Social status and hormones on cognition and cocaine abuse in female macaques

描述（由申请人提供）：可卡因滥用（COC）是一个重大的公共卫生问题，估计有160万美国人确认目前使用COC （SAMHSA， 2010年）。尽管进行了多年的治疗研究，但目前还没有fda批准的药物可用，因此有必要继续调查与COC滥用有关的因素，以改进药物开发。有效的治疗依赖于对介导COC行为效应的机制的全面理解。这些机制在女性和男性之间可能有所不同，临床和临床前研究中的性别差异证据表明，女性尤其可能面临易受COC滥用的风险（O'Brien和Anthony， 2005）。使个体易受COC滥用影响的因素和复发风险的潜在指标是药物滥用领域的活跃研究领域，因此，关于这些因素的许多研究仅在男性受试者中进行，这是一个令人担忧的趋势。因此，本提案的目标之一是将已经完成的公猴群居研究扩展到公猴群居研究。行为和神经化学证据支持内源性激素的假设，特别是那些在月经周期波动的激素——雌激素和黄体酮，与已知参与药物自我给药（SA）和认知的受体相互作用。此外，社会地位和COC SA已被证明会影响内源性激素浓度。因此，本应用程序将使用雌性非人类灵长类动物模型来研究内源性激素和认知表现如何随着社会等级的建立和COC SA的启动而改变。该研究的第一部分旨在描述基线激素状况如何影响每只动物的认知表现，并可能使动物在群体中获得一定的等级（未来的优势与未来的从属）。其次，拟议的研究将评估这些变量（激素水平和认知表现）是如何随着集体住房的社会衍生压力而改变的。最后，我将阐明在食物-COC选择范式中，内源性女性激素的变化如何影响对COC SA的易感性。此外，本研究将评估COC SA与认知的行为相关性，考察其对认知表现的影响。建议的研究将

DESCRIPTION (provided by applicant): Abuse of cocaine (COC) is a major public health issue with an estimated 1.6 million Americans confirming current COC use (SAMHSA, 2010). Despite years of treatment research, no FDA-approved medications are currently available, warranting continued investigation of factors involved in COC abuse for improved medication development. Effective treatments relay on a comprehensive understanding of the mechanisms that mediate the behavioral effects of COC. These mechanisms may differ between women and men, and women in particular may be at risk for vulnerability to COC abuse as indicated by evidence of sex differences in both clinical and preclinical research (O'Brien and Anthony, 2005). The factors that predispose an individual to susceptibility to COC abuse and potential indicators for risk of relapse are active aras of research in the drug abuse field~ therefore it is an alarming trend that much of the research regarding these factors is being conducted solely in male subjects. Therefore, one goal of this proposal is to extend the research that has been completed using socially housed male monkeys to socially housed female monkeys. Behavioral and neurochemical evidence supports the hypothesis that endogenous hormones, specifically those which fluctuate across the menstrual cycle- estrogen and progesterone, interact with receptors known to be involved in drug self-administration (SA) and cognition. Additionally, social status and COC SA have been shown to influence endogenous hormone concentrations. Therefore, this application will use a female nonhuman primate model to investigate how endogenous hormones and cognitive performance is altered as social hierarchies are established and COC SA is initiated. The first part of the study aims to characterize how baseline hormonal profiles affect cognitive performance in each animal and may predispose animals to attain a certain rank once group-housed (future dominant vs future subordinate). Secondly, the proposed study will assess how these variables (hormonal profile and cognitive performance) are altered following socially derived stress as a result of group-housing. Finally, I will elucidate how alteratons to endogenous female hormones influence susceptibility to COC SA in a food-COC choice paradigm. Additionally, this research will assess the behavioral relevance of COC SA on cognition examining the effects it has on cognitive performance. The proposed studies will effectively model the role of chronic stress and hormone/cognitive dysregulation on vulnerability to the reinforcing effects of COC. The studies that have previously attempted to examine these factors individually are inconsistent and limited in that assessing each manipulation individually (i.e. social status, COC SA and cognition) with different paradigms does not encompass the potential synergistic effects that these variables can have in human abusers. These studies will enhance the understanding of these effects to ultimately provide translational insight into novel pharmacotherapeutic treatment strategies.