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，对可卡因滥用的易感性存在性别差异，尽管在研究中男性的比例不成比例。本研究项目是资助工作的延续，旨在了解一种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：在群居的雌性猴子中静脉注射可卡因自我给药。我们成功地将灵长类动物的社会行为研究与静脉给药和无创脑成像程序正电子发射断层扫描（PET）结合起来，研究环境和药理学变量如何影响可卡因的行为和强化效应。特异性目标1将检查慢性可卡因自我给药对多巴胺（DA） D2/D3受体和DA转运体（DAT）的影响，这些大脑系统在男性中有很好的特征，但在女性中没有。特异性目标2将检验急性社会压力是否会对可卡因自我给药产生不同的社会等级影响，以及主导女性和从属女性对慢性药物治疗的反应是否相似。最后，在Specific Aim 3中，我们将结合环境富集和慢性药物治疗，努力降低主导和从属猴子对可卡因的强化强度。我们假设个体差异，基于社会等级引起的D2/D3和DAT可用性差异，以响应环境挑战和药物治疗。多年来，对雌性猴子的社会地位和PET成像的研究将使我们更好地了解社会背景和DA受体功能之间的相互作用，这对制定行为和药物治疗策略至关重要。

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.