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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
5GABA_A 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. Orser^1,2,6

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 GABA_A receptors that contain the 5 subunit (5GABA_ARs) 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 5GABA_ARs, 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 GABA_ARs 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 GABA_AR subtype pharmacology.

Key words: amnesia; anesthesia; GABA_A receptor; tonic inhibition; etomidate; learning and memory

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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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