Clinical and rodent studies aimed at understanding the impact of OPRM1 A118G on AUDs have yielded mixed conclusions. Work using humanized 118GG mice shows an increased rate of ethanol intake when compared to 118AA mice (Henderson-Redmond et al., 2018). This work supports both clinical (Anton et al., 2008; Bart et al., 2005; Chamorro et al., 2012; Hendershot et al., 2016; Oslin et al., 2003; Ray & Hutchison, 2004, 2007) and rodent studies that suggest that G minor allele carriers may bestow a genetic susceptibility toward AUDs. However, these studies hypothesize that ethanol reinforcement observed for G allele carriers (animals and humans) is mediated by the endogenous opioid system (reviewed by Herz, 1997), ultimately increasing dopamine release along mesolimbic dopamine neurocircuitry (reviewed by Koob, 1992). Our recent functional study, utilizing patient-derived iPS cells harboring OPRM1 A118G, found that in response to an opioid agonist, MOR N40D allele iNs consistently exhibited stronger suppression, which suggests that this SNP causes a gain of MOR function. These data show altered opioid responsivity and/or dependence between human MOR genetic variants (Halikere et al., 2019). The
