Cocaine discrimination, self-administration and microdialysis in monkeys

猴子可卡因歧视、自我给药和微透析

• 批准号: 7663240
• 负责人: Paul W. Czoty
• 金额: $ 29.01万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663240
• 关键词: Address; Agonist; Animal Model; Animals; Attenuated; Behavioral; Behavioral Research; Brain; Cocaine; Cocaine Abuse; Cocaine Dependence; Conflict (Psychology); Corpus striatum structure; Data; Development; Discrimination; Dopamine; Dopamine Agonists; Dopamine Receptor; Dose; Drug Addiction; Drug Interactions; Drug abuse; Goals; Human; Injection of therapeutic agent; Knowledge; Laboratory Animals; Lead; Macaca mulatta; Measures; Mediating; Microdialysis; Monkeys; Moods; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Play; Procedures; Production; Research; Research Personnel; Role; Saline; Schedule; Self Administration; Self-Administered; Serotonin; Stimulus; Techniques; Training; Translating; Ventral Striatum; design; dopamine transporter; drug discrimination; experience; extracellular; human subject; inhibitor/antagonist; innovation; monoamine; neurobiological mechanism; neurochemistry; nonhuman primate; novel; programs; psychostimulant; receptor; response; uptake

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.

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发挥着重要作用，但对人类的研究表明，药物的辨别刺激（SD）和强化（SR）效应之间不完全重叠。此外，由于对多巴胺 (DA)、血清素 (5-HT) 和去甲肾上腺素 (NE) 在这些作用中的确切作用缺乏清晰的了解，阻碍了开发可卡因依赖药物的努力。本提案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，恒河猴将接受训练以区分注射 0.1 毫克/千克可卡因和盐水，并有机会在区分部分后立即按照二级时间表自行注射 0.1 毫克/千克可卡因。使用此程序，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，包括刺激 D1 和 D2 样 DA 受体功效不同的直接激动剂（具体目标 1）。为了表征可卡因产生这些滥用相关效应所涉及的神经化学机制的重叠程度，平行微透析研究将在选定剂量的辨别和自我给药成分期间测量腹侧纹状体的细胞外 DA（具体目标 2）。 5-HT 和 NE 调节可卡因行为影响的机制将在随后的行为和微透析研究（具体目标 3）中进行检查，这些研究表征 5-HT 和 NE 间接和直接激动剂对 SD、SR 和神经化学物质的影响可卡因的影响。通过评估同一只猴子的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）更清楚地阐明参与滥用产生的多巴胺能机制。 （3）提供药理学和神经化学机制的独特特征，这将有助于开发针对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，以帮助开发有效治疗可卡因成瘾的药物，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。