The aim of this study is to elucidate ethanol’s cellular and synaptic impact, both acutely and chronically, on human neurons of the GABAergic variety, carrying MOR N40D gene variants. Specifically, we were focused on the effect of ethanol on GABAergic transmission in iNs expressing MOR N40D, independent of opioidergic signaling. We found that acute application of ethanol caused an increase in sIPSC and mIPSC frequency for N40-harboring iNs, while only a modest increase was observed in D40 human iNs. In agreement with these data, we also observed a significant decrease in spontaneous action potential firing frequency for N40-containing iNs, due to an increased GABA release. Interestingly, we observed a significant increase in inhibitory synaptic release exclusively in iNs harboring D40 MOR allelic variants, following a 10-day chronic intermittent ethanol (CIE) exposure paradigm, intended to mimic a diurnal drinking pattern common in AUD subjects. Our findings suggest that ethanol treatment alone results in a differential sensitivity to acute and chronic treatment between genotypes. These results may provide a better mechanistic understanding of the interaction between alcohol and opioid signaling in humans.
