Amnestic concentrations of etomidate modulate GABAA,slow synaptic inhibition in hippocampus.
BACKGROUND
Gamma-aminobutyric acid type A (GABA(A)) 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 (GABA(A,fast)) and slow (GABA(A,slow)) IPSCs. By virtue of its dendritic location and kinetics, GABA(A,slow) has been proposed to control synaptic plasticity and memory. Etomidate is a nonbarbiturate, intravenous anesthetic that selectively modulates GABA(A) receptors and produces amnesia at low doses in vivo. This study tested whether correspondingly low concentrations of etomidate in vitro alter GABA(A,fast) and GABA(A,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 microm.


RESULTS
Etomidate 0.25 microm (the half maximal effective concentration) doubled the time constant of decay of GABA(A,slow) IPSCs, but it had no detectable effect on GABA(A,fast) IPSCs. Higher concentrations of etomidate had stronger effects on both types of phasic inhibition: 0.5 and 1 microm etomidate prolonged the time constant of decay by 310% and 410% for GABA(A,slow) and by 25% and 78% for GABA(A,fast). Concentrations of etomidate up to 1 microm had no significant effects on the amplitudes of either GABA(A,fast) or GABA(A,slow) IPSCs.


CONCLUSIONS
At concentrations that impair hippocampus-dependent memory, etomidate modulates GABA(A,slow) more strongly than GABA(A,fast) IPSCs. Effects of etomidate on GABA(A,slow) IPSCs may contribute to etomidate-induced amnesia.
Dai
Shuiping
S
Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Perouansky
Misha
M
Pearce
Robert A
RA
D000647:Amnesia / Q000139:chemically induced*; D000818:Animals; D004594:Electrophysiology; D005045:Etomidate / Q000008:administration & dosage / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D051379:Mice; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D018756:GABA Antagonists; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D005045:Etomidate