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The Journal of Neuroscience, April 5, 2006, 26(14):3713-3720; doi:10.1523/JNEUROSCI.5024-05.2006
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Cellular/Molecular
 5GABAA Receptors Mediate the Amnestic But Not Sedative-Hypnotic Effects of the General Anesthetic Etomidate
Victor Y. Cheng,1 *
Loren J. Martin,1 *
Erin M. Elliott,1
John H. Kim,2,3
Howard T. J. Mount,1,2,3
Franco A. Taverna,4
John C. Roder,4
John F. MacDonald,2
Amit Bhambri,1
Neil Collinson,5
Keith A. Wafford,5 and
Beverley A. Orser1,2,6
1Institute of Medical Science, 2Department of Physiology, and 3Centre for Research in Neurodegenerative Diseases, Department of Medicine, Division of Neurology, University of Toronto, Toronto, Ontario, Canada M5S 1A8, 4Mount Sinai Hospital Research Institute, University of Toronto, Toronto, Ontario, Canada M5G 1X5, 5Merck Sharp and Dohme Research Laboratories, Neuroscience Research Center, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom, and 6Department of Anesthesia, Sunnybrook and Women's College Health Science Center, Toronto, Ontario, Canada M4N 3M5
Correspondence should be addressed to Dr. Beverley A. Orser, Department of Physiology, Medical Sciences Building, Room 3318, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. Email: beverley.orser{at}utoronto.ca
A fundamental objective of anesthesia research is to identify the receptors and brain regions that mediate the various behavioral components of the anesthetic state, including amnesia, immobility, and unconsciousness. Using complementary in vivo and in vitro approaches, we found that GABAA receptors that contain the  5 subunit (5GABAARs) play a critical role in amnesia caused by the prototypic intravenous anesthetic etomidate. Whole-cell recordings from hippocampal pyramidal neurons showed that etomidate markedly increased a tonic inhibitory conductance generated by 5GABAARs, whereas synaptic transmission was only slightly enhanced. Long-term potentiation (LTP) of field EPSPs recorded in CA1 stratum radiatum was reduced by etomidate in wild-type (WT) but not 5 null mutant (5–/–) mice. In addition, etomidate impaired memory performance of WT but not 5–/– mice for spatial and nonspatial hippocampal-dependent learning tasks. The brain concentration of etomidate associated with memory impairment in vivo was comparable with that which increased the tonic inhibitory conductance and blocked LTP in vitro. The 5–/– mice did not exhibit a generalized resistance to etomidate, in that the sedative-hypnotic effects measured with the rotarod, loss of righting reflex, and spontaneous motor activity were similar in WT and 5–/– mice. Deletion of the 5 subunit of the GABAARs reduced the amnestic but not the sedative-hypnotic properties of etomidate. Thus, the amnestic and sedative-hypnotic properties of etomidate can be dissociated on the basis of GABAAR subtype pharmacology.
Key words: amnesia; anesthesia; GABAA receptor; tonic inhibition; etomidate; learning and memory
Received Aug. 26, 2005;
revised Feb. 15, 2006;
accepted Feb. 16, 2006.
Correspondence should be addressed to Dr. Beverley A. Orser, Department of Physiology, Medical Sciences Building, Room 3318, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. Email: beverley.orser{at}utoronto.ca
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