Behavioral Phenotypes and Kappa Opioid Receptor Availability Related to Cocaine Self‐Administration in Socially Housed Female and Male Monkeys
Authors: Johnson Bernard N. , Czoty Paul N. , Gould Robert , Coller Michael , Odom Jillian , Nader Susan , Sai Kiran Solingapuram , Nader Michael 
Published: April 2020

Cocaine use disorder (CUD) persists as a worldwide public health problem for which there is no FDA‐approved pharmacotherapy. The kappa opioid receptor (KOR) system and its endogenous ligand, dynorphin, are implicated in the regulation of aversive states, stress and substance abuse. A recent positron emission tomography (PET) study with a novel KOR agonist tracer [11C]EKAP in humans reported that lower social status was associated with higher KOR availability in “anti‐reward”/stress brain regions (Matuskey et al. Neuropsychopharm, 2019); sex differences were noted. Differences in KOR availability have also been shown with PET to correlate with cocaine choice in CUD subjects (Martinez et al. Neuropsychopharm, 2019). The aim of this study is to extend the investigation of the dynorphin/KOR system using a homologous nonhuman primate model of CUD involving cocaine self‐administration (SA) in socially housed female and male monkeys. Cynomolgus monkeys living in same‐sex social groups form linear social hierarchies, conceptualized as a continuum indicative of chronic social stress at the lower, subordinate end, and environmental enrichment at the upper, dominant end; social rank can influence the behavioral and reinforcing effects of drugs of abuse, including cocaine. The utilization of the dominance hierarchy allows the combination of primate social behavior with intravenous drug SA and PET imaging to examine how environmental and pharmacological variables, along with sex differences, influence cocaine SA.

This ongoing study utilizes socially housed male and female cynomolgus monkeys (N=16/sex), some experimentally naïve at the start of the study and others with a cocaine SA history. Naive monkeys were trained under a 1‐ vs. 3‐food pellets delay discounting choice procedure and the other monkeys under a cocaine (0.01–0.1 mg/kg/inj) vs. food (1‐pellet) delay discounting choice procedure. The primary dependent variable was indifference point (IP) or the delay that results in 50% choice. In all monkeys, executive function was assessed using two different cognitive tasks utilizing CANTAB systems. Finally, all naive monkeys received a [11C]EKAP PET scan in order to examine the relationship between KOR availability and social rank and eventually to examine how those measures change with cocaine history. The PET data are currently being analyzed.

Preliminary data indicates that when a low, non‐preferred, cocaine dose was available and food was delayed, dominant females had higher IPs compared to dominant males (140‐s vs 45‐s) suggesting that they were less “impulsive”. Preliminary comparisons suggest no relationship between IP and errors under various cognitive tasks, indicating that we are assessing nonoverlapping cognitive domains that, along with PET data, may prove to be sensitive biomarkers for decreasing cocaine SA.

Support or Funding Information

DA017763