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Research ArticleBehavioral Pharmacology

Mifepristone Decreases Chronic Voluntary Ethanol Consumption in Rhesus Macaques

Vanessa A. Jimenez, Nicole A.R. Walter, Tatiana A. Shnitko, Natali Newman, Kaya Diem, Lauren Vanderhooft, Hazel Hunt and Kathleen A. Grant
Journal of Pharmacology and Experimental Therapeutics November 2020, 375 (2) 258-267; DOI: https://doi.org/10.1124/jpet.120.000169
Vanessa A. Jimenez
Division of Neuroscience, Oregon National Primate Research Center, Hillsboro, Oregon (V.A.J., N.A.R.W., T.A.S., N.N., K.D., L.V., K.A.G.); Corcept Therapeutics, Menlo Park, California (H.H.); and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon (K.A.G.)
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Nicole A.R. Walter
Division of Neuroscience, Oregon National Primate Research Center, Hillsboro, Oregon (V.A.J., N.A.R.W., T.A.S., N.N., K.D., L.V., K.A.G.); Corcept Therapeutics, Menlo Park, California (H.H.); and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon (K.A.G.)
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Tatiana A. Shnitko
Division of Neuroscience, Oregon National Primate Research Center, Hillsboro, Oregon (V.A.J., N.A.R.W., T.A.S., N.N., K.D., L.V., K.A.G.); Corcept Therapeutics, Menlo Park, California (H.H.); and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon (K.A.G.)
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Natali Newman
Division of Neuroscience, Oregon National Primate Research Center, Hillsboro, Oregon (V.A.J., N.A.R.W., T.A.S., N.N., K.D., L.V., K.A.G.); Corcept Therapeutics, Menlo Park, California (H.H.); and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon (K.A.G.)
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Kaya Diem
Division of Neuroscience, Oregon National Primate Research Center, Hillsboro, Oregon (V.A.J., N.A.R.W., T.A.S., N.N., K.D., L.V., K.A.G.); Corcept Therapeutics, Menlo Park, California (H.H.); and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon (K.A.G.)
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Lauren Vanderhooft
Division of Neuroscience, Oregon National Primate Research Center, Hillsboro, Oregon (V.A.J., N.A.R.W., T.A.S., N.N., K.D., L.V., K.A.G.); Corcept Therapeutics, Menlo Park, California (H.H.); and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon (K.A.G.)
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Hazel Hunt
Division of Neuroscience, Oregon National Primate Research Center, Hillsboro, Oregon (V.A.J., N.A.R.W., T.A.S., N.N., K.D., L.V., K.A.G.); Corcept Therapeutics, Menlo Park, California (H.H.); and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon (K.A.G.)
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Kathleen A. Grant
Division of Neuroscience, Oregon National Primate Research Center, Hillsboro, Oregon (V.A.J., N.A.R.W., T.A.S., N.N., K.D., L.V., K.A.G.); Corcept Therapeutics, Menlo Park, California (H.H.); and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon (K.A.G.)
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Abstract

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.

Footnotes

    • Received June 16, 2020.
    • Accepted August 17, 2020.
  • This work was supported by National Institutes of Health National Institute of Alcoholism and Alcohol Abuse [Grants AA019431, AA013510, AA013641] (to K.A.G.).

  • H.H. is an employee at Corcept Therapeutics.

  • https://doi.org/10.1124/jpet.120.000169.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 375 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 2
1 Nov 2020
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Research ArticleBehavioral Pharmacology

Mifepristone Decreases Ethanol Consumption in Monkey Model

Vanessa A. Jimenez, Nicole A.R. Walter, Tatiana A. Shnitko, Natali Newman, Kaya Diem, Lauren Vanderhooft, Hazel Hunt and Kathleen A. Grant
Journal of Pharmacology and Experimental Therapeutics November 1, 2020, 375 (2) 258-267; DOI: https://doi.org/10.1124/jpet.120.000169

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Research ArticleBehavioral Pharmacology

Mifepristone Decreases Ethanol Consumption in Monkey Model

Vanessa A. Jimenez, Nicole A.R. Walter, Tatiana A. Shnitko, Natali Newman, Kaya Diem, Lauren Vanderhooft, Hazel Hunt and Kathleen A. Grant
Journal of Pharmacology and Experimental Therapeutics November 1, 2020, 375 (2) 258-267; DOI: https://doi.org/10.1124/jpet.120.000169
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