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

社会地位和激素对雌性猕猴认知和可卡因滥用的影响

• 批准号: 8647634
• 负责人: Sarah Kromrey
• 金额: $ 4.27万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647634
• 关键词: Address; Affect; Amenorrhea; American; Animals; Behavioral; Biological Process; Chronic; Chronic stress; Clinical Research; Cocaine; Cocaine Abuse; Cocaine Dependence; Cognition; Cognitive; Development; Drug abuse; Estrogens; FDA approved; Female; Food; Future; Goals; Hormonal; Hormones; Housing; Human; Hydrocortisone; Impairment; Incidence; Individual; Intravenous; Investigation; Laboratory Animals; Lead; Longitudinal Studies; Macaca; Mediating; Memory; Menstrual cycle; Modeling; Monkeys; National Research Service Awards; Neurobiology; Neuropsychological Tests; Ovarian hormone; Performance; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Play; Predisposing Factor; Predisposition; Progesterone; Public Health; Randomized; Relapse; Research; Research Design; Risk; Role; Self Administration; Sex Characteristics; Short-Term Memory; Social Hierarchy; Social status; Stress; Testosterone; Therapeutic; United States Substance Abuse and Mental Health Services Administration; Woman; Women' s Health; base; cocaine exposure; cocaine use; cognitive function; effective therapy; executive function; human male; improved; insight; male; men; neurochemistry; nonhuman primate; novel; pre-clinical research; proliferative phase Menstrual cycle; public health relevance; receptor; role model; social; social group; social stress; treatment strategy; trend

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.

描述（由申请人提供）：可卡因 (COC) 的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 COC 的使用（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，需要继续调查 COC 滥用的相关因素，以改进药物开发。 有效的治疗依赖于对 COC 行为效应介导机制的全面理解。 这些机制在女性和男性之间可能有所不同，临床和临床前研究中性别差异的证据表明，女性尤其可能面临 COC 滥用的风险（O'Brien 和 Anthony，2005）。导致个体对COC滥用易感性的因素和潜在的复发风险指标是药物滥用领域的活跃研究领域~因此，一个令人震惊的趋势是，许多关于这些因素的研究仅在男性受试者中进行。因此，该提案的一个目标是将已使用社会饲养的雄性猴子完成的研究扩展到社会饲养的雌性猴子。 行为和神经化学证据支持这样的假设：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，该应用程序将使用雌性非人类灵长类动物模型来研究随着社会等级制度的建立和 COC SA 的启动，内源激素和认知表现如何改变。 该研究的第一部分旨在描述基线荷尔蒙分布如何影响每只动物的认知表现，并可能使动物在集体饲养后达到一定的等级（未来的主导地位与未来的从属地位）。 其次，拟议的研究将评估这些变量（荷尔蒙分布和认知表现）在集体居住造成的社会压力后如何改变。 最后，我将在食物-COC 选择范例中阐明内源性女性激素的改变如何影响对 COC SA 的敏感性。此外，本研究将评估 COC SA 对认知的行为相关性，检查其对认知表现的影响。 拟议的研究将 有效地模拟了慢性压力和激素/认知失调对 COC 增强作用脆弱性的影响。 先前试图单独检验这些因素的研究是不一致且有限的，因为用不同范式单独评估每种操纵（即社会地位、COC SA 和认知）并没有涵盖这些变量对人类施虐者可能产生的潜在协同效应。 这些研究将增强对这些效应的理解，最终为新型药物治疗策略提供转化见解。