Here, we asked whether OPRM1 A118G modulates striatal DA release in response to alcohol. We first carried out a human positron emission tomography (PET) study using displacement of the DA-D2 ligand [11C]-raclopride, an indirect measure of endogenous DA release 16, and found that 118G carriers had a markedly more vigorous striatal DA response to alcohol compared to subjects homozygous for the major 118A allele. In parallel, we isolated the influence of OPRM1 A118G variation by generating humanized mice, carrying the human exon 1 of the OPRM1 gene, either as the major 118A allele, or with the 118G SNP introduced through site directed mutagenesis. Direct microdialysis measures of the response to a rewarding dose of alcohol showed a four-fold higher peak DA response to the alcohol challenge.
