Extrasynaptic GABAA receptors are critical targets for sedative-hypnotic drugs

Abstract

The gamma-aminobutyric acid subtype A (GABAA) receptor is widely considered to be an important target for most clinically effective sedative-hypnotic compounds, including general anesthetics, benzodiazepines, barbiturates, and gaboxadol or THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol). GABAA receptors are highly expressed in anatomical regions that are implicated in sleep processes, notably the thalamus. Furthermore, concentrations of these drugs that modify behavior in vivo also increase GABA-induced inhibitory conductances in vitro. This review will summarize the functional, regional distribution, and pharmacologic properties of various classes of GABAA receptors. Particular emphasis is placed on subpopulations of GABAA receptors that are expressed in extrasynaptic regions of neurons, as these receptors are exquisitely sensitive to several classes of sedative-hypnotic compounds. Evidence to date suggests that extrasynaptic GABAA receptors can be broadly classified into two groups; those containing the δ subunit and the non-δ subunit-containing GABAA receptors. Finally, the probable contribution of extrasynaptic GABAA receptors in the modulation of sleep will be considered.