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.

Environment, social factors and sex are variables that influence vulnerability, maintenance, withdrawal and treatment outcome in human drug addiction. The research proposed in this application will examine all three phases of addiction with a focus on the kappa opioid receptor (KOR) system and extend behavioral (cocaine self-administration), pharmacological (long-term cocaine exposure) and brain changes (using positron emission tomography), in socially housed female and male monkeys. Results from these studies should aid in the development of personalized medicine strategies for drug addiction and the implementation of the KOR system across the addition cycle.