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

描述(由申请人提供)：滥用可卡因(COC)是一个主要的公共卫生问题，估计有160万美国人确认目前正在使用COC(SAMHSA，2010)。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调节COC行为效应的机制的全面了解。这些机制在女性和男性之间可能不同，尤其是女性可能面临易受COC滥用的风险，临床和临床前研究中的性别差异证据表明了这一点(O‘Brien和Anthony，2005)。使个人易患COC滥用的因素和复发风险的潜在指标是药物滥用领域研究的活跃领域~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，这项提议的一个目标是将已经完成的使用社会安置的雄性猴子的研究扩展到社会安置的雌性猴子。行为和神经化学证据支持这样的假设，即内源性激素，特别是那些在月经周期中波动的激素--雌激素和孕酮，与已知参与药物自我给药和认知的受体相互作用。此外，社会地位和COC SA已被证明影响内源性激素浓度。因此，该应用程序将使用女性非人灵长类动物模型来研究随着社会等级的建立和COC SA的启动，内源性激素和认知表现是如何改变的。这项研究的第一部分旨在表征基线荷尔蒙特征如何影响每只动物的认知表现，并可能使动物在群居后达到一定的级别(未来的优势与未来的从属)。其次，这项拟议的研究将评估这些变量(荷尔蒙概况和认知表现)在由于集体住房而产生的社交压力之后是如何改变的。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在认知方面的行为相关性，以检验其对认知表现的影响。拟议的研究将 有效地模拟慢性压力和激素/认知失调对COC强化效应的易感性的作用。以前试图单独考察这些因素的研究是不一致和有限的，因为用不同的范式单独评估每个操作(即社会地位、COC SA和认知)并不包括这些变量对人类施虐者可能产生的潜在协同效应。这些研究将加强对这些影响的理解，最终为新的药物治疗策略提供翻译洞察力。

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.