Studies of Mice with one or Two Copies of G Allele of Human Oprm1 Genetic Variations in Excessive Alcohol Drinking - Abstract
Endogenous opioid system plays an essential role in regulating alcohol consumption. Genetic deletion of mu-opioid receptor (MOP-r) decreases alcohol intake and reward in mouse models. A single-nucleotide polymorphism (SNP; A118G, rs1799971) in human MOP-r gene (Oprm1) is associate with altered MOP-r activity, resulting in enhanced alcohol consumption and increased risk of developing alcoholism in individuals with at least one copy of G allele (AG and GG). The present study determined the impact of Oprm1 SNP on alcohol drinking using A112G mice (a functionally equivalent SNP in Oprm1 with a similar amino acid substitution in humans) in chronic excessive drinking model. We found that both AG and GG males had greater alcohol intake than AA males, suggesting that increased MOP-r signaling with one or two copies of G allele promoted alcohol consumption. Though AG+GG males showed more sucrose intake than AA males, there was no genotypic difference in saccharin intake. In contrast to males, females did not show any genotypic difference in alcohol, sucrose or saccharin consumption. Pharmacological blockade of MOP-r with low-dose naltrexone reduced intake in AG+GG males, with blunted effects in AA males, confirming that increased MOP-r signaling by G allele contributes to MOP-r mediated modulation of alcohol drinking. However, activation of kappaopioid receptors [KOP-] by nalfurafine only decreased intake in AA males, suggesting altered KOP-r responses by G allele. Together, our data suggest that there is selective involvement of Oprm1 G allele (one or two copies) in excessive alcohol drinking with sex difference and altered opioid receptor responses.