Discriminative stimulus effects and metabolism of ethanol in rhesus monkeys.

Abstract

BACKGROUND\nAnimal 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, endocrine orchestration of stress response and menstrual cycle characteristics. However, the clearance rates of ethanol have not been reported in this species, and the GABAA and NMDA receptor involvement in ethanol s discriminative stimulus effects have not been fully characterized.\n\n\nMETHODS\nEthanol clearance rates following two doses of ethanol on separate days (0.5 and 1.0 g/kg, i.g.) were determined in eight young adult male rhesus macaques. The ethanol was given by nasogastric gavage and repeated blood samples were taken over 5 hours without sedation. Next, all subjects were trained on a two-choice 1.0 g/kg ethanol (i.g.) vs. water discrimination with a 60 min pre-treatment period to capture peak blood ethanol concentration (BEC). Substitution testing was conducted with GABAA ligands pentobarbital (i.g. and i.m.) and midazolam (i.g.), as well as NMDA antagonist MK-801 (i.m.).\n\n\nRESULTS\nPeak blood ethanol concentrations (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 GABAA and NMDA ligands tested resulted in responding on the ethanol-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) > ethanol (ED50 : 700 mg/kg, or 0.7 g/kg) in these subjects.\n\n\nCONCLUSIONS\nThese results suggest that the compound discriminative stimulus effects of ethanol are highly consistent across species, providing further support for the rhesus macaque as strong model for pharmacotherapy development for AUD. This article is protected by copyright. All rights reserved.