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: 10558460
• 负责人: Bernard N Johnson
• 金额: $ 4.77万
• 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/10558460
• 关键词: Abstinence; Acute; Animal Model; Animals; Autopsy; Behavioral; Binding; Biological Markers; Brain; Characteristics; Chronic; Cocaine; Cocaine Abuse; Cocaine use disorder; Darkness; 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; Pharmacotherapy; Phase; Phenotype; Positron-Emission Tomography; Predisposition; Psychological reinforcement; Public Health; Regulation; Reporting; Research; Research Design; Research Project Grants; Role; Scanning; Schedule; Self Administration; Sex Differences; Side; Social Behavior; Social status; Study Subject; System; Tracer; Treatment outcome; Withdrawal; Work; abuse liability; acute stress; addiction; clinically relevant; clinically significant; cocaine exposure; cocaine overdose; cocaine self-administration; cocaine use; dopamine system; drug abuse vulnerability; drug of abuse; experience; imaging study; interest; kappa opioid receptors; male; non-drug; nonhuman primate; overdose death; personalized medicine; pharmacologic; prolonged abstinence; 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）是一个全球性的公共卫生问题，没有FDA批准 药物治疗.具有临床意义的是，在美国，可卡因的使用正在增加，同时可卡因过量 死亡人数从2012年到2018年增加了两倍多[1，2]。文献中的空白和 这个应用程序，是从多巴胺系统的研究，与欣快， 强啡肽/κ阿片受体（KOR）系统，涉及成瘾的“黑暗面”。本研究项目 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- 给药（SA）和正电子发射断层扫描（PET）。的 拟议的纵向受试者内研究设计将进一步加深我们对神经生物学相关的理解。 与可卡因滥用的脆弱性和维持有关。该提案的最初目标1使用PET成像 使用KOR放射性示踪剂[11 C]EKAP，以获得KOR可用性的基线测量值并评估 可卡因初治的雄性和雌性猴子的KOR可用性和社会等级之间的关系。在这方面的研究 已完成总的来说，在所有感兴趣的区域中观察到最低的受体可用性， 占主导地位的女性和从属男性;根据以前的研究，两个最脆弱的表型， 可卡因强化KOR措施的基线评估允许评估关系的能力 可卡因滥用的受体可用性和脆弱性之间的关系（目标1），以及这些措施如何变化 慢性可卡因自我给药后（目的2）。此外，目标3中的研究将在临床上评估 与戒断/禁欲相关的相关因素，并评估KOR系统的神经可塑性 长期禁欲使用PET作为与脆弱性和治疗结果相关的生物标志物， 为治疗CUD的个性化药物方法提供证据。