Mechanisms Mediating Cocaine Abuse in Socially Housed Female and Male Monkeys

毒品滥用仍然是世界范围内的一个主要公共卫生问题，有超过150万美国人 确认目前可卡因的使用情况，目前还没有FDA批准的可卡因成瘾治疗方法。 这一研究项目是旨在了解可卡因神经生物学的资助工作的继续。 一种独特的非人灵长类动物模型中的虐待行为：社交场所中静脉注射可卡因的自我管理 食蟹猴。本申请的目的是继续使用这种同源动物 考察调节社会等级和社会等级之间相互作用的行动机制的模型 雌性和雄性猕猴药物自我给药的环境和药理学调节。完毕 在上一个资助期，我们注意到与性别和社会等级有关的可卡因易感性差异。 自我给药(SA)和对几种急性药物操作的反应。在目标1中，我们将 将这一特征扩展到社会寄养猴子自我注射可卡因的慢性药物治疗 另一种非药物增强剂(食物-可卡因的选择)的背景。我们还将研究这些 治疗会影响可卡因诱导的恢复。目标2中的研究将扩大这些性别和社会等级 通过推迟食物和可卡因的使用来改变冲动行为。当食物被耽搁时，我们 假设女性会比男性更“冲动”，并且当可卡因被延迟时， 下属将需要更长的延迟才能改变偏好。长期吸食可卡因SA和慢性吸毒者的影响 药物治疗对群居猴子认知能力的影响将在目标3中进行研究。 假设可卡因对女性认知能力的影响比可卡因对女性认知能力的影响更大 雄性和那些从属的猴子会比占主导地位的动物更敏感。我们已经报道了社交- 用[18F]氟脱氧葡萄糖和正电子发射计算机断层扫描及多巴胺测定脑部葡萄糖利用率的等级相关差异 D2/D3受体利用度[11C]拉氯普利和最近使用的kappa阿片受体利用度 [11C]ECAP。目标4的目标是检查可卡因SA和慢性药物治疗如何影响不同的 这些措施在群居的雌性和雄性猴子身上进行。科学前提是不同的 机制根据社会地位和性别维持可卡因SA，因此将需要不同的药物来 在这些群体中产生积极的结果。我们正在提出一种临床前个性化药物战略， 治疗包括性别和社会变量在内的药物滥用。这些研究的结果应该有助于 开发针对药物成瘾的新的和个性化的治疗策略。

Drug abuse continues to be a major public health problem worldwide, with over 1.5 million Americans confirming current cocaine use and, at present, there are no FDA-approved treatments for cocaine addiction. 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 cynomolgus monkeys. The goals of the present application are to continue using this homologous animal model to examine the mechanisms of action mediating the interactions between social hierarchy and environmental and pharmacological modulation of drug self-administration in female and male monkeys. Over the previous funding period, we have noted sex- and social-rank related differences in vulnerability to cocaine self-administration (SA) and in response to several acute pharmacological manipulations. In Aim 1, we will extend this characterization to chronic drug treatment in socially housed monkeys self-administering cocaine in the context of an alternative, non-drug, reinforcer (food-cocaine choice). We will also examine how these treatments affect cocaine-induced reinstatement. The studies in Aim 2 will extend these sex- and social-rank differences to impulsive-like behavior by implementing delays to food and cocaine. When food is delayed, we hypothesize that females will be more “impulsive” compared to males and when cocaine is delayed, subordinates will require longer delays to shift preference. The effects of long-term cocaine SA and chronic drug treatment on cognitive performance in socially housed monkeys will be examined in Aim 3. We hypothesize that cognitive performance of females will be more disrupted by cocaine than performance by males and that subordinate monkeys will be more sensitive than dominant animals. We have reported social- rank related differences in brain glucose utilization using [18F]fluorodeoxyglucose and PET and in dopamine D2/D3 receptor availability using [11C]raclopride and most recently in kappa opioid receptor availability using [11C]ECAP. The goal of Aim 4 is to examine how cocaine SA and chronic drug treatment differentially affects these measures in socially housed female and male monkeys. The scientific premise is that different mechanisms maintain cocaine SA based on social rank and sex and thus different drugs will be required to produce a positive outcome in these groups. We are proposing a preclinical personalized-medicine strategy for treating drug abuse that incorporates sex and social variables. Results from these studies should aid in the development of novel and individualized treatment strategies for drug addiction.