Effects of Long-Term Cocaine Self-Administration on Kappa Opioid Receptors in Socially Housed Cynomolgus Monkeys as Assessed with PET Imaging and Neuronally Derived Exosomes.

Background: The present study utilized PET imaging to examine how long-term cocaine self-administration (SA) and time-off from 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 SA intravenous cocaine. PET imaging with the KOR selective agonist [C]EKAP occurred after monkeys had SA ∼100 mg/kg total cocaine intake and after ∼30 days off from cocaine; in a subset of monkeys, a third PET scan was conducted after ∼100 days off from 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 from cocaine in dominant females. In a subset of monkeys, no differences were observed in [C]EKAP binding between 30- and 100-days off from cocaine. NDEs showed significant interactions between sex and condition, providing a peripheral measure consistent with the PET results.

Conclusions: These findings extend previous research in socially housed monkeys to the KOR and suggest that KOR may be a viable target for pharmacological interventions for cocaine misuse, especially in women.