Inhibitory transmission plays a similarly critical role in cognition, learning, and memory in the hippocampus (and the cortex at large) (129). In addition to alcohol’s reduction of glutamatergic transmission via impairment of GluN function, alcohol also acts as a non-competitive agonist, directly enhancing the chloride transmission of the gamma-aminobutyric acid A (GABAa) channel (130) effectively hyperpolarizing the neural cells (see Figure 1A for a summary). Similar to GluN, the GABAa receptor (GABAaR) is comprised of five subunits, typically two alpha (A1-6), two beta (B1-3), and one subunit, which could be comprised of a gamma (G1-3) or delta. However, unlike GluN, the precise site of action on a given subunit is of debate [reviewed in Ref. (21)], with many subunits demonstrating sensitivity to alcohol (131), and much evidence is contradictory; for example, Wallner et al. (20) suggested that the B3 subunit was mediating the receptor’s sensitivity to alcohol, but this was later contradicted in a mutant mouse model void of the B3 subunit, but still demonstrated GABA-ergic enhancement following alcohol administration (132). It is highly possible that alcohol’s capacity to enhance inhibitory function of the GABAaR is dependent on the specific conformation of subunits instead of acting at a single subunit.
