Title | Isoflurane is a potent modulator of extrasynaptic GABA(A) receptors in the thalamus. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Jia F, Yue M, Chandra D, Homanics GE, Goldstein PA, Harrison NL |
Journal | J Pharmacol Exp Ther |
Volume | 324 |
Issue | 3 |
Pagination | 1127-35 |
Date Published | 2008 Mar |
ISSN | 1521-0103 |
Keywords | Animals, 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. |
DOI | 10.1124/jpet.107.134569 |
Alternate Journal | J. Pharmacol. Exp. Ther. |
PubMed ID | 18094320 |
Grant List | AA 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 |