Social Rank, Behavioral Phenotypes and Kappa Opioid Receptor: PET Imaging Studies of Socially Housed Female and Male Monkey Models of Cocaine Use Disorder

Abstract

In the US, cocaine use is increasing, alongside cocaine overdose deaths, which doubled from 2014 to 2016 (Nolan et al., J Urban Health 2019; John and Wu, Drug Alcohol Depend 2017). While dopamine (DA) has been implicated in the positive reinforcing effects of drugs, the kappa opioid receptor (KOR) system and its endogenous ligand, dynorphin, are implicated in the neurobiological regulation of aversive states, including stress associated with substance abuse. Both chronic stress and cocaine exposure increase dynorphin/KOR system function and sensitivity to stress-induced relapse (Tejeda and Bonci, Brain Research 2019). A recent positron emission tomography (PET) study with KOR agonist tracer [11C]EKAP, in humans, reported an inverse correlation between social status and KOR availability in “anti-reward”/stress brain regions (Matuskey et al. Neuropsychopharmacology 2019). Differences in KOR availability have also been shown to correlate with cocaine choice in subjects with CUD (Martinez et al. Neuropsychopharmacology 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, primate social behavior, and PET imaging. The ongoing study utilizes cocaine-naïve male and female monkeys (N=8/sex) living in same-sex social groups of 4/pen. The first aim was to investigate the KOR system, combining [11C]EKAP PET imaging and primate social behavior to assess the relationship between social rank and KOR availability. The second aim was to extend our research to include measures of impulsivity using a delayed discounting procedure. Monkeys were trained under a 1- vs. 3-food pellets delay discounting choice procedure. The primary dependent variable was indifference point (IP), or the delay that results in 50% choice for both reinforcers. In PET studies, the lowest binding potentials (BPs) across all regions of interest were observed in dominant (Dom) females and subordinate (Sub) males; the two most vulnerable phenotypes to cocaine reinforcement (Morgan et al., Nature Neurosci 2002; Nader et al., Biol Psych 2012). We hypothesize this was due to increased basal dynorphin levels, indicative of chronic social stress. Studies are currently underway to assess cocaine acquisition. We hypothesis Dom females and Sub males, those with lower KOR BPs will acquire cocaine reinforcement at lower doses compared to Dom males and Sub females. In delay discounting studies, the IP values ranged from 23-107 seconds (Mdn = 38). Preliminary data indicates no sex or social rank differences in IP values. However, redetermining the delay discounting curve resulted in significantly higher IP values, which were correlated with BP in several brain regions in males but not females. The redetermined IP values may provide an index of adaptability; we speculate that this may be a behavioral phenotype that supports epidemiological data that women are more vulnerable than men in developing CUDs.