Naltrexone and alcohol drinking in mice lacking β-endorphin by site-directed mutagenesis

• Published in: Pharmacology, biochemistry and behavior Vol. 67; no. 4; pp. 759 - 766
• Main Authors: Grahame, Nicholas J, Mosemiller, Anne K, Low, Malcolm J, Froehlich, Janice C
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2000
• Subjects: Alcohol deprivation effect; Alcohol Drinking - drug therapy; Alcohol Drinking - genetics; Alcohol preference; Animals; b-endorphin; beta-Endorphin - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutagenesis, Site-Directed - drug effects; Mutagenesis, Site-Directed - genetics; Naltrexone - therapeutic use; Narcotic Antagonists - therapeutic use; β-Endorphin-deficient mice; Alcohol deprivation effect; β-Endorphin-deficient mice; Alcohol preference
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/S0091-3057(00)00411-1

Alcohol-induced activation of the opioid system may contribute to the reinforcing properties of alcohol. This study investigated whether elimination of β-endorphin (BE) synthesis via site-directed mutagenesis in embryonic stem cells would alter alcohol intake in mice. Both BE-deficient and wildtype (WT) mice generated from the targeted stem cells were backcrossed for nine generations onto a C57BL/6 background, and were maintained with ad libitum food and water. Mice had access to alcohol (10% v/v) under the following conditions: 24 h, scheduled access for 2 h/day, following acute (1 or 2 days) or chronic (5 weeks) alcohol deprivation, and scheduled access following six doses of naltrexone (0.125–16.0 mg/kg BW, ip) or saline treatment. Alcohol intake was similar in BE-deficient and WT mice given chronic access to alcohol, but greater in BE-deficient compared with WT mice during the first 10 days of scheduled access to alcohol, but not after more extensive experience with scheduled access. BE-deficient, but not WT mice, increased alcohol intake following 2 days, but not 1 day or 5 weeks, of deprivation. Naltrexone reduced alcohol drinking both in BE-deficient and WT mice, suggesting that drinking is mediated, in part, by activation of opioid receptors in both genotypes.