Recently we reported the generation of genetically modified, ‘humanized’ mouse lines that are homozygous either for the wild-type (118AA) or variant (118GG) human OPRM1 allele and express the respective MOR25. It is known that mesolimbic dopamine neurons are under tonic gamma aminobutyric acid-ergic inhibition that can be lifted through activation of MOR on gamma aminobutyric acid -ergic terminals in the ventral tegmental area. It is further known that alcohol administration results in release of endogenous opioids in the ventral tegmental area, and through the cascade outlined ultimately in striatal dopamine release. Using this as a functional readout, and employing brain microdialysis, we found that 118GG mice exhibited a fourfold greater peak dopamine response following an alcohol challenge, demonstrating that A118G variation is functional in this animal model25. This study, however, left unresolved the molecular mechanism mediating the functional role of the A118G polymorphism, since binding of classical mu-agonists (β-endorphin, DAMGO) as well as signaling induced by these were unaffected by genotype.
