Cocaine discrimination, self-administration and microdialysis in monkeys

描述(申请人提供)：尽管可卡因的主观影响被认为在可卡因滥用中起着重要作用，但对人类的研究表明，药物的歧视性刺激(SD)和强化(SR)效应之间存在不完全的重叠。此外，对多巴胺(DA)、5-羟色胺(5-HT)和去甲肾上腺素(NE)在这些效应中的确切作用缺乏明确的了解，这阻碍了开发治疗可卡因依赖的药物的努力。这项研究的首要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，将训练恒河猴区分注射0.1毫克/公斤可卡因和生理盐水的反应，并有机会在识别部分之后的第二级时间表下立即自我注射0.1毫克/公斤可卡因。利用这一程序，将表征一系列剂量的可卡因和其他间接和直接DA受体激动剂的效果，包括在刺激D_1和D_2样多巴胺受体(特定目标1)方面效果不同的直接激动剂。为了确定产生这些与滥用可卡因有关的影响的神经化学机制的重叠程度，平行的微透析研究将测量辨别过程中腹侧纹状体的细胞外多巴胺和选定剂量的自我给药成分(具体目标2)。5-羟色胺和去甲肾上腺素调节可卡因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，以表征5-羟色胺和去甲肾上腺素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。通过评估同一猴子在行为过程中的行为和神经化学效应，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)更清楚地阐明与可卡因滥用相关效应的产生所涉及的多巴胺能机制，以及(3)提供有助于开发有效的可卡因依赖药物疗法的独特的药理学和神经化学机制的特征。相关性：拟议的研究将提供关于产生可卡因成瘾效应的神经生物学机制的独特信息。重要的是，这些结果将为帮助开发有效的可卡因成瘾药物的努力提供新的信息，并将加强我们对在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.