DOPAMINE D2 RECEPTORS IN PRIMATE MODELS OF COCAINE ABUSE

可卡因滥用灵长类动物模型中的多巴胺 D2 受体

• 批准号: 6097429
• 负责人: Michael A Nader
• 金额: $ 32.63万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6097429
• 关键词: Macaca mulatta; cocaine; craving; disease /disorder model; dopamine antagonists; dopamine receptor; drug abuse; psychological reinforcement; psychopharmacology; receptor expression; substance abuse related behavior

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.

对动物的研究表明，多巴胺（DA）受体介导了coaine的许多行为效应。 在DA系统内，存在两个受体家族，D1和D2，主要基于不同的解剖定位和功能机制。临床前研究已经表明，D2样拮抗剂可以减少可卡因自我给药，但通常仅在减少其他强化行为的剂量下。在D2家族中，分子克隆技术已经鉴定出三种受体亚型，称为D2、D3和D4。 由于大鼠腹侧纹状体中D3和D4受体mRNA的相对表达显著低于D2受体mRNA的相对表达，因此我们假设优先阻断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中研究新合成的对D2、D3和D4受体具有选择性的化合物如何改变可卡因在几种药物滥用动物模型中的作用。 本研究的具体目的是在猴中评价DA选择性拮抗剂对以下方面的影响：（1）可卡因的辨别刺激效应。 我们假设，D3-选择性拮抗剂将是最有效的衰减可卡因的刺激作用;（2）可卡因的增强作用时，响应是保持在一个多个固定间隔（FI）的时间表的食物和可卡因介绍。 根据FI时间表，可卡因摄入量和应答率相对独立。 我们假设D3选择性拮抗剂在降低可卡因摄入量方面相对于应答率更有效，并且对可卡因与食物维持应答更具选择性;以及（3）可卡因诱导的恢复。 我们假设，D3选择性拮抗剂将是最有效的衰减可卡因的能力，恢复“药物寻求”。 当完成时，来自本申请的结果将提供关于D2、D3和D4拮抗剂选择性降低可卡因的增强和辨别刺激作用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。