权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

中心嘌呤、苯二氮卓和 GABA 系统对多巴胺模拟药物耐受性和反向耐受性发展的作用。

基本信息

批准号：
01570608
负责人：
MIZUKI Yasushi
金额：
$ 1.28万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01570608/
关键词：
Tolerance Reverse tolerance Apomorphine Methamphetamine Haloperidol Adenosine Benzodiazepine GABA 薬物耐性現象

项目摘要

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

长期暴露于精神抑制剂经常导致耐受性的发展，即对药物的反应性降低或剂量反应曲线向右移动。与耐受相反，作为多巴胺（DA）激动剂长期治疗的结果，是反向耐受现象，其是反应性的增加或向剂量-反应曲线的左侧移动。（苯二氮卓类（BDZ）拮抗剂或反向激动剂），咖啡因（腺苷拮抗剂），印防己毒素在停药1天和2天后，仅β-DMCM诱导的强直性惊厥阈值降低。地西泮（BDZ激动剂）和Ro 15 -1788（BDZ拮抗剂或部分激动剂）可逆转停药2天后的β-DMCM惊厥。在这种情况下，Ro 15 -1788和beta-DMCM分别作为激动剂和拮抗剂对BDZ系统起作用。有一个维 ...更多信息在慢性氟哌啶醇引起的癫痫发作阈降低过程中，DA和BDZ系统之间存在直接的相互作用，而DA和GABA神经元之间不存在直接的相互作用，慢性氟哌啶醇可抑制氟哌啶醇的癫痫反应，从而激活突触后DA D-2受体。抑制作用被N^6-环己基腺苷（腺苷激动剂）、地西泮、β-DMCM和蝇蕈醇（GABA α激动剂）逆转。与β-DMCM惊厥形成鲜明对比的是，Ro 15 -1788和β-DMCM在氟哌啶醇catarepsy中分别作为拮抗剂和激动剂反应。这些结果表明，中枢抑制系统可能在耐受的形成中起着调节DA神经元的作用，在高剂量阿扑吗啡诱导的刻板行为中，慢性阿扑吗啡戒断与对照组有不同的作用，即：例如，增加嗅闻（反向耐受）和减少舔咬（耐受）。BDZ模拟药物对不同刻板行为的影响不同。BDZ-DA神经元相互作用的多灶性作用部位可能参与了对DA拮抗剂耐受和对DA激动剂逆转耐受的形成。撤药阿扑吗啡可抑制阿扑吗啡引起的哈欠，而抑制阿扑吗啡引起的哈欠是由于合成前DA D-2受体活性的抑制，而不影响合成后D-2受体活性介导的氟哌啶醇诱发的哈欠。撤药后，甲苯丙胺可激活突触前DA D-2受体，抑制突触后D-2受体，即：例如，阿扑吗啡打哈欠和氟哌啶醇catarepsy反应的刺激。少