Background Alcohol potentiates GABAergic neurotransmission via action at the GABAA receptor. α1 subunit-containing GABAA receptors have been implicated as mediators, in part, of the behavioral and abuse-related effects of alcohol in rodents. Methods We systematically investigated the effects of one α1-preferring benzodiazepine agonist, zolpidem, and two antagonists, βCCT and 3-PBC, on oral self-administration of alcohol (2% w/v) or sucrose solution and observable behavior in rhesus macaques. We compared these effects to those of the nonselective benzodiazepine agonist triazolam, antagonist flumazenil, and inverse agonist βCCE. Results Alcohol and sucrose solutions maintained reliable baseline drinking behavior across the study. The α1-preferring compounds did not affect intake, number of sipper extensions, or blood alcohol levels at any of the doses tested. Zolpidem, βCCT, and 3-PBC increased latency to first sipper extension in animals self-administering alcohol, but not sucrose, solution. Triazolam exerted biphasic effects on alcohol drinking behavior, increasing intake at low doses but decreasing BAL and increasing latency at higher doses. At doses higher than those effective in alcohol-drinking animals, triazolam increased sucrose intake and latency. Flumazenil non-systematically increased number of extensions for alcohol but decreased BAL, with no effects on sucrose drinking. βCCE decreased sipper extensions for alcohol and increased latency for first sucrose sipper extension, but full dose-effect relationships could not be determined due to seizures at higher doses. Conclusions Alcohol-drinking animals appeared more sensitive to the effects of GABAergic compounds on drinking behavior. However, these results do not support a strong contribution of α1GABA receptors to the reinforcing effects of alcohol in primates.

Studies in humans indicate that specific single nucleotide polymorphisms (SNPs) in the gene encoding the μ‐opioid receptor (OPRM1) may influence sensitivity to the abuse‐related effects of alcohol. Rhesus macaques express a functionally analogous SNP (C77G) and serve as a highly translational model of the human variant. We selected rhesus macaques (n=18) a priori such that the genotypes (G/G, C/G, C/C) were equally represented, and characterized alcohol pharmacokinetics and self‐administration behavior via established oral induction paradigms. Preliminary results suggest that G/G animals met drinking criteria sooner and more often during the induction period than C/C animals. We then evaluated their sensitivity to the reinforcing effects of alcohol by varying the concentration available (1–8%) for self‐administration during a 3‐hr daily access period. All animals maintained stable intakes with little variation in dose ingested across different alcohol concentrations. G‐allele carriers drank significantly higher doses of alcohol across the different concentrations. No significant pharmacokinetic differences between genotypes were observed. These data suggest that the G‐allele in macaques may increase alcohol drinking behavior, potentially modeling a pharmacogenetically‐determined vulnerability to alcohol use disorders in humans. Funding: AA016828 (DMP) and RR000168 (NEPRC; OD011103)