Naltrexone and alcohol drinking in mice lacking beta-endorphin by site-directed mutagenesis.
Alcohol-induced activation of the opioid system may contribute to the reinforcing properties of alcohol. This study investigated whether elimination of beta-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.
Grahame
N J
NJ
Departments of Medicine and Psychiatry, Indiana University School of Medicine, 791 Union Drive PR 311, Indianapolis, IN 46222, USA. ngrahame@iupui.edu
Mosemiller
A K
AK
Low
M J
MJ
Froehlich
J C
JC
D000428:Alcohol Drinking / Q000188:drug therapy / Q000235:genetics*; D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed / Q000187:drug effects / Q000235:genetics*; D009271:Naltrexone / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use; D001615:beta-Endorphin / Q000235:genetics*
D009292:Narcotic Antagonists; D009271:Naltrexone; D001615:beta-Endorphin