Ethanol consumption and reward are decreased in mu-opiate receptor knockout mice

Rationale: Differences in mu -opiate receptor (MOR) gene expression may mod ulate the rewarding effects of ethanol. Objective. The effects of MOR gene knockout (KO) were examined in wild-type (+/+), heterozygote MOR KO (+/-), and homozygote MOR KO (-/-) mice on voluntary ethanol consumption, conditio ned place preference produced by ethanol, and locomotor responses to ethano l in separate groups of mice. Methods: Voluntary ethanol consumption (2-32% v/v) was examined in a two-bottle home-cage consumption test. The conditio ned place preference paradigm was a biased design. Mice received four pairi ngs of ethanol (2.0 g/kg IP) on the initially preferred side and four pairi ngs on the initially non-preferred side with saline. The difference in time spent on the initially non-preferred side (pre- versus post-conditioning) was the measure of drug-induced preference. After habituation to a novel lo comotor test chamber mice were tested, on subsequent sessions, for ethanol induced locomotion (0.0, 0.5, 1.0, and 2.0 g/kg IP). Results: Heterozygous and homozygous MOR KO mice consumed less ethanol than wildtype mice. These effects appeared to be greater in female KO mice than in male KO mice. MOR KO mice, especially females, exhibited less ethanol reward in a conditioned place preference paradigm. These effects on ethanol reward were produced b y reductions in MOR expression levels as small as 50%. MOR KO mice exhibite d less ethanol-stimulated locomotion than did wild-type mice, an effect tha t was also largest in females. Conclusions: These data fit with the reporte d therapeutic efficacy of MOR antagonists in the treatment of human alcohol ism. Allelic variants that confer differing levels of MOR expression could provide different degrees of risk for alcoholism.