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Impact of Chronic Ethanol Self‐Administration on Kappa Opioid Receptor Regulation of Dopamine Signaling in Nonhuman Primates

Although alcoholism is one of the most prevalent disorders in the United States, with over 18 million individuals meeting the criteria for an alcohol use disorder, the exact neurobiological bases of this condition remain obscure. Recently, it has been demonstrated that kappa‐opioid receptor (KOR) signaling in the striatum plays a critical role in the increased reinforcing efficacy of ethanol following ethanol vapor exposure in rodent models. Here we examined the effects of chronic voluntary ethanol self‐administration in macaques on dopamine neurotransmission and the ability of KORs to regulate dopamine release in the nucleus accumbens core. Three cohorts of nonhuman primates were given free access to 4% ethanol (w/v) for 22 hr/day. These cohorts were composed of male cynomolgus, female rhesus or male rhesus macaques, and were given access to ethanol for 6, 12, or 18 months, respectively. Ex vivo fast‐scan cyclic voltammetry was then conducted the nucleus accumbens core to determine dopamine signaling kinetics as well as the ability of U50,488 (KOR agonist) to inhibit dopamine release. We found that chronic ethanol drinking increased dopamine uptake rates, which could have implications for reductions in basal dopamine tone in vivo during ethanol withdrawal. Further, across sex, strain and exposure length, ethanol use augmented the ability of KORs to inhibit dopamine release, demonstrating that ethanol‐induced increases in KOR sensitivity are widespread and independent of other factors. Finally, KOR sensitivity was positively correlated with lifetime ethanol intake, suggesting that changes in KOR regulation of dopamine release may be a determinant of aberrant drinking behaviors. Nonhuman primate models of ethanol abuse represent a highly translational avenue for identifying molecular targets for pharmacotherapeutic compounds, and here we show, for the first time, that voluntary ethanol self‐administration has a unique effect on KOR sensitivity and regulation of dopamine release directly at the dopamine terminal that was positively correlated with drinking behavior. Together, these data provide novel insight into ethanol‐induced dysregulation of opioid signaling and suggest that dopaminergic dysfunction may be mediating increases in voluntary drinking. Importantly, KOR antagonists may be efficacious in reducing drinking behaviors in alcoholics.