To investigate the role of A118G in response to ethanol, the effects of acute and long‐term ethanol exposure were examined. Previous studies in rodents showed that ethanol potentiates GABAergic transmission. 53 Acute application of 40 mM ethanol increased the frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSC and mIPSC) in N40‐expressing inhibitory iNs, suggesting a presynaptic origin of GABA potentiation. 38 In addition, the increases of sIPSC and mIPSC were larger for major N40‐harboring iNs, compared with neurons from D40 minor allele carriers. N40 iNs also exhibited a significant reduction of spontaneous action potential firing, consistent with pronounced GABA release. Conversely, a 10‐day intermittent ethanol exposure (IEE), intended to mimic diurnal drinking patterns, produced stronger GABA potentiating responses exclusively in iNs harboring the minor D40 MOR allelic variant but not in iNs with the major allele, as was observed with acute ethanol exposure (Figure 3). Collectively, these studies demonstrate the contribution of non‐synonymous variants to altered ethanol responses and provide a better mechanistic understanding of AUD pathology.
