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NEUROPHARMACOLOGY

Isoflurane Is a Potent Modulator of Extrasynaptic GABA_A Receptors in the Thalamus

C.V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, Weill Cornell Medical College, New York, New York (F.J., M.Y., P.A.G., N.L.H.); and Departments of Anesthesiology and Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania (D.C., G.E.H.)

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 µM), 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 µM) 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 µM) produced no sustained current in VB neurons from GABA_A-R ₄-subunit knockout (Gabra4^–/–) mice, although 250 µM isoflurane enhanced synaptic inhibition in VB neurons from both wild-type and Gabra4^–/– mice. These data indicate an obligatory requirement for ₄-subunit expression in the generation of the isoflurane-activated current. In addition, isoflurane directly activated ₄β₂ GABA_A-Rs expressed in human embryonic kidney 293 cells, and it was more potent at ₄β₂ than at ₁β₂₂ 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.

Address correspondence to: Dr. Neil Harrison, Department of Anesthesiology, Weill Cornell Medical College, 1300 York Avenue, Room A-1050, New York, NY 10065. E-mail: neh2001{at}med.cornell.edu

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