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

长期接触抗精神病药物通常会导致耐受性的形成，即对药物的反应性降低或剂量-反应曲线右移。与耐受相反，多巴胺(DA)激动剂慢性给药导致的是一种反向耐受现象，即反应性增加或剂量-反应曲线左移。给小鼠每天给一次氟哌啶醇18天，并在停药1天和2天后分别用β-DMCM(苯二氮卓(BDZ)拮抗剂或反向激动剂)、咖啡因(腺苷拮抗剂)、印防己毒素(Cl~+-通道阻滞剂)或荷包牡丹碱(GABAA拮抗剂)激发小鼠强直惊厥的阈值。安定(BDZ激动剂)和Ro15-1788(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，Ro15-1788和β-DMCM分别作为激动剂和拮抗剂对BDZ系统做出贡献。有一个d…慢性氟哌啶醇可抑制氟哌啶醇癫痫发作反应，引起突触后DA D-2受体的激活，而DA和BDZ系统之间的直接相互作用不明显。这种抑制作用可被腺苷激动剂N^6-环己基腺苷、安定、β-DMCM和GABAA激动剂麝香酚逆转。与β-DMCM惊厥形成鲜明对比的是，Ro15-1788和β-DMCM在氟哌啶醇癫痫中分别起拮抗剂和激动剂的作用。这些结果表明，中枢抑制系统似乎对DA神经元的耐受发展起着调节作用。在大剂量阿朴吗啡诱导的刻板行为中，慢性阿朴吗啡(DA受体激动剂)的作用与对照组不同，即嗅觉(反向耐受)增加，舔咬(耐受)减少。BDZ类药物对不同的刻板行为有不同的影响。BDZ-DA神经元之间的相互作用可能参与了BDZ-DA神经元对DA拮抗剂的耐受和对DA激动剂耐受的逆转。戒断阿朴吗啡可抑制阿朴吗啡引起的打哈欠，引起突触前DA D-2受体的抑制，但不影响突触后D-2受体活性介导的氟哌啶醇麻木。戒断甲基苯丙胺可激活突触前DA D-2受体，抑制突触后D-2受体，即刺激阿朴吗啡打哈欠和氟哌啶醇癫痫反应。较少

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