Discriminative Stimulus Effects and Metabolism of Ethanol in Rhesus Monkeys

Background: Animal models are an essential feature of drug and pharmacotherapy development for treating alcohol use disorders (AUDs). The rhesus macaque is a robust animal model for many aspects of AUDs particularly in exploiting individual differences in oral self-administration of ethanol (EtOH), endocrine orchestration of stress response, and menstrual cycle characteristics. However, the clearance rates of EtOH have not been reported in this species, and the GABA_A and N-methyl-D-aspartate (NMDA) receptor involvement in EtOH's discriminative stimulus effects has not been fully characterized. Methods: EtOH clearance rates following 2 doses of EtOH on separate days (0.5 and 1.0 g/kg, i.g.) were determined in 8 young adult male rhesus macaques. The EtOH was given by nasogastric gavage, and repeated blood samples were taken over 5 hours without sedation. Next, all subjects were trained on a 2-choice 1.0 g/kg EtOH (i.g.) versus water discrimination with a 60-minutes pretreatment period to capture peak blood EtOH concentration (BEC). Substitution testing was conducted with GABA_A ligands pentobarbital (i.g. and i.m.) and midazolam (i.g.), as well as NMDA antagonist MK-801 (i.m.). Results: Peak BECs were 34 and 87 mg/dl for 0.5 and 1.0 g/kg doses, respectively, and occurred at 66 and 87 minutes following gavage. All GABA_A and NMDA ligands tested resulted in responding on the EtOH-appropriate lever with the potency ranking of MK-801 (ED₅₀: 0.017 mg/kg) > midazolam (ED₅₀: 1.6 mg/kg) > pentobarbital (ED₅₀: 3.7 mg/kg) > EtOH (ED₅₀: 700 mg/kg, or 0.7 g/kg) in these subjects. Conclusions: These results suggest that the compound discriminative stimulus effects of EtOH are highly consistent across species, providing further support for the rhesus macaque as strong model for pharmacotherapy development for AUD.