Chronic Stress and Vulnerability to Cocaine Abuse in Female Monkeys

描述(由申请人提供)：药物滥用仍然是世界范围内的一个主要公共卫生问题，估计有160万美国人确认目前正在使用可卡因。有证据表明，在可卡因滥用的易感性方面存在性别差异，尽管研究中男性的比例不成比例。这项研究项目是资助工作的继续，旨在了解在一种独特的非人类灵长类动物模型中滥用可卡因的神经生物学：社交寄养雌性猴子的静脉注射可卡因自我管理。我们已经成功地将灵长类社会行为的研究与静脉给药和非侵入性脑成像程序正电子发射断层扫描(PET)相结合，以研究环境和药物变量如何影响可卡因的行为和增强效应。具体目标1将研究长期服用可卡因对多巴胺(DA)D2/D3受体和DA转运体(DAT)的影响，这两个系统在男性身上表现得很好，但在女性身上没有。具体目标2将审查严重的社会压力是否作为社会等级的一种功能而不同地影响可卡因的自我管理，以及主导和从属女性是否对慢性药物治疗做出类似的反应。最后，在具体目标3中，我们将结合环境浓缩和慢性药物治疗，努力降低可卡因在优势和从属猴子身上的强化强度。我们假设个体差异，基于社会等级导致的D2/D3和DAT可获得性的差异，以应对环境挑战和药物治疗。多年来在雌性猴子身上研究的社会等级和PET成像的结合，将允许更好地理解社会背景和DA受体功能之间的相互作用，这将是开发行为和药物治疗策略的关键。 公共卫生相关性：易受药物滥用影响的个体差异是人类吸毒成瘾的一个标志。这些研究将进一步探讨与群居雌性猴子滥用药物的病因和维持有关的因素，这将有助于开发新的治疗策略。

DESCRIPTION (provided by applicant): Drug abuse continues to be a major public health problem worldwide, with an estimated 1.6 million Americans confirming current cocaine use. There is evidence of sex differences in vulnerability to cocaine abuse, although males are disproportionately represented in research. This research project is a continuation of funded work aimed at understanding the neurobiology of cocaine abuse in a unique nonhuman primate model: intravenous cocaine self-administration in socially housed female monkeys. We have successfully combined the study of primate social behavior with intravenous drug self-administration and the noninvasive brain imaging procedure positron emission tomography (PET) to examine how environmental and pharmacological variables influence the behavioral and reinforcing effects of cocaine. Specific Aim 1 will examine the effects of chronic cocaine self-administration on dopamine (DA) D2/D3 receptors and DA transporters (DAT), brain systems that have been well characterized in males, but not females. Specific Aim 2 will examine whether acute social stress differentially affects cocaine self- administration as a function of social rank and whether dominant and subordinate females respond similarly to chronic drug treatment. Finally, in Specific Aim 3, we will combine environmental enrichment and chronic drug treatment in an effort to decrease the reinforcing strength of cocaine in dominant and subordinate monkeys. We hypothesize individual differences, based on social rank-induced differences in D2/D3 and DAT availability, in response to environmental challenges and drug treatments. The combination of social rank and PET imaging studied over years, in female monkeys, will allow for a better understanding of the interactions between social context and DA receptor function, which will be critical to developing behavioral and pharmacological treatment strategies. PUBLIC HEALTH RELEVANCE: Individual differences in vulnerability to drug abuse is a hallmark of human drug addiction. These studies will further explore factors related to etiology and maintenance of drug abuse in socially housed female monkeys, which should aid in the development of novel treatment strategies.