A new meaning for “Gin & Tonic”: tonic inhibition as the target for ethanol action in the brain

Gamma-aminobutyric acid (GABA) is the main chemical inhibitory neurotransmitter in the brain. In the central nervous system, it acts on two distinct types of receptor: an ion channel, that is, an “ionotropic” receptor permeable to Cl− and HCO3− (GABAA receptors [GABAARs]) and a G-protein coupled “metabotropic” receptor that is linked to various effector mechanisms (GABAB receptors). This review will summarize novel developments in the physiology and pharmacology of GABAARs, specifically those found outside synapses. The focus will be on a particular combination of GABAAR subunits responsible for mediating tonic inhibition and sensitive to concentrations of ethanol legally considered to be sobriety impairing. Since the same receptors are also a preferred target for the metabolites of steroid hormones synthesized in the brain (neurosteroids), the ethanol-sensitive tonic inhibition may be a common pathway for interactions between the effects of alcohol and those of ovarian and stress-related neurosteroids.