GABAA receptor subtypes: the “one glass of wine” receptors

Abstract

This review discusses evidence for and apparent controversy about, GABA A receptor subtypes that mediate alcohol effects experienced during social drinking. GABA A receptors that contain the β3 and δ subunits were shown to be enhanced by alcohol concentrations that mirror the concentrationdependence of alcohol responses in humans. A mutation (α6R100Q) previously found in alcohol non-tolerant (ANT) rats in the cerebellar GABA A receptor α6 subunit is sufficient for increased alcohol-induced ataxia in rats homozygous for this mutation (α6-100QQ) and further increases alcohol-sensitivity of tonic GABA currents (mediated by α6βδ receptors) in cerebellar granule cells of α6-100QQ rats and in recombinant α6R100Qβ3δ receptors. This provided the first direct evidence that these types of receptors mediate behavioral effects of ethanol. Furthermore the behavioral alcohol antagonist Ro15-4513 specifically reverses ethanol enhancement on α4/6β3δ receptors. Unexpectedly, native and recombinant α4/6β3δ receptors bind the behavioral alcohol antagonist Ro15-4513 with high affinity and this binding is competitive with EtOH, suggesting a specific and mutually exclusive (competitive) ethanol/Ro15-4513 site which explains the puzzling activity of Ro15-4513 as a behavioral alcohol antagonist.Our conclusion from these findings is that alcohol/Ro15-4513-sensitive GABA A receptor subtypes are important alcohol targets and that alcohol at relevant concentrations is more specific than previously thought. In this review we discuss technical difficulties in expressing recombinant δ subunit-containing receptors in oocytes and mammalian cells, that may have contributed to negative results and confusion. Not only because we have reproduced detailed positive results numerous times, and we and many others have built extensively on basic findings, but also because we explain and combine many previously puzzling results into a coherent and highly plausible paradigm on how alcohol exerts an important part of its action in the brain, we are confident about our findings and conclusions. However, many important open questions remain to be answered.

Oxytocin prevents ethanol actions at δ subunit-containing GABA A receptors and attenuates ethanol-induced motor impairment in rats

“…The δ-GABA A Rs, sometimes called the "one-glass-of-wine" receptors (24), are located in several brain regions, including the thalamus, cerebellum, hippocampus, and striatum (25,26), and show high sensitivity to relatively low doses of ethanol (2)(3)(4)(5)(6)(7)(8)27). A number of previous studies demonstrate the involvement of δ-GABA A Rs in a range of ethanolinduced functional effects, including ataxia, sedation, and reward (2-8).…”

The role of GABAA receptors in the development of alcoholism

“…Some studies have shown that low concentrations of ethanol (1-30mM) potentiate extrasynaptic receptors (≤ 5% of all receptors), predominantly composed of the non-BZ sensitive α 4 , α 6 and δ subunits, but have no effect on receptors with γ 2 subunits, i.e. the vast majority of synaptic GABA A receptors (Hanchar et al, 2006;Krystal et al, 2006;Olsen et al, 2007;Sundstrom-Poromaa et al, 2002). This is relevant because these relatively low concentrations of ethanol are experienced in social drinking; for example, 17mM is the legal upper limit of intoxication in most US States (Lovinger and Homanics, 2007).…”

Deleterious Effects of a Low Amount of Ethanol on LTP-Like Plasticity in Human Cortex

“…Cellular studies showed that low-dose EtOH (p30 mM) produces mainly two effects: potentiation of extrasynaptic gamma-aminobutyric acid type A receptor (GABAAR)-mediated tonic inhibition (Sundstrom-Poromaa et al, 2002;Wallner et al, 2003;Wei et al, 2004) (for review, (Olsen et al, 2007)), although this has not been unanimously supported (Borghese et al, 2006;Yamashita et al, 2006), and N-methyl-D-aspartate receptor (NMDAR) inhibition (Lovinger et al, 1989(Lovinger et al, , 1990Weitlauf and Woodward, 2008).…”