate’ receptor: Its visualization by tritium-sensitive film.
        in: Proc Natl Acad Sci USA. 78. 1981: 5881-5885
        • Rothman R.B.
        • Bykov V.
        • Cadet J.C.
        • Kleinman J.E.
        A postmortem study of the effect of chronic opiate abuse on psychotomimetic binding sites of human frontal cortex.
        Neuropeptides. 1987; 10: 261-264
        • Seeman P.
        Dopamine receptors and the dopamine hypothesis of schizophrenia.
        Synapse. 1987; 1: 133-152
        • Sircar R.
        • Zukin S.R.
        Characterization of specific sigma opiate/phencyclidine (PCP)-binding sites in the human brain.
        Life Sci. 1983; 33: 259-262
        • Snider S.R.
        Cerebellar pathology in schizophrenia—cause of consequence?.
        Neurosci Biobehav Rev. 1982; 6: 47-53
        • Steinfels G.F.
        • Tam S.W.
        Selective σ receptor agonist and antagonist affect dopamine neuronal activity.
        Eur J Pharmacol. 1989; 163: 167-170
        • Stevens J.R.
        An anatomy of schizophrenia?.
        Arch Gen Psychiatry. 1973; 29: 177-189
        • Su T.-P.
        Evidence for sigma opioid receptor: Binding of [3H]SKF-1047 to etorphine-inaccessible sites in guinea pig brain.
        J Pharmacol Exp Ther. 1982; 223: 284-290
        • Su T.-P.
        • Weissman A.D.
        • Yeh S.Y.
        Endogenous ligands for sigma receptors in the brain (“sigmaphin”): Evidence from binding assays.
        Life Sci. 1986; 38: 2199-2210
        • Tam S.W.
        • Cook L.
        σ-opiates and certein antipsychotic drugs mututally inhibit (+)-[3]SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes.
        in: Proc Natl Acad Sci USA. 81. 1984: 5618-5621
        • Tam S.W.
        • Zhang A.-Z.
        σ and PCP receptors in human frontal cortex membranes.
        Eur J Pharmacol. 1988; 154: 343-344
        • Vignon J.
        • Chicheportiche R.
        • Chicheportiche M.
        • Kamenka J.M.
        • Geneste P.
        • Lazdunski M.
        [3H]TCP: a new tool with high affinity for the PCP receptor in rat brain.
        Brain Res. 1983; 280: 194-197
        • Volkow N.D.
        • Wolf A.P.
        • Van Gelder P.
        • et al.
        Phenomenological correlates of metabolic activity in 18 patients with chronic schizophrenia.
        Am J Psychiatry. 1987; 144: 151-158
        • Vu T.H.
        • Weissman A.D.
        • London E.D.
        Pharmacological characteristics and distribution of σ and phencyclidine receptors in the animal kingdom.
        J Neurochem. 1990; (in press)
        • Wachtel S.
        • White F.
        Electrophysiological effects of BMY 14802, a new potential antipsychotic drugs, on midbrain dopamine neurons in the rat: Acute and chronic studies.
        J Pharmacol Exp Ther. 1988; 244: 410-416
        • Walker J.M.
        • Matsumoto R.R.
        • Bowen W.D.
        • Gans D.L.
        • Jones K.D.
        • Walker F.O.
        Evidence for a role of haloperidol-sensitive sigma-‘opiate’ receptors in the motor effects of antipsychotic drugs.
        Neurology. 1988; 38: 961-965
        • Weber E.
        • Sonders M.
        • Quarum M.
        • McLean S.
        • Pou S.
        • Keana J.F.W.
        1,3-Di(2[5-3H]tolyl)guanidine: A selective ligand that labels σ-type receptors for psychotomimetic opiates and antipsychotic drugs.
        in: Proc Natl Acad Sci USA. 83. 1986: 8784-8788
        • Weinberger D.R.
        Schizophrenia and the frontal lobe.
        TINS. 1988; 11: 367-370
        • Weissman A.D.
        • Dam M.
        • London E.D.
        Alterations in local cerebral glucose utilization induced by phencyclidine.
        Brain Res. 1987; 435: 29-40
        • Weissman A.D.
        • Su T.-P.
        • Hedreen J.C.
        • London E.D.
        Sigma receptors in postmortem human brains.
        J Pharmacol Exp Ther. 1988; 247: 29-33
        • Weissman A.D.
        • Casanova M.F.
        • De Souza E.B.
        Phencyclidine (PCP) exposure in human addicts does not alter regional sigma (σ) binding.
        Soc Neurosci. 1989; (Abstract 15)
        • Williams P.V.
        • McGlashan T.H.
        Schizoaffective psychosis.
        Arch Gen Psychiatry. 1987; 44: 130-131
        • Wolfe Jr., S.A.
        • Kulsakdinum C.
        • Battaglia G.
        • Jaffe J.H.
        • De Souza E.B.
        Initial identification and characterization of sigma receptors in human peripheral blood leukocytes.
        J Pharmacol Exp Ther. 1988; 247: 1114-1119
        • Zhang A.-Z.
        • Mitchell K.N.
        • Cook L.
        • Tam S.W.
        Human endogenous brain ligands for sigma and phencyclidine receptors.
        in: Domino E.F. Kamanka J.M. Sigma and Phencyclidine-like Compounds as Molecular Probes in Biology. NPP Books, Ann Arbor, MI1987: 335-343