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

可卡因使用障碍(Cud)一直是一个世界性的公共卫生问题，目前尚无fda批准的治疗方法。 药物疗法。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]。文学上的空白和主要关注点 这一应用是为了将研究从与欣快感相关的多巴胺系统扩展到 强啡肽/kappa阿片受体(KOR)系统，与成瘾的“黑暗面”有关。这项研究项目 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身结合起来 给药(SA)和正电子发射断层扫描(PET)，在药物幼稚的雌性和雄性猴子。这个 拟议的纵向、受试者内研究设计将加深我们对相关神经生物学的理解 与可卡因滥用的脆弱性和维持性有关。该提案的最初目标1使用的是PET成像 使用KOR放射性示踪剂[11C]EKAP，以获得KOR可用性的基线测量并评估关系 在可卡因幼稚的雄性和雌性猴子中，KOR可获得性和社会地位之间的关系。以此为目标的研究 已经完工了。总体而言，在所有感兴趣的区域中，受体利用率最低的是 主要的雌性和从属的雄性；根据以前的研究，两种最脆弱的表型 可卡因增援。通过对KOR措施的基线评估，可以评估关系 受体可获得性与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 在慢性可卡因自我给药后(目标2)。此外，目标3中的研究将进行临床评估。 戒断/戒断的相关因素及KOR系统神经可塑性的评估 长期禁欲。将PET用作与易损性和治疗结果相关的生物标记物可能 为治疗CUD的个体化医学方法提供证据。

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.