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1995 Fiscal Year Final Research Report Summary

Molecular pharmacological approach to the disturbances of brain neuron circuits involved in schizophrenia

Research Project

Project/Area Number 06670993
Research Category

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

Allocation TypeSingle-year Grants
Research Field Psychiatric science
Research InstitutionNational Center of Neurology and Psychiatry

Principal Investigator

NISHIKAWA Toru  National Institute of Neuroscience, Director, 神経研究所・疾病研究第3部, 部長 (00198441)

Co-Investigator(Kenkyū-buntansha) TAKAHASHI Katunobu  National Institute of Neuroscience, Section Cheef, 神経センター・神経研究所疾病研究第3部, 室長 (40183850)
Project Period (FY) 1994 – 1995
KeywordsSchizophrenia / Methamphetamine / Phencyclidine / c-fos expression / Development / Neocortex / RNA arbitrarily primed PCR / Neuron circuits
Research Abstract

A psychotomimetic drug methamphetamine (MAP) produces a neuroleptic-responsive schizophreniform psychosis in humans while phencyclidine (PCP) psychosis includes neuroleptic-resistant symptoms which are indistinguishable from those of schizophrenis. Acute administration of MAP (4.8 mg/kg, subcutaneously (s.c.)) caused a widespread induction of nuclear c-Fos-like immunoreactivity in rat brain at 56-80 postnatal days in a dopamine antagonist-sensitive manner. The greatest density of c-Fos positive cells was found in the pyriform cortex and olfactory tubercle followed by the entorhinal cortex, II-VI layrs of the neocortex, striatum, amygdala, nucleus accumbens, septal unclei, granular cell layr of the cerebellum, thalamus, hypothalamus, substantia nigra, etc. In 8-day-old neonatal rats, acute injection of these drugs failed to cause c-fos expression from the laver II htrough V of the neocortex, but induced the proto-oncogene product in a deeper aprt of the layr VI of the neocortex, the pal … More eocortex (including the pyriform and entorhinal cortex) and the above 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. The distribution patterns of c-Fos-positive cells after PCP treatment were different from those after MAP.Thus, a single injection of PCP (5-10mg/kg, s.c.) produced the dense expression of c-Fos-like immunoreactivity in the deeper layrs (IV-VI) of the neocortex and pyriform cortex, but the very sparse expression in the striatum, olfactory tubercle and superficial layrs (I-III) of the necortex in the young adult periods in a dopamine antagonist-resistant fashion. These expression patterns were similar to those of a selective NMDA receptor antagonist dizocilpine. In the neonatal periods, PCP induced very low levels of c-Fos-like immunoreactivity in the neocortex while the pyriform cortex was dense with c-Fos positive cells. PCP-induced c-Fos-immunostaining in th brain showed the adult pattern after 21-25 postnatal days. The above developmental changes in the patterns of c-fos expression in the neocortical areas might reflect differences in responsive neuronal circuits to the drugs between the neonatal and young adult periods. Because acute or long-term behavioral effects of these drugs alter around the third week of postnatal life, these results suggest that the maturation of certain neuronal circuits in the neocortex might be crucial for the acquisition of the adult patterns of behavioral responses or motor functions. We have nowtried to identify molecules contributing to such developmental changes in the discrete brain regions because these molecules should play a pivotal role in expression and regulation of psychomotor functions that may be disturbed in schizopherenic patients. To this end, we have employed a RNA arbitarily primed PCR technique for the detection of cDNAs that represent developmentally regulate Less

  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Shirayama Y, Nishikawa T and Takahashi K: "Differantial effects of repeated dl-pentazocine treatment on sigma binding sites in discrete brain areas of the rat." Neurosc. Lett.165. 219-222 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tanii Y. Nishikawa T, Hashimoto A and Takahashi K: "Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactiviy, Stereotypy and ataxia in the rat." J. Pharmacol. Exp. Ther.269. 1040-1048 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishijima K, Kashiwa A and Nishikawa T: "Preferential stimulation of extracellular release of dopamine in rat frontal cortex to striatum following competitive inhibition of the N-methyl-D-aspartate receptor." J. Neurochem.63. 375-378 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 橋本篤司、西川 徹: "フェンサイクリジン投与動物を用いた精神分裂病の研究" 脳と精神の医学. 5(Suppl.). 47-57 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 西川 徹: "神経化学から 特別企画/分裂病の現在「II-精神分裂病の本態に迫る」" こころの科学. 60. 29-34 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Umino A. Nishikawa T and Takahashi K: "Methamphatamine-induced nuclear c-Fos in rat brain regions." Neurochem. Int.26. 85-90 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishijima K, Kashiwa A, Hashimoto A, Iwama H, Umino A and Nishikawa T:"Differential effects of phencyclidine and methamphetamine on dopamine metabolism in rat medial frontal cortex and striatum as revealed by in vivo dialysis." Synapse. (in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kashiwa A, Nishikawa T, Nishijima K, Umino A and Takahashi K.: "Dizocilpine(MK-801)elicits a tetrodotoxin-sensitive increase in extracellular release of dopamine in rat medial frontal cortex." Neurochem. Int.26. 85-90 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hashimoto A, Oka T and Nishikawa T.: "Extracellular concentration of endogenous free D-serine in the rat brain as revealed by in vivo dialysis." Neurosci.66. 635-643 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kumashiro S, Hashimoto A and Nishikawa T.: "Free D-serine in post-mortem brains and spinal cords of individuals with and without neuropsychiatric diseases." Brain Res.681. 117-125 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsui T, Sekiguchi M, Hasgimoto A, Tomita U, Nishikawa T and Wada K:"Functional comparison of D-serine and glycine in rodents: The effects on cloned NMDA receptors and the extracellular concentration." J Neurochem.65. 454-458 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hashimoto A, Oka T and Nishikawa T.: "Anatomical distribution and postnatal changes in endogenous free D-aspartate and D-serine in rat brain and periphery." Eur. J. Neurosci.7. 1657-1663 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shibayama Y, Sasaki S, Tomita U, Nishikawa T and Maeda M:"Synthesis and evaluation of new ^<18>F-labelled thienylcyclohexylpiperidine(TCP)analogues as radioligands for the NMDA receptor-channel complex." J. Labelled Compounds and Radiopharmaceuticals,. XXXVIII. 77-86 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 西川 徹・海野麻未・柏 淳: "分裂病の再発と神経伝達異常 精神医学レビューNO.12「精神分裂病の再発」(太田龍彦編)" ライフサイエンス,東京,3 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 岩間久行・西川 徹: "慢性期病像の治療反応性 3.精神薬理「精神科症例集2、精神分裂病II-主に病因・病態論の立場から」" 中山書店、東京, 3 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishikawa T and Scatton B:"GAB Aergic inhibition of ascending serotonergic neurons in rat brain. In Serotonin in the Gentral Nervous System and Periphery(eds. A. Takada)" Elsevier, Amsterdam,6 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishikawa T, Hashimoto A, Tanii Y, Umino A, Kashiwa A, et. al.: "Disturbed neurotransmission via the N-methyl-D-aspartate receptor and schizophrenia: In The Biology of Schizophrenia(eds. T. Moroji and K. Yamamoto)Development of Psychiatry Series," Elsevier, Amsterdam,11 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 西川 徹: "分裂病と興奮性アミノ酸伝達異常 精神医学レビュー 別巻「21世紀に向けて精神分裂病を考える」(融 道男・大森健一編)" ライフサイエンス,東京,12 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shirayama Y,Nishikawa T and Takahashi K: "Differential effects of repeated dl-pentazocine treatment on sigma binding sites in discret brain areas of the rat." Neurosc.Lett.165. 219-222 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanii Y,Nishikawa T,Hashimoto A and Takahashi K: "Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactiviy, stereotypy and ataxia in the rat." J.Pharmacol.EXP.Ther.269. 1040-1048 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishijima K,Kashiwa A and Nishikawa T: "Preferential stimulation of extracellular release of dopamine in rat frontal cortex to striatum following competitive inhibition of the N-methyl-D-aspartate receptor." J.Neurochem.63. 375-378 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishikawa T,Hashimoto A,Tanii Y,Umino A,Kashiwa A, Kumashiro S,Nishijima K,Oka T,Shirayama Y and Takahashi K: "Disturbed neurotransmission via the N-methyl-D-aspartate receptor and schizophrenia." In The Biology of Schizophrenia (eds.T.Moroji & K.Yamamoto) Development of Psychiatry Series, Elsevier, Amsterdam. 197-207 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Umino A,Nishikawa T and Takahashi K: "Methamphatamine-induced nuclear c-Fos in rat brain regions." Neurochem.Int.26. 85-90 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kashiwa A,Nishikawa T,Nishijima K,Umino A and Takahashi K: "Dizocilpine (MK-801) elicits a tetrodotoxin-sensitive increase in extracellular release of dopamine in rat medial frontal cortex." Neurochem.Int.26. 85-90 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hashimoto A,Oka T and Nishikawa T: "Extracellular concentration of endogenous free D-serine in the rat brain as revealed by in vivo dialysis." Neurosci.66. 635-643 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kumashiro S,Hashimoto A and Nishikawa T: "Free D-serine in post-mortem brains and spinal cords of individuals with and without neuropsychiatric diseases." Brain Res.681. 117-125 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsui T,Sekiguchi M,Hasgimoto A,Tomita U,Nishikawa T and Wada K: "Functional comparison of D-serine and glycine in rodents : The effects on cloned NMDA receptors and the extracellular concentration." J.Neurochem.65. 454-458 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hashimoto A,Oka T and Nishikawa T: "Anatomical distribution and postnatal changes in endogenous free D-aspartate and D-serine in rat brain and periphery." Eur.J.Neurosci.7. 1657-1663 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shibayama Y,Sasaki S,Tomita U,Nishikawa T and Maeda M: "Synthesis and evaluation of new ^<18>F-labelled thienylcyclohexylpiperidine (TCP) analogues as radioligands for the NMDA receptor-channel complex." J.Labelled Compounds and Radiopharmaceuticals. XXXVIII. 77-86 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishikawa T and Scatton B: "GA BA ergic inhibition of ascending serotonergic neurons in rat brain." In Serotonin in the Central Nervous System and Periphery (eds.A.Takada & G.Curzon), Elsevier, Amsterdam. 153-158 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishijima K,Kashiwa A,Hashimoto A,Iwama H,Umino A and Nishikawa T: "Differential effects of phencyclidine and methamphetamine on dopamine metabolism in rat medial frontal cortex and striatum as revealed by in vivo dialysis." Synapse. (in press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1997-03-04  

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