Ethanol’s interactions with GABA-mimetic drugs have long been known, and the synergism of ethanol and barbiturates was studied extensively before it was clear that both of these drugs act on GABAA receptors (Mihic and Harris, 2011). Thus, a top-down analysis indicated that ethanol’s effect on GABAA-mediated fast synaptic transmission was likely to be a fruitful area of study to better understand intoxication and high-dose ethanol actions. Accordingly, it was natural to assume that ethanol would act on GABAA receptors in a manner similar to other sedative drugs. Indeed, ethanol potentiates GABAA receptors in some neurons and heterologous expression systems (Harris et al., 1997; Mihic, 1999). Examination of “tonic” GABAA currents consistently revealed increases in postsynaptic GABA responses in the cerebellum (Diaz and Valenzuela, 2016) (Figure 2K), hippocampus (Liang et al., 2006), and thalamus (Jia et al., 2008). These actions of ethanol often involve the GABAA δ subunit (Choi et al., 2008). However, there has been debate about the mechanisms involved in this tonic current effect. In the cerebellum, there is evidence that ethanol’s enhancement of interneuron firing is a key factor underlying increased tonic current (Valenzuela and Jotty, 2015), but this may not be the case in other brain regions.
