Effects of Long-Term Cocaine Self-Administration on Kappa Opioid Receptors in Socially Housed Cynomolgus Monkeys as Assessed With Positron Emission Tomography Imaging and Neuronally Derived Exosomes

Abstract

Background: The current study utilized positron emission tomography (PET) imaging to examine how long-term cocaine self-administration (SA) and time off cocaine affected kappa opioid receptor (KOR) availability in the brain of previously cocaine-naïve monkeys. In addition, neuronally derived small extracellular vesicles (NDEs) were measured from plasma to identify peripheral measures of KORs. Methods: Female (n = 6) and male (n = 7) cynomolgus monkeys, living in stable same-sex social groups, were trained to self-administer intravenous cocaine. PET imaging with the KOR selective agonist [11C]EKAP occurred after monkeys had self-administered ∼100-mg/kg total cocaine intake and after ∼30 days off cocaine; in a subset of monkeys, a third PET scan was conducted after ∼100 days off cocaine. Blood samples were obtained prior to each PET study, and NDEs from the plasma were isolated by immunocapture method and analyzed for percentage of KOR+. Results: There were significant interactions between condition (100 mg/kg cocaine and 30 days off cocaine), sex, and social rank in KOR availability across 7 of 15 brain regions. More specifically, these interactions were associated with increased KOR availability following cocaine SA and after 30 days off cocaine in dominant females. In a subset of monkeys, no differences were observed in [11C]EKAP binding between 30 and 100 days off cocaine. NDEs showed significant interactions between sex and condition, providing a peripheral measure consistent with the PET results. Conclusions: These findings extend previous research with socially housed monkeys on KORs and suggest that KOR may be a viable target for pharmacological interventions for cocaine misuse, especially in women.