Our data demonstrate that the 118G allele, which encodes an amino acid substitution in the N-terminal extracellular loop of the receptor, confers a higher striatal DA-activation in response to alcohol regardless of whether it occurs in the context of other markers within its haplotype block or not. However, the molecular mechanism that mediates functional consequences of the 118G variant remains controversial. Initially described as a gain-of-function mutation due to increased affinity for β-End 11, OPRM1 118G has since been proposed to instead confer decreased expression in several systems, including human post-mortem brain tissue 55, and a mouse model where a mutation was introduced in a position corresponding to the human A118G marker 56. The latter model differs from that used in our study, in that it introduced the N → D substitution in the context of a murine N-terminal receptor protein sequence. In contrast, we generated mice expressing humanized receptors throughout this region by replacing all of exon 1, the main region of divergence between the two species (Figure 2A). Using this model, our present findings show that a key
