Study of model for pathophysiology and mechanism for the treatment of the treatment resistant schizophrenia

• Project/Area Number: 15591207
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Hokkaido University
• Principal Investigator: ABEKAWA Tomohiro Hokkaido Universiry, Hokkaido University Hospital, Inst., 大学病院, 助手 (80301901)
• Co-Investigator(Kenkyū-buntansha): KUSUMI Ichiro Hokkaido University, Hokkaido University Hospital, Lec., 大学病院, 講師 (30250426)
• Project Period (FY): 2003 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥2,900,000 (Direct Cost: ¥2,900,000); Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000); Fiscal Year 2004: ¥600,000 (Direct Cost: ¥600,000); Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: schizophrenia / treatment-resistant / model for pathophysiology / prefrontal cortex / psychostimulant

Research Abstract

We can use an NMDA receptor dysfunction model for the treatment-resistant schizophrenia, and methamphetamine model for the treatment-responsive model for schizophrenia. We hypothesized that increased glutamate levels in the medial prefrontal cortex(mPFC) and the nucleus accumbens(NA) induced by high dose of methamphetamine play an important role for the development of behavioral cross-sensitization to an NMDA receptor antagonist. We have shown that a protein kinase C inhibitor, staurosporine and a GABA stimulant, valproate block the development of the cross-sensitization to dizocilpine. Valproate and olanzapine potently, and risperidone moderately inhibited high dose of methamphetamine-induced delayed increases in glutamate levels in the mPFC and the NA.
These findings suggest that valproate, olanzapine, and risperidone may block the development of the treatment-resistance of schizophrenia.

Research Products

• [Journal Article] Valproate blocks high-dose methamphetamine-induced behavioral cross-sensitization to locomotion-inducing effect of dizocilpine(MK-801), but not methamphetamine (2006)
  • Author(s): Ito K, Abekawa T, Koyama T
  • Journal Title: Psychopharmacology (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 「研究成果報告書概要(和文)」より (2006)
  • Author(s): Ito K, Abekawa T, Koyama T
  • Journal Title: Psychopharmacology (In press)
• [Journal Article] Valproate blocks high-dose methamphetamine-induced behavioral cross-sensitization to dizocilpine(MK-801), but not methamphetamine (2006)
  • Author(s): Ito K, Abekawa T, Koyama T
  • Journal Title: Psychopharmacology (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Relationship between the development of cross-sensitization to MK-801 and a high dose of methamphetamine-induces delay increases in glutamate levels in the nucleus accumbes (2006)
  • Author(s): Ito K, Abekawa T, Koyama T
  • Journal Title: Psychopharmacology (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Tougou shicchoushou no Shinkeihattatsushougai, Byoutaishinnkou to Kouseishinbyouyaku (2006)
  • Author(s): Abekawa T, Ito K, Koyama T
  • Journal Title: Bunshi seishinigaku 6 Pages: 28-36
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Valproate blocks high dose methamphetamine-induced behavioral cross-sensitization to locomotion-inducing effect of dizocilpine(MK-801), but not methamphetamine. (2006)
  • Author(s): Ito K, Abekawa T, Koyama T
  • Journal Title: Psychopharmacology On-line(In press)
• [Journal Article] 統合失調症の神経発達障害、病態進行と抗精神病薬 (2006)
  • Author(s): 安部川智浩, 伊藤侯輝, 小山 司
  • Journal Title: 分子精神医学 6 Pages: 28-36
• [Journal Article] <統合失調症研究の最前線>分子生物学 (2006)
  • Author(s): 安部川智浩, 伊藤侯輝, 小山 司
  • Journal Title: カレントテラピー (印刷中)
• [Journal Article] Effect of the protein kinase C inhibitor, staurosporine, on the high dose of methamphetamine-induced behavioral sensitization to MK-801 (2005)
  • Author(s): Fang YR, Abedkawa T, Li XB, Wang ZC, Inoue T, Koyama T
  • Journal Title: Psychopharmacology 180 Pages: 100-106
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 統合失調症の神経発達障害、病態進行と抗精神病薬 (2005)
  • Author(s): 安部川智浩, 伊藤侯輝, 小山司
  • Journal Title: 分子精神医学 6巻 Pages: 28-36
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of the protein kinase C inhibitor, staurosporine, on the high dose of methamphetamine-induced behavioral sensitization to MK-801. (2005)
  • Author(s): Fang YR, Abekawa T, LiXB, Wang ZC, Inoue T, Koyama T
  • Journal Title: Psychopharmacology 180 Pages: 100-106
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 統合失調症の病因病態仮説と治療戦略 (2005)
  • Author(s): 安部川智浩, 伊藤侯輝, 小山 司
  • Journal Title: 総合臨床 54 Pages: 3018-3022
• [Journal Article] Effect of the protein kinase C inhibitor, staurosporine, on the high dose of methamphetamine-induced behavioral sensitization to MK-801 (2005)
  • Author(s): Fang YR, Abekawa T, Li XB, Wang ZC, Inoue T, Koyama T
  • Journal Title: Psychopharmacology On-line(In press)
• [Journal Article] 「統合失調症の警告期状態」に対する非定型抗精神病薬の使用経験 (2004)
  • Author(s): 安部川智浩, 北市雄士, 松山哲晃, 小山司
  • Journal Title: 精神神経学雑誌 106巻11号 Pages: 1357-1372
  • NAID: 10018962562
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Treatment of The Premonitary State of Schizophrenia with atypical antipsychotics (2004)
  • Author(s): Abekawa T, Kitaichi Y, Matsuyama T, Koyama T
  • Journal Title: Seisin Shinkeigaku Zassi Vol 106(11) Pages: 1357-1372
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] "Tougoushicchoushou no Keikokukijyoutai" ni taisuru Hiteikeikouseihinnbyouyaku no Shiyoukeikenn (2004)
  • Author(s): Abekawa T, Kitaichi Y, Matsuyama T, Koyama T
  • Journal Title: Seishinn shinkeigaku-zasshi 106 Pages: 1357-1372
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gyakutaisei genshou to Koufunsei aminosannshinnkeidenntatsu (2004)
  • Author(s): Koyama T, Abekawa T, Honda M, Ito K
  • Journal Title: Kakuseizai seishinnbyou to Mayakuizonn Pages: 68-78
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Selective serotonin reuptake inhibitor reduces conditioned fear through its effect in the amygdala (2004)
  • Author(s): Inoue T, Li XB, Abekawa T, Kitaichi Y, Izumi T, Nakagawa S, Koyama T
  • Journal Title: Eur J Pharmacology 497 Pages: 311-316
• [Journal Article] Effect of MS-153 on the acquisition and expression of conditioned fear in rats (2004)
  • Author(s): Li XB, Inoue T, Abekawa T, Fang YR, Koyama T
  • Journal Title: Eur J Pharmacology 505 Pages: 145-149
• [Journal Article] 「統合失調症の警告期状態」に対する非定型抗精神病薬の使用経験 (2004)
  • Author(s): 安部川 智浩, 北市 雄士, 松山 哲晃, 小山 司
  • Journal Title: 精神神経学雑誌 106 Pages: 1357-1372
  • NAID: 10018962562
• [Journal Article] 統合失調症の病態モデルと治療メカニズム -治療抵抗性モデルと治療メカニズム (2004)
  • Author(s): 安部川 智浩, 伊藤 侯輝, 小山 司
  • Journal Title: Schizophrenia Frontier 5 Pages: 37-43
• [Journal Article] 治療抵抗性分裂病への対処 薬物療法-Clozapine (2004)
  • Author(s): 久住 一郎, 小山 司
  • Journal Title: Schizophrenia Frontier 4 Pages: 13-18
• [Journal Article] Effect of NRA0045, a novel potent antagonist at dopamine D_4, 5-HT_<2A>, and α1 adrenalin receptors, and NRA10160, a selectiveD_4 receptor antagonist, on phencyclidine-induced behavior and glutamate release in rats (2003)
  • Author(s): Abekawa T, Honda M, Ito K, Koyama T
  • Journal Title: Psychopharmacology 169 Pages: 247-256
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 統合失調症/専門医の管理・治療が必要な疾患のガイドライン (2006)
  • Author(s): 安部川智浩, 小山 司
  • Publisher: 日経メディカル開発(印刷中)
• [Book] 覚醒剤精神病と麻薬依存 (2004)
  • Author(s): 小山司, 安部川智浩, 本田稔, 伊藤耕一
  • Publisher: 逆耐性現象と興奮性アミノ酸神経伝達
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 精神科 (2004)
  • Author(s): 豊巻 敦人, 久住 一郎, 小山 司
  • Publisher: 前部帯状皮質下位領域と精神疾患
• [Publications] Abekawa T., Honda M., Ito K., Koyama T.: "Effects of NRA0045, a novel potent antagonist at dopamine D4,5-HT2A, and alpha1 adrenaline receptors and a selective D4 dopamine rece antagonist, on phencyclidine-induced behavior and glutamate release in rats"Psychopharmacology. 169. 247-256 (2003)