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Schizophrenic sympyoms-related disturbance of cerebral neurotransmission

Research Project

Project/Area Number 04670718
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Psychiatric science
Research InstitutionNational Institute of Neuroscience, Naional Center of Neurology and Psychiatry

Principal Investigator

NISHIKAWA Toru  Natl.Inst.Neurosci., Mental Disorder Res., Section Chief, 神経研究所・疾病研究第3部, 室長 (00198441)

Co-Investigator(Kenkyū-buntansha) KUMASHIRO Shin  Natl.Inst.Neurosci., Mental Disorder Res., Graduate Student, 神経センター神経研究所・疾病研究第3部, 大学院生
HASHIMOTO Atsushi  Natl.Inst.Neurosci., Mental Disorder Res., Senior Reseacher, 神経センター神経研究所・疾病研究第3部, 外来研究員
KASHIWA Atsushi  Natl.Inst.Neurosci., Mental Disorder Res., Postdoc., 神経センター神経研究所・疾病研究第3部, 研究生
UMINO Asami  Natl.Inst.Neurosci., Mental Disorder Res., Res.Associate, 神経センター神経研究所・疾病研究第3部, センター研究員
MIKUNI Masahiko  Natl.Inst.Neurosci., Mental Disorder Res., Section Chief, 神経センター神経研究所・疾病研究第3部, 室長 (00125353)
Project Period (FY) 1992 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1993: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1992: ¥1,300,000 (Direct Cost: ¥1,300,000)
KeywordsSchizophrenia / Methamphetamine / Cocaine / Phencyclidine / c-fos gene / Reverse tolerance / D-Serine / NMDA receptor / c‐fos遺伝子 / D‐セリン / 大脳新皮質 / 大脳旧皮質 / 発達
Research Abstract

In order to get an insight into the possible dysregulation of cerebral neurotransmission and neural networks in schizophrenic disorders, we investigated the effects of schizophrenomimetic drugs including methamphetamine (MAP), cocaine and phencyclidine (PCP) on c-fos gene expression and dopamine (DA) metabolism in rat brain. Since D-serine, which has recently been shown to be an endogenous amino acid, antagonizes the psychotomimetic action of PCP and MAP in the rat, the anatomical distribution of the D-amino acid was examined in rat, mouse and human tissues.
Acute administration of MAP caused a widespread induction of nuclear c-Fos protein-like immunoreactivity in rat brain at 56-80 postnatal days. The greatest density of c-Fos positive cells was found in the pyriform cortex and olfactory tubercle followed by the II-VI layrs of the neocortex, septum, striatum, etc.In 8-day-old neonatal rats, acute MAP injection failed to cause c-fos expression in the II-V layrs of the neocortex, but ind … More uced the proto-oncogene product in a deeper part of the layr VI of the neocortex, the paleocortex including the pyriform and the subcortical areas. MAP-induced c-Fos positive cells in the neocortex increased in number and distribution with postnatal development and showed the adult pattern after 21-23 postnatal days. In agreement with the results of immunohistochemical studies, Northen blot analysis revealed that, in the neocortex, a marked c-fos induction was observed after MAP injection at 21, 23, 25, 30 and 49 days postpartum, whereas the MAP treatment caused a low expression of the immediate early gene at 8 and 14 postnatal days. These distinct patterns of c-fos expression in the neocortical areas might reflect differences in responsive neuronal circuits to the drugs at the neonatal and young adult periods, because the effects of pharmacological, electrical and physiological stimuli have been considered to be traced by the prote-oncogene expression in the nervous system. Together with the observation that stimulant-induced sensitization occurs sometime after the third week of postnatal life, the present results, therefore, suggest that the maturation of certain neuronal circuits in the neocortex might be needed to develop behavioral sensitization to MAP and cocaine.
At 8 and 56 postnatal days, the distibution patterns of c-Fos positive cells after MAP were similar to those after DA agonists, cocaine and apomorphine, but clearly distinct from those after PCP and dizocilpine which are NMDA antagonists. Moreover, MAP markedly augmented extracellular DA release in the frontal cortex and striatum in a tetrodotoxin-insensitive manner in adult rats while PCP produced a frontal cortex-preferring and tetrodotoxin-sensitive increase in DA liberation. The differential effects of MAP and PCP could, in part, explain the differences between PCP-and MAP-induced psychosis.
An endogenous anti-PCP and-MAP substance D-serine was found to exclusively occur in brains with a persistent high content throughout life in the rat, mouse and human. The patterns of the regional variations in brain D-serine were closely correlated with those of the NMDA type glutamate receptor. Together with a selective stimuditribution of the NMDA-related glycine site by D-serine, these data suggest that the D-amino acid is a novel canditate as an intrinsic ligand for the glycine modulatory aite of the NMDA receptor and might be involved in pathophysiology of certain neuropsychiatric disorders including a subtype of schizophrenia. Less

Report

(3 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • 1992 Annual Research Report
  • Research Products

    (51 results)

All Other

All Publications (51 results)

  • [Publications] M.Takashima,et al: "Modulation of cerebral acetylcholine metabolism by the dorsal diencephalic conduction system in the rat." Neurochem.Int.20. 583-589 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Hahsimoto,et al: "Determination of free amino acid enantiomers in rat brain and serum by high performance liquid chromatography after derivatization with N-tert.-butyloxycarbonyl-L-cysteine and ophthaldialdehyde." J.Chromatog. 582. 41-48 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] M.Toru.,et al: "Excitatory aminoacidergic neurones in chronic schizophrenic brain." Mol.Neuropharmacol.2. 241-243 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Hahsimoto,et al: "Endogenous D-serine in rat brain:N-Methyl-D-aspartate receptor-related distribution and aging." J Neurochem.60. 783-786 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] H.Mitsushio,et al: "Effects of 40-day treatment with carbamazepine,sodium valproate and clonazepam on GABA content in rat substantia nigra" Molecular Neuropharmacology.2. 185-188 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 西川 徹,ほか: "フェンサイクリジンの脳に対する作用-興奮性アミノ酸伝達遮断作用を中心として-" 精神医学. 34. 891-900 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Hashimoto,et al: "Free D-serine,D-aspartate and D-alanine in central nervous system and serum in mutant mice lacking D-amino acid oxidase." Neuroscience letters. 152. 33-36 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Y.Shirayama,et al: "p-Chlorophenylalanine-reversible reduction of σ binding sites by chronic imipramine treatment in rat brain" European Journal of Pharmacology. 237. 117-126 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] H.Mitsushio,et al: "Effects of subacute repeated injections of phencyclidine and MK-801 on substance P content in the rat brain." Regulatory Peptides. 46. 352-353 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Hashimoto,et al: "Embryonic development and postnatal changes in free D-aspartate and D-serine in the human prefrontal cortex." Journal of Neurochemistry. 61. 348-351 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Hashimoto,et al: "Widespread distribution of free D-aspartate in rat periphery." Federation of European Biochemical Societies. 331,1,2. 4-8 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Y.Shirayama,et al: "Differential effects of repeated dl-pentazocine treatment on sigma binding sites in discrete brain areas of the rat." Neuroscience Lett.,. 165. 219-222 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Y.Tanii,et al.: "Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactivity,stereotypy and ataxia in the rat." J.Pharmacol.Exp.Ther.(in press). (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 西川 徹: "グルタミン酸と精神疾患" ブレインサイエンス. 4. 187-198 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 西川 徹: "興奮性アミノ酸と精神分裂病" 神経精神薬理. 15. 651-663 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 西川 徹: "躁うつ病の薬理生化学[II]GABAによる脳内セロトニン伝達の調節" 金剛出版(三国雅彦、樋口輝彦、加藤進昌、高橋清久編), p111-128 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 西川徹,岩間久行: "興奮性アミノ酸受容体と新しい抗精神病薬 精神分裂病はどこまでわかったか" 星和書店(町山幸輝,樋口輝彦編), 123-157 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] T.Nishikawa: "Stimulant-induced behavioral sensitization and cerebral neurotransmission." In Neurotransmitters in neuronal plasticity and psychiatric disorders.Excerpta Medica,Ltd., p53-62 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] T.Nishikawa,et al.: "Disturbed neurotransmission via the N-methyl-D-aspartate receptor and schizophrenia" In The biology of schizophrenia(eds.T.Moroji and K.Yamamoto)Elsevier(In press.), (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] M.Takashima, M.Takita, A.umino, T.Nishikawa, H.Mitsushio, K.Takahashi: "Modulation of cerebral acetylcholine metabolism by the dorsal diencephalic conduction system in the rat." Neurochem.Int.20. 583-589 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Hahsimoto, T.Nishikawa, T.Oka, K.Takahashi, T.Hayashi: "Determination of free amino acid enantiomers in rat brain and serum by high performaceliquid chromatography after devivatization with N-tert. -butyloxycarbonyl-L-cysteine and ophthaldialdehyde." J.Chromatog.582. 41-48 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] M.Toru., A Kurumaji, S.Kumashiro, I.Suga, M.Takashima, T.Nishikawa: "Excitatory aminoacidergic neurones in chronic schizxophrenic brain." Mol.Neuropharmacol.2. 241-243 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] H.Mitsushio, M.Takashima, K.Takahashi: "Effects of 40-day treatment with carbamazepine, sodium valproate and clonazepam on GABA content in rat substantia nigra." Mol.Neuropharmacol.2. 185-188 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Hahsimoto, T.Nishikawa, T.Oka, K.Takahashi: "Endogenous D-serinein rat brain : N-Methyl-D-aspartate receptor-related distribution and aging." J Neurochem.60. 783-786 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Hashimoto, T.Nishikawa, R.Konno, A.Niwa, Y.Yasumura, T.Oka, K.Takahashi: "Free D-serine, D-aspartate and D-alanine in central nervous system and serum in mutant mice lacking D-amino acid oxidase." Neurosici.lett. 152. 33-36 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Y.Shirayama, T.Nishikawa, A.Umino and K.Takahashi: "p-Chlorophenylalanine-reversible reduction of sigma binding sites by chronic imipramine treatment in rat brain" Eur.J.Pharmacol.237. 117-126 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] H.Mitsushio, Y.Shirayama, T.Nishikawa and K.Takahashi: "Effects of subacute repeated injections of phencyclidine and MK-801 on substance P content in the rat brain." Reg.Peptides. 46. 352-353 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Hashimoto, S.Kumashiro, T.Nishikawa, T.Oka, K.Takahashi, T.Mito, S.Takashima, N.Doi, Y.Mizutani, T.Yamazaki: "T.Kaneko, E.Ootomo, Embryonic development and postnatal changes in free D-aspartate and D-serine in the human prefrontal cortex." J.Neurochem.61. 348-351 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Hashimoto, T.Nishikawa, T.Oka, T.Hayashi, K.Takahashi.: "Widespreade distribution of free D-aspartate in rat periphery." FEBS Lett.331, 1/2. 4-8 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] T.Nishikawa, A.Umino, A.Kashiwa, A.Ooshima, N.Nomura, K.Takahashi: "Stimulant-induced behavioral sensitization and cerebral neurotransmission." In, Neuronal plasticity and psychiatric disorders.Excerpta Medica, Ltd.p53-62 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Y.Shirayama, T.Nishikawa, K.Takahashi.: "Defferential effects of repeated dl-pentazocine treatment on sigma binding sites in discrete brain areas of the rat." Neurosci.Lett.165. 219-222 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] T.Nishikawa, A.Hashimoto, Y.Tanii, A.Umino, A.Kashiwa, S.Kumashiro, K.Nishijima, T.Oka, Y.Shirayama, K.Takahashi :: In The Biology of Schizophrenia (eds.T.Moroji and K.Yamamoto) Elsevier, (In press.),

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Hashimoto,et al: "Free D‐serine,D‐aspartate and D‐alanine in central nervous system and serum in mutant mice lacking D‐amino acid oxidase." Neuroscience letters,. 152. 33-36 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Y.Shirayama,et al: "p‐Chlorophenylalanine‐reversible reduction of sigma binding sites by chronic imipramine treatment in rat brain" European Journal of Pharmacology,. 237. 117-126 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] H.Mitsushio,et al: "Effects of subacute repeated injections of phencyclidine and MK‐801 on substance P content in the rat brain." Regulatory Peptides,. 46. 352-353 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] A.Hashimoto,et al: "Embryonic development and postnatal changes in free D‐aspartate and D‐serine in the human prefrontal cortex." Journal of Neurochemistry. 61. 348-351 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] A.Hashimoto,et al: "Widespread distribution of free D‐aspartate in rat periphery." Federation of European Biochemical Societies,. 331,1,2,. 4-8 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Y.Shirayama,et al: "Differential effects of repeated dl‐pentazocine treatment on sigma binding sites in discrete brain areas of the rat." Neuroscience Lett.165. 219-222 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Y.Tanii,et al.: "Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine‐induced hyperactivity,stereotypy and ataxia in the rat." J.Pharmacol.Exp.Ther.(in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 西川 徹: "グルタミン酸と精神疾患" ブレインサイエンス. 4. 187-198 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 西川 徹: "興奮性アミノ酸と精神分裂病" 神経精神薬理. 15. 651-663 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] T.Nishikawa,: "Stimulant‐induced behavioral sensitization and cerebral neurotransmission ." In Neurotransmitters in neuronal plasticity and psychiatric disorders.Excerpta Medica, Ltd., p53-62, (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] T.Nishikawa,et al.: "Disturbed neurotransmission via the N‐methyl‐D‐aspartate receptor and schizophrenia:" In The biology of schizophrenia(eds. T. Moroji and K. Yamamoto ) Elsevier(In press.), (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hashimoto,A.et al: "Determination of free amino acid enantiomers in rat brain and serum by high performance liquid chromatography after derivatization with N-tert.-buty loxycarbony 1-L-Cystein and D-phthaldialdehyde." J.Chromatogr.582. 41-48 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Takashima,M.et al.: "Modulation of cerebral acetylcholine metaoclism by the dorsal diencephalic conduction system in the rat." Neurochem.Int.20. 583-589 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Hashimoto,A.et al.: "Endogenous D-serine in rat brain:N-Methy 1-D-aspartate receptor-related distribution and aging." J.Neurochem.60. 783-786 (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Hashimoto,A.et al.: "Free D-serine,D-aspartate and D-alanine in central nervous system and serum in mutant mice lacking D-amino acid oxydase." Neurosu.Lett.

    • Related Report
      1992 Annual Research Report
  • [Publications] Shirayama,Y.et al.: "p-Chlorophenylalanine-revesible reduction of a binding sites by chronic imipramine treatment in rat brain." Eur,J.Pharmacol.

    • Related Report
      1992 Annual Research Report
  • [Publications] 西川 徹ほか: "フェンサイクリジンの脳に対する作用ー興奮性アミノ酸伝達庶断作用を中心としてー" 精神医学. 34. 891-900 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 西川 徹,岩間 久行: "興奮性アミノ酸受要体と新しい抗精神病薬「精神分裂病はどこまでわかったか」(町山幸輝、樋口輝彦編)" 星和書店, 123-157 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 西川 徹: "GABAによる脳内セロトニン伝達の調節「躁うつ病の薬理・生化学[II]」(躁うつ病の薬理・生化学的研究懇話会編)" 金剛出版, 111-128 (1992)

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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