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.

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.