The mechanisms underlying ethanol potentiation of GABA release are not well-understood. Examination of mice lacking protein kinase A (PKA) or PKC epsilon indicate loss of the presynaptic actions of ethanol (Bajo et al., 2008; Proctor et al., 2003) and inhibition of AC has been shown to prevent this ethanol effect at some synapses (Talani and Lovinger, 2015) (Figure 2O). Activation of a variety of Gi/o-coupled G-protein coupled receptors (GPCRs) counteracts ethanol’s potentiation of GABA release at synapses in several brain regions (Ariwodola and Weiner, 2004; Kelm et al., 2011; Roberto et al., 2010; Talani and Lovinger, 2015). These findings reinforce the idea that signaling through AC and PKA is involved in ethanol’s actions and are in accord with findings from invertebrate models (Moore et al., 1998). In cerebellar granule neurons, although ethanol inhibits the function of GABAA receptors through a mechanism involving postsynaptic PKC, ethanol also enhances GABA release via inhibition of nitric oxide synthase (Kaplan et al., 2013) (Figure 2L).
