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

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• 作者：Berthold Drexler ; Rachel Jurd ; Uwe Rudolph ; Bernd Antkowiak
• 关键词：Etomidate ; Propofol ; Neocortex ; GABAA receptor ; Network activity ; Inhibitory postsynaptic currents
• 刊名：Neuropharmacology
• 出版年：2009
• 出版时间：September 2009
• 年：2009
• 卷：57
• 期：4
• 页码：446-455
• 全文大小：931 K

文摘

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 β3 subunits. Here the authors address the question as to whether etomidate and propofol are targeting different subpopulations of β3 subunit containing GABA_A receptors.

The effects of etomidate and propofol (0.5 μM and 1.0 μM) on spontaneous activity of neocortical neurons were investigated in organotypic slice cultures from wild-type and β3(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 β3(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 β3(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 β3(N265M) mutation, different subpopulations of β3-containing GABA_A receptors are likely to be involved.