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Animal Model of Neuroleptic Malignant Syndrome

Research Project

Project/Area Number 01570598
Research Category

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

Allocation TypeSingle-year Grants
Research Field Psychiatric science
Research InstitutionHokkaido University

Principal Investigator

KOYAMA Tsukasa  Hokkaido University School of Medicine, Associate Professor, 医学部, 助教授 (10113557)

Co-Investigator(Kenkyū-buntansha) MATSUBARA Shigehiro  Hokkaido University School of Medicine, Instructor, 医学部, 助手 (40142731)
YAMASHITA Itaru  Hokkaido University School of Medicine, Professor, 医学部, 教授 (60000923)
Project Period (FY) 1989 – 1990
Project Status Completed (Fiscal Year 1990)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1990: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1989: ¥1,400,000 (Direct Cost: ¥1,400,000)
KeywordsNeuroleptic malignant syndrome / Animal model / Fawn-Hooded rat / Dantrolene / FawnーHooded系ラット
Research Abstract

Although the neuroleptic malignant syndrome(NMS) is a potentially lethal consepuence of treatment with potent neuroleptics, the underlying pathogenetic mechanisms remain unclear. This presentation summarized the animal model of NMS which we develope13EA\ : d. We observed hyperthermia (up to 42゚C). rigidity, autonomic instability, and elevated CPK (up to 4,000mU/ml) only in Fawn-Hooded (FH) rats but not in Sprague-Dawley (SD) rats, by the combined treatment with pargyline and tryptophan. Nearly 100% of13EA\ : FH rats receiving this combined treatment died within 12 hrs. These effects in FH rats were potentiated by pretreatment with haloperidol, which is a potent dopamine D_2 receptor blocker. Moreover, pretreatment with dantrolene, which has been repor13EA\ : ted to reverse the symtoms of NMS, prevented the occurrence of hyperthermia or elevated CPK in FH rats. The investigation about neurochemical characteristics of FH rats.
The investigation about neurochemical characteristics of FH ra … More ts clarified the accelerated turnover of serotonin(5-HT) in N.hypothalamicus ant., with no changes noted in the dopamine turnover in comparison with SD rats. In addition, we observed a s13EA\ : ignificant enhancement of 5-MeODMT-induced hyperthermia and quipazine-induced "wet dog" shakes, which indicates the hypersensitivity of 5-HT_2 receptor, in FH rats. In the receptor binding assay, There was no differrence between FH and SD rats in B13EA\ : max or Kd values for [^3H]5-HT, [^3H] ketanserin or [H_3] paroxetine binding in the cerebral cortex or hippocampus and [^3H]SCH23390, [^3H] spiperone or [^3H]GBR12935 binding in the striatum. Dantrolene treatment resulted in no change of 5-HT synthesis in the terminal regions of various serotonergic neurons. However, dantrolene pretreatment prevented significatly 5-MeODMT-induced hyperthermia or guipazine-induced "wet dog" shakes in a dose dependent manner.
These resutlts suggest that symptomes and laboratory findings of animal model of NMS may result from excessive release of calcium into 5-HT_2 receptor or sketetal muscle cytoplasm due to defective membrane regulation and transport of calcium in the13EA\ : presence of exaggerated serotonergic stimulation.
Dantrolene treatment may interfere with excitation-contraction coupling in sketletal muscle, or 5-HT receptor-mediated hyperthermia, perhaps by decreasing the amount of calcium released. These effects may be related, in part, to the therapeutic effi13EA\ : cacy of dantrolene for elevated CPK or hyperthermia in animal model of NMS. Less

Report

(3 results)
  • 1990 Annual Research Report   Final Research Report Summary
  • 1989 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] 小山 司: "悪性症候群の病態と治療に関する実験的研究:病態モデル動物の作成" 神経化学. 27. 308-309 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 小山 司: "悪性症候群の病態と治療に関する実験的研究:脳内アミン代謝に対するdantrolene投与の影響" 薬物・精神・行動. 9. 136- (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 小山 司: "悪性症候群の病態と治療に関する実験的研究:高熱反応と5-HT_2受容体との関連について" 薬物・精神・行動. 10. 242- (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 阿部 全人子: "悪性症候群の病態と治療に関する実験的研究 Fawn-Hooded系ラットの5-HT_2受容体関連機能および行動について" 薬物・精神・行動. 10. 243- (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 小山 司: "悪性症候群の病態モデル" 脳と精神の医学. 投稿中.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Koyama T.: "Animal model of neuroleptic malignant syndrome" Jap.J.Psychiat and Neural.in press.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tsukasa Koyama: "Study on Pathophysiology and Treatment of Neuroleptic Malignant Syndrome : Animal Model of Neuroleptic Malignant Symdrome" Bulletin of the Japanese Neurochemical Society. 27. 308-309 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tsukasa Koyama: "Study on Pathophysiology and Treatment of Neuroleptic Malignant Syndrome : Effect of Dantrolene treatment on monoamine metabolism in various brain reagions" Japanese Journal of Psychopharmacology. 9. 136 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tsukasa Koyama: "Study on Pathophysiology and Treatment of Neuroleptic Malignant Syndrome : Hyperthermia might be mediated via 5-HT_2 receptor" Japanese Journal of Psychopharmacology. 10. 242 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Michiko Abe: "Study on Pathophysiology and Treatment of Neuroleptic Malignant Syndrome : 5-HT_2 receptor-mediated thermoregulation and behavior in Fawn-Hooded rat" Japanese Journal of Psychopharmacology. 10. 243 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tsukasa Koyama: "Animal mode of neuroleptic malognant syndrome" Brain Science and mental Disorders. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tsukasa Koyama: "Animal model of neruoleptic malignant syndrome" Jap.J.Psychiat. and Neural.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 小山 司: "悪性症候群の病態と治療に関する実験的研究:病態モデル動物の作成" 神経化学. 27. 308-309 (1988)

    • Related Report
      1990 Annual Research Report
  • [Publications] 小山 司: "悪性症候群の病態と治療に関する実験的研究:脳内アミン代謝に対するdantrolene投与の影響" 薬物・精神・行動. 9. 136 (1989)

    • Related Report
      1990 Annual Research Report
  • [Publications] 小山 司: "悪性症候群の病態と治療に関する実験的研究:高熱反応と5ーHT_2受容体との関連について" 薬物・精神・行動. 10. 242 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 阿部 全人子: "悪性症候群の病態と治療に関する実験的研究FawnーHooded系ラットの5ーHT_2受容体関連機能および行動について" 薬物・精神・行動. 10. 243 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] 小山 司: "悪性症候群の病態モデル" 脳と精神の医学.

    • Related Report
      1990 Annual Research Report
  • [Publications] Koyama T.: "Animal model of neuroleptic malignant syndrome" Jap.J.Psychiat and Neural.

    • Related Report
      1990 Annual Research Report
  • [Publications] 小山司: "悪性症候群の病態と治療に関する実験的研究:病態モデル動物の作成" 神経化学. 27. 308-309 (1988)

    • Related Report
      1989 Annual Research Report

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Published: 1989-04-01   Modified: 2016-04-21  

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