DOPAMINE D2 RECEPTORS IN PRIMATE MODELS OF COCAINE ABUSE

对动物的研究表明，多巴胺(DA)受体介导了可卡因的许多行为效应。在DA系统中，有两个受体家族，即D1和D2，主要基于不同的解剖定位和作用机制。临床前研究表明，D2样拮抗剂可以减少可卡因的自我给药，但通常只有在减少其他强化行为的剂量时。在D2家族中，分子克隆技术已经确定了三种受体亚型，分别为D2、D3和D4。由于D3和D4受体在大鼠腹侧纹状体的相对表达明显低于D2受体的相对表达，我们推测优先阻断D3和/或D4受体可能导致选择性拮抗可卡因的增强作用，而主要作用于D2受体的拮抗剂也可能导致锥体外系副作用。这些研究的总体目标是在恒河猴身上检验新合成的选择性D2、D3和D4受体的化合物如何在几种药物滥用的动物模型中改变可卡因的效果。这项建议的具体目的是在猴子身上评估DA选择性拮抗剂对以下方面的影响：(1)可卡因的歧视性刺激效应。我们假设D3选择性拮抗剂在减弱可卡因的刺激效应方面将是最有效的；(2)可卡因在反应时的强化效应在食物和可卡因呈现的多个固定间隔(FI)时间表下保持。在FI时间表下，可卡因摄入量和应答率相对独立。我们假设，与反应率相比，D3选择性拮抗剂在减少可卡因摄入量方面更有效，对可卡因的选择性比食物维持的反应更高；以及(3)可卡因诱导的恢复。我们推测，D3选择性拮抗剂将最有效地减弱可卡因恢复“寻求药物”的能力。完成后，本申请的结果将提供有关D2、D3和D4拮抗剂选择性地减少可卡因的增强和区别性刺激效应的能力的临床相关信息。这些知识对于了解可卡因的神经药理学和开发有效的可卡因滥用药物疗法至关重要。

Research with animals has shown that dopamine (DA) receptors mediate many of coaine's behavioral effects. Within the DA system there are two receptor families, D1 and D2, based mainly upon different anatomical localization and functional mechanisms. Preclinical studies have shown that D2-like antagonists can decrease cocaine self- administration, but typically only at doses that decrease other reinforced behaviors. Within the D2 family, molecular cloning techniques have identified three receptor subtypes, termed D2, D3 and D4. Because the relative expression of D3 and D4 receptor mRNA in rat ventral striatum is significantly less than that for D2 receptor mRNA, we hypothesize that preferential blockade of D3 and/or D4 receptors may lead to selective antagonism of cocaine's reinforcing effects, whereas antagonists acting primarily at D2 receptors are also likely to result in extrapyramidal side effects. The overall goal of these studies is to examine, in rhesus monkeys, how newly synthesized compounds selective for D2, D3 and D4 receptors modify cocaine's effects in several animal models of drug abuse. The Specific Aims of this proposal are to evaluate, in monkeys, the effects of DA-selective antagonists on: (1) cocaine's discriminative stimulus effects. We hypothesize that D3-selective antagonists will be the most effective at attenuating cocaine's stimulus effects; (2) cocaine's reinforcing effects when responding is maintained under a multiple fixed-interval (FI) schedule of food and cocaine presentation. Under the FI schedule, cocaine intake and response rates are relatively independent. We hypothesize that D3-selective antagonists will be more potent at decreasing cocaine intake relative to response rates and will be more selective on cocaine vs. food-maintained responding; and (3) cocaine-induced reinstatement. We hypothesize that D3-selective antagonists will be most effective at attenuating cocaine's ability to reinstate "drug seeking". When complete, results from the present application will provide clinically relevant information regarding the ability of D2, D3 and D4 antagonists to selectively decrease the reinforcing and discriminative stimulus effects of cocaine. Such knowledge will be vital for understanding the neuropharmacology of cocaine and to the development of effective pharmacotherapies for cocaine abuse.