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 μM), enhances fast synaptic inhibition in the brain mediated by GABAA receptors (GABAA-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 GABAA-R antagonist gabazine. Isoflurane (25–250 μM) produced no sustained current in VB neurons from GABAA-R α4-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 α4-subunit expression in the generation of the isoflurane-activated current. In addition, isoflurane directly activated α4β2δ GABAA-Rs expressed in human embryonic kidney 293 cells, and it was more potent at α4β2δ than at α1β2γ2 receptors (the presumptive extrasynaptic and synaptic GABAA-R subtypes in VB neurons). We conclude that the extrasynaptic GABAA-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 GABAA-Rs by isoflurane may contribute to the sedation and hypnosis associated with low doses of this anesthetic agent.
Footnotes
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The work was supported by grants from the National Institutes of Health (AA 16393 to N.L.H.; AA 13004 and GM 47818 to G.E.H.; and GM 066840 to P.A.G.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.134569.
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ABBREVIATIONS: GABAA-R(s), GABAA receptor(s); VB, ventrobasal; HEK, human embryonic kidney; IPSC, inhibitory postsynaptic current; KO, knockout; EIso, isoflurane-activated current; ECl, Cl– equilibrium potential; AP, action potential; Rm, membrane input resistance; WT, wild-type.
- Received November 21, 2007.
- Accepted December 18, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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