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

描述（由申请方提供）：可卡因（COC）滥用是一个主要的公共卫生问题，估计有160万美国人确认目前使用COC（SAMHSA，2010）。尽管多年的治疗研究，目前没有FDA批准的药物可用，阻碍了继续调查COC滥用的因素，以改善药物开发。 有效的治疗依赖于对COC行为效应介导机制的全面理解。 这些机制可能在女性和男性之间存在差异，尤其是女性可能面临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（奥布莱恩和Anthony，2005年）。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研究的活跃领域，因此，关于这些因素的大部分研究仅在男性受试者中进行是一个令人担忧的趋势。因此，该提案的一个目标是将已经完成的使用社会圈养的雄性猴子的研究扩展到社会圈养的雌性猴子。 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-雌激素和孕激素，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，本申请将使用雌性非人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。 本研究的第一部分旨在描述基线激素谱如何影响每只动物的认知表现，并可能使动物在分组饲养后易于达到一定的等级（未来的主导与未来的从属）。 其次，拟议的研究将评估这些变量（荷尔蒙和认知能力）是如何改变后，社会衍生的压力，由于集体住房。 最后，我将阐明如何alteratons内源性雌性激素的影响易感性COC SA在食品COC的选择范例。此外，本研究还将评估COC SA对认知的行为相关性，研究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强化效应的脆弱性的作用。 先前试图单独检查这些因素的研究是不一致的，并且局限于用不同的范式单独评估每种操纵（即社会地位，COC SA和认知）不包括这些变量可能在人类滥用者中产生的潜在协同效应。 这些研究将增强对这些效应的理解，最终为新型药物治疗策略提供翻译见解。

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.