TY - JOUR T1 - Mifepristone Decreases Chronic Voluntary Ethanol Consumption in Rhesus Macaques JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 258 LP - 267 DO - 10.1124/jpet.120.000169 VL - 375 IS - 2 AU - Vanessa A. Jimenez AU - Nicole A.R. Walter AU - Tatiana A. Shnitko AU - Natali Newman AU - Kaya Diem AU - Lauren Vanderhooft AU - Hazel Hunt AU - Kathleen A. Grant Y1 - 2020/11/01 UR - http://jpet.aspetjournals.org/content/375/2/258.abstract N2 - The efficacy of short-term treatment with mifepristone (MIFE), a high-affinity, nonselective glucocorticoid receptor antagonist, to reduce ethanol drinking was tested in a rhesus macaque model. Stable individual daily ethanol intakes were established, ranging from 1.6 to 4.0 g/kg per day (n = 9 monkeys). After establishment of chronic ethanol intake, a MIFE dosing regimen that modeled a study of rodent drinking and human alcohol craving was evaluated. Three doses of MIFE (17, 30, and 56 mg/kg per day) were each administered for four consecutive days. Both 30 and 56 mg/kg decreased ethanol intake compared with baseline drinking levels without a change in water intake. The dose of 56 mg/kg per day of MIFE produced the largest reduction in ethanol self-administration, with the average intake at 57% of baseline intakes. Cortisol was elevated during MIFE dosing, and a mediation analysis revealed that the effect on ethanol drinking was fully mediated through cortisol. During a forced abstinence phase, access to 1.5 g/kg ethanol resulted in relapse in all drinkers and was not altered by treatment with 56 mg/kg MIFE. Overall, these results show that during active drinking MIFE is efficacious in reducing heavy alcohol intake in a monkey model, an effect that was related to MIFE-induced increase in cortisol. However, MIFE treatment did not eliminate ethanol drinking. Further, cessation of MIFE treatment resulted in a rapid return to baseline intakes, and MIFE was not effective in preventing a relapse during early abstinence.SIGNIFICANCE STATEMENT Mifepristone reliably decreases average daily ethanol self-administration in a nonhuman primate model. This effect was mediated by cortisol, was most effective during open-access conditions, and did not prevent or reduce relapse drinking. ER -