Sedation and anesthesia mediated by distinct GABAA receptor isoforms

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

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    Abstract

    The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABAA 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 GABAA receptor subtypes.
    Original languageEnglish
    Pages (from-to)8608-8617
    Number of pages10
    JournalJournal of Neuroscience
    Volume23
    Issue number24
    Publication statusPublished - Sep 2003

    Keywords

    • Anaesthetics pharmacology
    • Etomidate pharmacology
    • Hypnotics and sedatives pharmacology
    • Receptors
    • GABA-A metabolism

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    Reynolds, D. S., Rosahl, T. W., Cirone, J., O'Meara, G. F., Haythornthwaite, A., Newman, R. J., Myers, J., Sur, C., Howell, O., Rutter, A. R., Atack, J., Macaulay, A. J., Hadingham, K. L., Hutson, P. H., Belelli, D., Lambert, J., Dawson, G. R., McKernan, R., Whiting, P. J., & Wafford, K. A. (2003). Sedation and anesthesia mediated by distinct GABAA receptor isoforms. Journal of Neuroscience, 23(24), 8608-8617. http://www.jneurosci.org/content/23/24.toc