β3-containing GABA_A receptors mediate the immobilizing and, in part, the hypnotic actions of etomidate and propofol

The molecular mechanisms underlying general anesthesia are only beginning to be understood. In this summary, we describe how the role of specific GABA_A receptor subtypes in mediating the clinically relevant actions of general anesthetics has been defined by genetic studies in vivo. In particular, we describe our findings with mice engineered to contain a point mutation, N265M, in the β3 subunit of the GABA_A receptor. This mutation has previously been shown to render recombinant β3-containing GABA_A receptors essentially insensitive to etomidate and propofol. β3(N265M) mice exhibited a completely abolished immobilizing response to etomidate and propofol, as measured by loss of hindlimb withdrawal reflexes. In addition, the respiratory depressant action of etomidate and propofol, as determined by blood gas analysis, was almost absent in β3(N265M) mice. Furthermore, there was a significantly reduced hypnotic response, as measured by loss of righting reflex duration, compared with wild-type mice. In contrast, sedation, as measured by a decrease in motor activity, and the cardiac depressant and hypothermic effects, as determined by radiotelemetry, remained unchanged in the mutant mice. We conclude that the immobilizing and respiratory depressant and, in part, the hypnotic action of etomidate and propofol, but not the cardiac, hypothermic and sedative effects, are mediated by β3-containing GABA_A receptor subtypes.