Kappa Opioid Receptor Availability, Social Rank, and Cocaine Self-Administration in Female and Male Monkeys

雌性和雄性猴子中的 Kappa 阿片受体可用性、社会等级和可卡因自我给药

• 批准号: 10389440
• 负责人: Bernard N Johnson
• 金额: $ 4.68万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10389440
• 关键词: Abstinence; Acute; Animal Model; Animals; Autopsy; Behavioral; Binding; Biological Markers; Brain; Characteristics; Chronic; Cocaine; Cocaine Abuse; Cocaine use disorder; Development; Dopamine; Dopamine Receptor; Dose; Drug Addiction; Dynorphins; Environment; Euphoria; Exhibits; FDA approved; Female; Human; Individual; Intake; Intravenous; Laboratories; Ligands; Literature; Maintenance; Measures; Mediating; Modeling; Monkeys; Negative Reinforcements; Neurobiology; Neuronal Plasticity; Opioid Receptor Binding; Opioid agonist; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phenotype; Positron-Emission Tomography; Predisposition; Psychological reinforcement; Public Health; Regulation; Reporting; Research; Research Design; Research Project Grants; Role; Schedule; Self Administration; Sex Differences; Side; Social Behavior; Social status; Study Subject; System; Tracer; Treatment outcome; Withdrawal; Work; abuse liability; acute stress; addiction; base; clinically relevant; clinically significant; cocaine exposure; cocaine overdose; cocaine self-administration; cocaine use; dopamine system; drug abuse vulnerability; drug of abuse; experience; human male; imaging study; interest; kappa opioid receptors; male; non-drug; nonhuman primate; overdose death; personalized medicine; psychostimulant; radiotracer; receptor; receptor binding; receptor function; response; sex; social; social factors

Cocaine use disorder (CUD) persists as a worldwide public health problem for which there is no FDA-approved pharmacotherapy. Of clinical significance, in the US, cocaine use is increasing, alongside cocaine overdose deaths, which have more than tripled from 2012 to 2018 [1, 2]. A gap in the literature and the primary focus of this application, is to extend research from the dopamine system, associated with euphoria, to the dynorphin/kappa opioid receptor (KOR) system, implicated in the “dark side” of addiction. This research project utilizes a highly homologous nonhuman primate model, incorporating social behavior with intravenous drug self- administration (SA) and positron emission tomography (PET), in drug-naive female and male monkeys. The proposed longitudinal, within-subject study design will further our understanding of the neurobiology associated with the vulnerability and maintenance of cocaine abuse. The initial Aim 1 of this proposal used PET imaging with a KOR radiotracer, [11C]EKAP, to obtain baseline measures of KOR availability and assess the relationship between KOR availability and social rank in cocaine-naïve male and female monkeys. The studies in that Aim have been completed. Overall, the lowest receptor availability across all regions of interest were observed in dominant females and subordinate males; based on previous studies, the two most vulnerable phenotypes to cocaine reinforcement. The baseline assessment of KOR measures allows the ability to assess the relationship between receptor availability and vulnerability of cocaine abuse (Aim 1), as well as how those measures change following chronic cocaine self-administration (Aim 2). In addition, the studies in Aim 3 will assess clinically relevant factors associated with withdrawal/abstinence and assess the neural plasticity of KOR system following protracted abstinence. The use of PET as a biomarker related to vulnerability and treatment outcome may provide evidence for a personalized medicine approach to treating CUD.

可卡因使用障碍 (CUD) 仍然是一个全球性的公共卫生问题，目前尚无 FDA 批准的治疗方法 具有临床意义的是，在美国，可卡因的使用量正在增加，同时可卡因过量服用也正在增加。 死亡人数从 2012 年到 2018 年增加了两倍多 [1, 2]。 该应用旨在将研究从与欣快感相关的多巴胺系统扩展到 强啡肽/卡帕阿片受体（KOR）系统，与成瘾的“阴暗面”有关。 利用高度同源的非人类灵长类动物模型，将社会行为与静脉注射药物自我结合 在未接受药物治疗的雌性和雄性猴子中进行给药（SA）和正电子发射断层扫描（PET）。 拟议的纵向、受试者内研究设计将进一步加深我们对相关神经生物学的理解 该提案的最初目标 1 使用 PET 成像。 使用 KOR 放射性示踪剂 [11C]EKAP，获得 KOR 可用性的基线测量并评估关系 未接触过可卡因的雄性和雌性猴子的 KOR 可用性和社会等级之间的关系。 总体而言，观察到所有感兴趣区域的受体可用性最低。 女性和从属男性；根据之前的研究，两种最容易受到影响的表型 可卡因强化。KOR 措施的基线评估允许评估关系。 受体可用性和可卡因滥用脆弱性之间的关系（目标 1），以及这些措施如何变化 长期自我服用可卡因（目标 2）后，目标 3 中的研究将进行临床评估。 与戒断/戒断相关的因素，并评估 KOR 系统的神经可塑性 使用 PET 作为与脆弱性和治疗结果相关的生物标志物可能。 为治疗 CUD 的个性化医疗方法提供证据。