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The Journal of Neuroscience, September 17, 2003, 23(24):8608-8617

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Sedation and Anesthesia Mediated by Distinct GABA_A Receptor Isoforms

David S. Reynolds,^1 * Thomas W. Rosahl,^1 * Jennifer Cirone,^1 * Gillian F. O'Meara,¹ Alison Haythornthwaite,² Richard J. Newman,¹ Janice Myers,¹ Cyrille Sur,¹ Owain Howell,¹ A. Richard Rutter,¹ John Atack,¹ Alison J. Macaulay,¹ Karen L. Hadingham,¹ Peter H. Hutson,¹ Delia Belelli,² Jeremy J. Lambert,² Gerard R. Dawson,¹ Ruth McKernan,¹ Paul J. Whiting,¹ and Keith A. Wafford¹

¹Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, Essex CM20 2QR, United Kingdom, and ²Department of Pharmacology and Neuroscience, Ninewells Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom

The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABA_A receptors, with selectivity for 2 and 3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive 2 subunit (2 N265S) to determine the role of 2 and 3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through 3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the 2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABA_A receptor subtypes.

Key words: GABA; transgenic; etomidate; general anesthesia; sedation; loreclezole; GABA_A 2 subunit

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Received May 12, 2003; revised July 31, 2003; accepted August 1, 2003.

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