Department of Anesthesiology

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Isoflurane is a potent modulator of extrasynaptic GABA(A) receptors in the thalamus.

TitleIsoflurane is a potent modulator of extrasynaptic GABA(A) receptors in the thalamus.
Publication TypeJournal Article
Year of Publication2008
AuthorsJia F, Yue M, Chandra D, Homanics GE, Goldstein PA, Harrison NL
JournalJ Pharmacol Exp Ther
Volume324
Issue3
Pagination1127-35
Date Published2008 Mar
ISSN1521-0103
KeywordsAnimals, Cell Line, Dose-Response Relationship, Drug, Humans, Inhibitory Postsynaptic Potentials, Isoflurane, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Receptors, GABA-A, Synapses, Thalamus
Abstract

Volatile anesthetics are used clinically to produce analgesia, amnesia, unconsciousness, blunted autonomic responsiveness, and immobility. Previous work has shown that the volatile anesthetic isoflurane, at concentrations that produce unconsciousness (250-500 microM), enhances fast synaptic inhibition in the brain mediated by GABA(A) receptors (GABA(A)-Rs). In addition, isoflurane causes sedation at concentrations lower than those required to produce unconsciousness or analgesia. In this study, we found that isoflurane, at low concentrations (25-85 microM) associated with its sedative actions, elicits a sustained current associated with a conductance increase in thalamocortical neurons in the mouse ventrobasal (VB) nucleus. These isoflurane-evoked currents reversed polarity close to the Cl(-) equilibrium potential and were totally blocked by the GABA(A)-R antagonist gabazine. Isoflurane (25-250 microM) produced no sustained current in VB neurons from GABA(A)-R alpha(4)-subunit knockout (Gabra4(-/-)) mice, although 250 microM isoflurane enhanced synaptic inhibition in VB neurons from both wild-type and Gabra4(-/-) mice. These data indicate an obligatory requirement for alpha(4)-subunit expression in the generation of the isoflurane-activated current. In addition, isoflurane directly activated alpha(4)beta(2)delta GABA(A)-Rs expressed in human embryonic kidney 293 cells, and it was more potent at alpha(4)beta(2)delta than at alpha(1)beta(2)gamma(2) receptors (the presumptive extrasynaptic and synaptic GABA(A)-R subtypes in VB neurons). We conclude that the extrasynaptic GABA(A)-Rs of thalamocortical neurons are sensitive to low concentrations of isoflurane. In view of the crucial role of the thalamus in sensory processing, sleep, and cognition, the modulation of these extrasynaptic GABA(A)-Rs by isoflurane may contribute to the sedation and hypnosis associated with low doses of this anesthetic agent.

DOI10.1124/jpet.107.134569
Alternate JournalJ. Pharmacol. Exp. Ther.
PubMed ID18094320
Grant ListAA 13004 / AA / NIAAA NIH HHS / United States
AA 16393 / AA / NIAAA NIH HHS / United States
GM 066840 / GM / NIGMS NIH HHS / United States
GM 47818 / GM / NIGMS NIH HHS / United States