Chunk #15 — Acute effects of ethanol on GABAA receptors — Direct effects on GABAA receptor subtypes — Low dose effects of ethanol (≤30 mM) on tonic inhibition
While much work has shown that ethanol enhances GABAA receptor potentiation, the exact mechanism of ethanol actions on these receptors remains unclear. Recent work has addressed the contribution of specific GABAA receptor subtypes in distinct cellular localizations at ethanol concentrations typically found in social settings (3–30 mM). Several groups have shown that ethanol enhances the inhibition of α4/6βδ-GABAA receptors (found extra-synaptically), whereas receptors containing a γ2 subunit (found synaptically) are significantly less sensitive to the ethanol enhancement of GABAergic responses (Sundstrom-Poromaa et al. 2002; Wallner et al. 2003; Wei et al. 2004). Typically, δ-GABAA receptors are found extrasynaptically and are commonly associated with α4/α6 subunits (Jones et al. 1997; Sur et al. 1999; Wei et al. 2003). Additionally, these receptors have a greater affinity for GABA (Brown et al. 2002; Wallner et al. 2003) and knockout models display substantially reduced/absent tonic inhibition (Brickley et al. 2001; Chandra et al. 2006; Stell et al. 2003). Importantly, δ-GABAA receptor knockout mice also have reduced/ablated enhancement of tonic current by ethanol (Glykys et al. 2007). Therefore, it is likely that ethanol actions on α4/6βδ-GABAA receptors involve the modulation of tonic inhibition in vivo.
