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The Role of Central Purin, Benzodiazepine and GABA Systems on Development of Tolerance and Reverse Tolerance to Dopamine-Mimetic Drugs.

Research Project

Project/Area Number 01570608
Research Category

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

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

Principal Investigator

MIZUKI Yasushi  Department of Neuropsychiatry, Yamaguchi University School of Medicine, 医学部, 助教授 (00080721)

Co-Investigator(Kenkyū-buntansha) YAMADA Michio  Department of Neuropsychiatry, Yamaguchi University School of Medicine, 医学部, 教授 (00034942)
USHIJIMA Itsuko  Department of Neuropsychiatry, Yamaguchi University School of Medicine, 医学部, 助手 (30168679)
Project Period (FY) 1989 – 1990
Project Status Completed (Fiscal Year 1990)
Budget Amount *help
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1990: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1989: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsTolerance / Reverse tolerance / Apomorphine / Methamphetamine / Haloperidol / Adenosine / Benzodiazepine / GABA / 薬物耐性現象
Research Abstract

Chronic exposure to neuroleptics frequently results in the development of tolerance, that is, a decrease in responsiveness to a drug or shift to the right of the dose-response curve. In contrast to tolerance, as result of chronic treatment with Dopamine (DA) Agonists, is the phenomenon of reverse tolerance, which is an increase in responsiveness or sift to the left of the dose-response curve.
When mice were given once a day of haloperidol for 18 days and challenged with beta-DMCM (benzodiazepine (BDZ) antagonist or inverse agonist), caffeine (adenosine antagonist), picrotoxin (Cl^-channel blocker) or bicuculline (GABAa antagonist) after 1 and 2 days withdrawal, only the threshold of beta-DMCM-induced tonic convulsion was lowered. The beta-DMCM convulsion on 2 days withdrawal was reversed by diazepam (BDZ agonist) and Ro15-1788 (BDZ antagonist or partially agonist). In this case, Ro15-1788 and beta-DMCM contributed to BDZ system as an agonist and an antagonist, respectively. There is a d … More irect interaction between DA and BDZ systems but is not between DA and GABA neurons, in development of lowering seizure threshold following chronic haloperidol.
Chronic haloperidol produced an inhibition of haloperidol catarepsy response, which results in an activation of postsynaptic DA D-2 receptors. The inhibitory effect was reversed by N^6-cyclohexyl adenosine (adenosine agonist), diazepam, beta-DMCM and muscimol (GABAa agonist). In striking contrast to beta-DMCM convulsion, Ro15-1788 and beta-DMCM responded as an antagonist and an agonist, respectively, in haloperidol catarepsy. These results suggest that central inhibitory systems seem to function as regulator to DA neurons in development of tolerance.
Withdrawal from chronic apomorphine (DA receptor agonist) exerted different effects from control in high dose of apomorphine-induced stereotyped behaviors, i. e., increase of sniffing (reverse tolerance) and decrease of licking and biting (tolerance). BDZ-mimetic drugs exerted differential effects to respective stereotyped behaviors. Multifocal site of action may be involved in BDZ-DA neuronal interaction in development of tolerance, to DA antagonist and reverse tolerance to DA agonist. Withdrawal apomorphine exerted inhibition of apomorphineinduced yawning, which causes in an inhibition of presynsptic DA D-2 receptor, whereas haloperidol catarepsy mediated by postsynsptic D-2 receptor activity was unaffected. Withdrawal methamphtamine produced activation of presynaptic DA D-2 receptors and inhibition of postsynaptic D-2 receptors, i. e., stimulation of both apomorphine yawning and haloperidol catarepsy responses. Less

Report

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

    (8 results)

All Other

All Publications (8 results)

  • [Publications] 稲野 秀、牛島 逸子、水木 泰、山田 通夫: "Caffeine痙攣に対するbenzodiazepine,GABAおよびNMDA系薬物の影響" 日本神経精神薬理学会誌に投稿予定.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 関本 正規、牛島 逸子、水木 泰、山田 通夫: "Haloperidolの反復投与によって生じる痙攣いき値低下に対する中枢の抑制性機構の関与について" 日本神経精神薬理学会誌に投稿予定.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 浮田 孟、牛島 逸子、水木 泰、山田 通夫: "Haloperidol反復投与による中枢ド-パミン性神経活動の変化と抑制性機構:カタレプシ-反応および常同行動を指標にして" 日本神経精神薬理学会誌に投稿予定.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 峰松 則夫、牛島 逸子、水木 泰、山田 通夫: "Apomorphineの反復投与によって生ずる常同行動の抑制および増強作用と中枢の抑制性機構:Methamphetamineとの比較" 日本神経精神薬理学会誌に投稿予定.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 稲野 秀、牛島 逸子、水木 泰、山田 通夫: "Caffeine痙攣に対するbenzodiazepine,GABAおよびNMDA系薬物の影響" 日本神経精神薬理学会誌.

    • Related Report
      1990 Annual Research Report
  • [Publications] 関本 正規、牛島 逸子、水木 泰、山田 通夫: "Haloperidolの反復投与によって生じる痙攣いき値低下に対する中枢の抑制性機構の関与について" 日本神経精神薬理学会誌.

    • Related Report
      1990 Annual Research Report
  • [Publications] 浮田 孟、牛島 逸子、水木 泰、山田 通夫: "Halooperidol反復投与による中枢ド-パミン性神経活動の変化と抑制性機構:カタレプシ-反応および常同行動を指標にして" 日本神経精神薬理学会誌.

    • Related Report
      1990 Annual Research Report
  • [Publications] 峰松 則夫、牛島 逸子、水木 泰、山田 通夫: "Apomorphineの反復投与によって生ずる常同行動の抑制のおよび増強作用と中枢の抑制性機構:Methamphetamineとの比較" 日本神経精神薬理学会誌.

    • Related Report
      1990 Annual Research Report

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

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