Mechanisms Mediating Cocaine Abuse in Socially Housed Female and Male Monkeys

药物滥用仍然是全球主要的公共卫生问题， 这证实了目前可卡因的使用，目前没有FDA批准的可卡因成瘾治疗方法。 这项研究项目是一个继续资助的工作，旨在了解可卡因的神经生物学 一个独特的非人灵长类动物模型中的滥用：在社会性圈养环境中静脉注射可卡因自我给药 食蟹猴本申请的目的是继续使用这种同源动物 模型，以研究调解社会等级和 雌性和雄性猴自我给药的环境和药理学调节。超过 在上一个资助期，我们注意到与性别和社会地位有关的可卡因脆弱性差异 自我给药（SA）和对几种急性药理学操作的反应。在目标1中，我们 将这一特征扩展到社会圈养的猴子的慢性药物治疗， 替代性、非毒品、可卡因（食物-可卡因选择）的背景。我们还将研究这些 治疗影响可卡因诱发的复发。目标2中的研究将扩展这些性别和社会等级， 通过延迟食物和可卡因的摄入来改变冲动行为。当食物延迟时，我们 假设女性比男性更“冲动”，当可卡因被延迟服用时， 下属将需要更长的延迟来改变偏好。长期服用可卡因SA和慢性服用可卡因 将在目标3中检查药物治疗对群居猴的认知表现的影响。我们 假设女性的认知能力会受到可卡因的干扰，而不是 雄性猴子和下属猴子将比占主导地位的动物更敏感。最近，我们报道了 使用[18F]氟脱氧葡萄糖和PET的脑葡萄糖利用率的社会等级相关差异， 使用[11 C]雷氯必利的多巴胺D2/D3受体可用性。目标4的目的是研究可卡因SA 和慢性药物治疗差异影响葡萄糖利用和D2/D3受体的可用性， 饲养着雌猴和雄猴。科学前提是不同的机制维持可卡因SA 基于社会地位和性别，因此需要不同的药物来产生积极的结果， 组我们正在提出一种临床前个性化药物治疗策略， 包括性别和社会变量。这些研究的结果应该有助于开发新的和 药物成瘾的个体化治疗策略。

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. Recently, we reported social-rank related differences in brain glucose utilization using [18F]fluorodeoxyglucose and PET and in dopamine D2/D3 receptor availability using [11C]raclopride. The goal of Aim 4 is to examine how cocaine SA and chronic drug treatment differentially affects glucose utilization and D2/D3 receptor availability 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.