Amnestic concentrations of etomidate modulate gabaa,slow synaptic inhibition in hippocampus

Abstract

BACKGROUND: γ-Aminobutyric acid type A (GABAA) receptor-mediated inhibition in the central nervous system exists in two forms: phasic (inhibitory postsynaptic currents, IPSCs) and tonic (nonsynaptic). Phasic inhibition is further subdivided into fast (GABAA,fast) and slow (GABAA,slow) IPSCs. By virtue of its dendritic location and kinetics, GABAA,slow has been proposed to control synaptic plasticity and memory. Etomidate is a nonbarbiturate, intravenous anesthetic that selectively modulates GABAA receptors and produces amnesia at low doses in vivo. This study tested whether correspondingly low concentrations of etomidate in vitro alter GABAA,fast and GABAA,slow phasic inhibition. METHODS: Electrophysiological recordings were obtained from hippocampal slices prepared from postnatal day 3-8 mice and maintained in organotypic culture for 10-14 days. Etomidate was applied at concentrations corresponding to one-half to four times the half maximal effective concentration that impairs hippocampus-dependent learning and memory-i.e., 0.125-1.0 μm. RESULTS: Etomidate 0.25 μm (the half maximal effective concentration) doubled the time constant of decay of GABAA,slow IPSCs, but it had no detectable effect on GABAA,fast IPSCs. Higher concentrations of etomidate had stronger effects on both types of phasic inhibition: 0.5 and 1 μm etomidate prolonged the time constant of decay by 310% and 410% for GABAA,slow and by 25% and 78% for GABAA,fast. Concentrations of etomidate up to 1 μm had no significant effects on the amplitudes of either GABAA,fast or GABAA,slow IPSCs. CONCLUSIONS: At concentrations that impair hippocampus-dependent memory, etomidate modulates GABAA,slow more strongly than GABAA,fast IPSCs. Effects of etomidate on GABAA,slow IPSCs may contribute to etomidate-induced amnesia. © 2009, the American Society of Anesthesiologists, Inc.