Mechanisms Mediating Cocaine Abuse in Socially Housed Female and Male Monkeys

社会饲养的雌性和雄性猴子中调节可卡因滥用的机制

• 批准号: 9789227
• 负责人: Michael A Nader
• 金额: $ 73.62万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789227
• 关键词: Acute; Affect; American; Animal Model; Animals; Behavior; Behavioral; Brain; Brain imaging; Brain region; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Cognition; Cognitive; Cognitive deficits; Complement; Data; Development; Dopamine; Dose; Drug Addiction; Drug Exposure; Drug Modelings; Drug Modulation; Drug abuse; Drug usage; Environmental Risk Factor; FDA approved; Female; Food; Funding; Glucose; Goals; Grant; Human; Imaging Techniques; Impulsivity; Individual Differences; Intravenous; Laboratories; Long-Term Effects; Macaca fascicularis; Maintenance; Measures; Mediating; Modeling; Monkeys; Neurobiology; Outcome; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Positron-Emission Tomography; Primates; Psychological reinforcement; Public Health; Raclopride; Reporting; Research; Research Design; Research Project Grants; Research Proposals; Sampling; Schedule; Self Administration; Sex Differences; Social Behavior; Social Environment; Social Hierarchy; Substance abuse problem; Training; Translational Research; Treatment Failure; Treatment outcome; Work; base; behavior influence; cocaine use; cognitive performance; environmental enrichment for laboratory animals; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose metabolism; individualized medicine; intravenous drug use; male; neurotransmission; non-drug; nonhuman primate; novel; personalized medicine; pre-clinical; preference; receptor; reinforcer; response; sex; social; social engagement; social group; social stress; treatment strategy

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.

药物滥用仍然是全球主要的公共卫生问题，超过 150 万美国人 确认目前可卡因的使用情况，目前尚无 FDA 批准的可卡因成瘾治疗方法。 该研究项目是旨在了解可卡因神经生物学的资助工作的延续 独特的非人类灵长类动物模型中的滥用：社会安置中的静脉注射可卡因自我给药 本申请的目标是继续使用这种同源动物。 模型来研究调节社会等级和等级之间相互作用的行动机制 雌性和雄性猴子自我给药的环境和药理调节。 在上一个资助期间，我们注意到可卡因脆弱性与性别和社会等级相关的差异 在目标 1 中，我们将进行自我给药 (SA) 和对几种急性药理学操作的反应。 将这一特征扩展到社会饲养的猴子的慢性药物治疗中，这些猴子自我施用可卡因 我们还将研究如何使用替代的非药物强化剂（食物可卡因选择）。 治疗会影响可卡因引起的恢复。目标 2 中的研究将扩大这些性别和社会等级。 通过延迟进食和可卡因来区别冲动行为。 重点是，与男性相比，女性会更“冲动”，并且当可卡因延迟时， 下属需要更长的时间才能改变偏好。 长期可卡因 SA 和慢性可卡因的影响。 药物治疗对社会饲养的猴子认知表现的影响将在目标 3 中进行研究。我们 最近，可卡因对女性认知能力的干扰程度高于可卡因对女性认知能力的干扰程度 最近，我们报道称，雄性猴子比占主导地位的猴子更敏感。 使用 [18F] 氟脱氧葡萄糖和 PET 进行脑葡萄糖利用的社会等级相关差异 使用 [11C]雷氯必利的多巴胺 D2/D3 受体可用性 目标 4 的目标是检查可卡因 SA 的作用。 慢性药物治疗对社交中的葡萄糖利用和 D2/D3 受体可用性有不同的影响 科学前提是维持可卡因SA的机制不同。 基于社会地位和性别，因此需要不同的药物才能在这些方面产生积极的结果 我们正在提出一种治疗药物滥用的临床前个性化医疗策略。 这些研究的结果应该有助于新颖和社会变量的发展。 药物成瘾的个体化治疗策略。