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ANESTHETIC PHARMACOLOGY

ß3-Containing Gamma-Aminobutyric Acid_A Receptors Are Not Major Targets for the Amnesic and Immobilizing Actions of Isoflurane

Mark Liao, BS^*, James M. Sonner, MD^*, Rachel Jurd, PhD, Uwe Rudolph, MD, Cecilia M. Borghese, PhD, R. Adron Harris, PhD, Michael J. Laster, DVM^*, and Edmond I. Eger, II, MD^*

*Department of Anesthesia and Perioperative Care, University of California, San Francisco, California; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; and Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, Texas

Address correspondence and reprint requests to Dr. Edmond I Eger II, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464. Address e-mail to egere{at}anesthesia.ucsf.edu.

Mice bearing an N265M point mutation in the gamma-aminobutyric acid (GABA)_A receptor ß3 subunit resist various anesthetic effects of propofol and etomidate. They also require a 16% larger concentration of enflurane and a 21% larger concentration of halothane to abolish the withdrawal reflex than do wild-type mice. Using a Pavlovian test, we measured whether this mutation increased the concentration of isoflurane required to impair learning and memory relative to wild-type mice. We found that the concentration was not significantly increased. We also measured MAC (the minimum alveolar concentration required to eliminate movement in response to noxious stimulation in 50% of subjects). Isoflurane MAC for mutant mice (1.93% ± 0.0.03%; mean ± se; n = 14) was 17.0% larger than MAC for wild-type mice (1.65 ± 0.04; n = 14; P < 0.001). Similarly, the cyclopropane MAC for mutant mice (27.6% ± 0.55%; n = 16) was 13.6% larger than MAC for wild-type mice (24.3 ± 0.46; n = 8; P < 0.01). The increase in MAC for cyclopropane was unexpected, because published reports find only minimal actions at 1ß22 GABA_A receptors whereas isoflurane provides a large enhancement. Consistent with previous work on 1ß22 GABA_A receptors, we found in Xenopus oocytes that 5 MAC cyclopropane enhanced the effect of GABA on 1ß22 GABA_A receptors by only 76%, and by a nearly identical enhancement in 1ß32, and 6ß32 receptors. In contrast, a much smaller concentration of isoflurane (1 MAC) produced a 160% to 310% enhancement in these receptors. If, relative to isoflurane, cyclopropane minimally increases GABA-induced chloride currents at any GABA_A receptor subtype, the present data for MAC are consistent with the notion that GABA_A receptors do not mediate the immobility produced by inhaled anesthetics.

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