Distinct actions of etomidate and propofol at β3-containing γ-aminobutyric acid type A receptors

Etomidate and propofol have clearly distinguishable effects on the central nervous system. However, studies in knock-in mice provided evidence that these agents produce anesthesia via largely overlapping molecular targets, namely GABA(A) receptors containing beta 3 subunits. Here the authors address the question as to whether etomidate and propofol are targeting different subpopulations of beta 3 subunit containing GABA(A) receptors. The effects of etomidate and propofol (0.5 mu M and 1.0 mu M) on spontaneous activity of neocortical neurons were investigated in organotypic slice cultures from wild-type and beta 3(N265M) knock-in mice. Firing patterns were characterized by mean burst length and number of action potentials per burst. Additionally, etomidate and propofol actions on GABA(A) receptor-mediated currents were investigated by whole-cell voltage clamp recordings. On the network level, the duration of spontaneously occurring bursts of action potentials was decreased by etomidate but increased by propofol in the wild-type. The effects of etomidate were abolished in beta 3(N265M) mutant slices while those of propofol were qualitatively inverted. On the receptor level, GABA(A) receptor-mediated inhibition of cortical neurons was modulated by etomidate and propofol in different ways. Again, drug-specific actions of etomidate and propofol were largely attenuated by the beta 3(N265M) mutation. Etomidate and propofol alter the firing patterns and GABA(A) receptor-mediated inhibition of neocortical neurons in different ways. This suggests that etomidate and propofol act via non-uniform molecular targets. Because the major effects induced by these anesthetics were attenuated by the beta 3(N265M) mutation, different subpopulations of beta 3-containing GABA(A) receptors are likely to be involved. (C) 2009 Elsevier Ltd. All rights reserved.