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

Abstract

Gamma-aminobutyric acid (GABA) is the main chemical inhibitory neurotransmitter in the brain. In the central nervous system (CNS) it acts on two distinct types of receptor: an ion channel, i.e., an "ionotropic" receptor permeable to Cl -and HCO 3 -(GABA A receptors) and a G-protein coupled "metabotropic" receptor that is linked to various effector mechanisms (GABA B receptors). This review will summarize novel developments in the physiology and pharmacology of GABA A receptors (GABA A Rs), specifically those found outside synapses. The focus will be on a particular combination of GABA A R 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.

Subunit-Specific Trafficking of GABAAReceptors during Status Epilepticus

“…Tonic inhibition is mediated predominantly by extrasynaptic ␦ subunit-containing GABARs Mody et al, 2007). A unique finding of this study was that, unlike the surface expression of the ␤2/3 and ␥2 subunits, the surface expression of the ␦ subunit in the SE-treated slices was not reduced after in vivo SE.…”

“…In an in vivo study (Naylor et al, 2005), SE resulted in altered GABA-mediated inhibition and a diminished colocalization of the ␤2/3 and ␥2 GABAR subunits with synaptic markers. Although the second study found an increase in tonic inhibition, neither study directly assessed changes in the trafficking of the extrasynaptic ␦ subunit-containing GABARs, the prime mediators of tonic inhibition Mody et al, 2007). These studies also offered two different explanations for the increased trafficking of GABARs during SE.…”

“…As ␦ subunit-containing GABARs are one of the prime mediators of tonic inhibition (for review, see Glykys and Mody, 2007;Mody et al, 2007), we hypothesized that in the absence of a reduction in the surface expression of the ␦ subunit in the SE-treated slices that GABA-mediated tonic inhibition is not reduced during the prolonged seizures of SE.…”

Endogenous GABA A and GABA B receptor-mediated electrical suppression is critical to neuronal anoxia tolerance

“…Conversely, anoxiatolerant turtle cortical neurons likely do not express extrasynaptic GABA A Rs because they lack an observable tonic current. This is not uncommon; many cell types do not express these receptors (32). More importantly, because E GABA is depolarizing relative to V m in normoxic turtle brain, any tonic GABAergic activity would be excitatory, and therefore the absence of such a tone in this model is not surprising.…”

“…Tonic currents are mediated by extrasynaptic GABA A Rs and set the excitability threshold for neurons in adult mammalian brain (32). Baseline tonic inhibition is typically >50 pA, and this activity increases greater than twofold postischemic insult in mammals and impairs functional recovery following stroke (9,33).…”