Ethanol exerts its effects through a plethora of molecular targets to produce intoxication. However, the clearest presynaptic effect for ethanol is at GABAergic synapses in several brain regions (Lovinger, 2018). The direct action of ethanol at GABAergic presynaptic terminals was shown in isolated “neuron-bouton” preparations (Kelm, Criswell, & Breese, 2007; Zhu & Lovinger, 2006), where ethanol produced a rapid and robust increase in the frequency of sIPSC and mIPSCs (Zhu & Lovinger, 2006). These data suggest that ethanol exerts a direct effect on GABAergic presynaptic terminals, which seems to be independent of modulatory or retrograde signals from postsynaptic neurons. Our study builds on these findings in a human-specific context and represents a significant advance in elucidating the neurobiological mechanisms underlying the ethanol sensitivity for human neurons expressing MOR N40D.
