Cocaine discrimination, self-administration and microdialysis in monkeys

描述（由申请人提供）：虽然可卡因的主观效应被认为在可卡因滥用中起重要作用，但人体研究显示，药物的辨别刺激（SD）和强化（SR）效应之间存在不完全重叠。此外，对多巴胺（DA）、5-羟色胺（5-HT）和去甲肾上腺素（NE）在这些作用中的确切作用缺乏明确的认识，阻碍了开发可卡因依赖药物的努力。本提案中研究的总体目标是更好地了解可卡因的SD和SR效应之间的关系，并更好地阐明这些效应背后的药理学和神经化学机制。为了实现这些目标，将训练恒河猴区分0.1 mg/kg可卡因与生理盐水的反应视情况注射，并有机会在区分部分之后立即按照二阶时间表自我给予0.1 mg/kg可卡因。使用该程序，将表征一系列剂量的可卡因、其他间接和直接DA受体激动剂的作用，包括在刺激D1-和D2-样DA受体方面功效不同的直接激动剂（具体目标1）。为了表征可卡因这些滥用相关效应产生中涉及的神经化学机制的重叠程度，平行微透析研究将测量选定剂量的辨别和自我给药组分期间腹侧纹状体中的细胞外DA（具体目标2）。5-HT和NE可调节可卡因的行为效应的机制将在随后的行为和微透析研究（特定目标3）中进行检查，这些研究表征了5-HT和NE间接和直接激动剂对可卡因的SD、SR和神经化学效应的影响。通过评估同一只猴子在行为会话中的行为和神经化学作用，这些创新研究将：（1）更好地描述SD效应对自我给药的重要性，（2）更清楚地阐明涉及可卡因滥用相关效应产生的多巴胺能机制，和（3）提供药理学和神经化学机制的独特表征，其将有助于开发用于可卡因依赖的有效药物疗法。相关性：拟议的研究将提供有关可卡因成瘾作用产生的神经生物学机制的独特信息。重要的是，这些结果将提供新的信息，以帮助开发有效的可卡因成瘾药物，并将增强我们对药物成瘾动物模型中收集的数据的理解和解释。

DESCRIPTION (provided by applicant): Although the subjective effects of cocaine are understood to play an important role in cocaine abuse, studies in humans have revealed an incomplete overlap between discriminative stimulus (SD) and reinforcing (SR) effects of drugs. Moreover, the lack of a clear understanding of the precise roles of dopamine (DA), serotonin (5-HT) and norepinepherine (NE) in these effects has hindered efforts to develop medications for cocaine dependence. The overarching goals of the research in this proposal are to gain a better understanding of the relationship between the SD and SR effects of cocaine and to better elucidate the pharmacological and neurochemical mechanisms that underlie these effects. To accomplish these aims, rhesus monkeys will be trained to discriminate a response-contingent injection of 0.1 mg/kg cocaine from saline, with an opportunity to self-administer 0.1 mg/kg cocaine under a second-order schedule immediately following the discrimination component. Using this procedure, the effects of a range of doses of cocaine, other indirect and direct DA receptor agonists will be characterized, including direct agonists that differ in efficacy at stimulating D1- and D2-like DA receptors (Specific Aim 1). To characterize the extent of overlap of the neurochemical mechanisms involved in production of these abuse-related effects of cocaine, parallel microdialysis studies will measure extracellular DA in the ventral striatum during discrimination and self- administration components of selected doses (Specific Aim 2). Mechanisms by which 5-HT and NE can modulate the behavioral effects of cocaine will be examined in subsequent behavioral and microdialysis studies (Specific Aim 3) that characterize the effects of 5-HT and NE indirect and direct agonists on the SD, SR and neurochemical effects of cocaine. By assessing behavioral and neurochemical effects within a behavioral session in the same monkeys, these innovative studies will: (1) better describe the importance of SD effects to self-administration, (2) more clearly elucidate dopaminergic mechanisms involved in production of the abuse-related effects of cocaine, and (3) provide a unique characterization of pharmacological and neurochemical mechanisms that will aid the development of effective pharmacotherapies for cocaine dependence. Relevance: The proposed studies will provide unique information about the neurobiological mechanisms through which the addictive effects of cocaine are produced. Importantly, the results will provide novel information to aid efforts to develop effective medications for cocaine addiction, and will enhance our understanding and interpretation of data collected in animal models of drug addiction.