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 万美国人确认目前使用可卡因。有证据表明，可卡因滥用的脆弱性存在性别差异，尽管研究中男性所占比例过高。该研究项目是资助工作的延续，旨在了解独特的非人类灵长类动物模型中可卡因滥用的神经生物学：社会饲养的雌性猴子静脉注射可卡因自我给药。我们成功地将灵长类动物社会行为研究与静脉注射药物自我给药和无创脑成像程序正电子发射断层扫描（PET）结合起来，以研究环境和药理学变量如何影响可卡因的行为和强化效果。具体目标 1 将检查长期自我服用可卡因对多巴胺 (DA) D2/D3 受体和 DA 转运蛋白 (DAT) 的影响，这些大脑系统已在男性而非女性中得到了很好的表征。具体目标 2 将研究急性社会压力是否会根据社会等级对可卡因自我给药产生不同的影响，以及主导和从属女性对长期药物治疗的反应是否相似。最后，在具体目标3中，我们将结合环境富集和慢性药物治疗，努力降低可卡因对优势猴和从属猴的增强强度。我们根据社会等级引起的 D2/D3 和 DAT 可用性差异来假设个体差异，以应对环境挑战和药物治疗。多年来在雌性猴子中研究的社会等级和 PET 成像相结合，将有助于更好地了解社会背景和 DA 受体功能之间的相互作用，这对于制定行为和药物治疗策略至关重要。 公共卫生相关性：药物滥用脆弱性的个体差异是人类药物成瘾的标志。这些研究将进一步探讨与社会饲养的雌性猴子中药物滥用的病因和维持相关的因素，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.