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ANESTHETIC PHARMACOLOGY

Acetylcholine Receptors and Thresholds for Convulsions from Flurothyl and 1,2-Dichlorohexafluorocyclobutane

Edmond I Eger, II, MD^*, Diane Gong, BS^*, Yilei Xing, MD^*, Douglas E. Raines, MD, and Pamela Flood, MD

*Department of Anesthesia and Perioperative Care, University of California, San Francisco; Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts; and Department of Anesthesiology, Columbia University, New York

Address correspondence and reprint requests to Edmond I. Eger II, MD, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143–0464.

There are acetylcholine receptors throughout the central nervous system, and they may mediate some forms and aspects of convulsive activity. Most high-affinity binding sites on nicotinic acetylcholine receptors for nicotine, cytisine, and epibatidine in the brain contain the ß2 subunit of the receptor. Transitional inhaled compounds (compounds less potent than predicted from their lipophilicity and the Meyer-Overton hypothesis) and nonimmobilizers (compounds that do not produce immobility despite a lipophilicity that suggests anesthetic qualities as predicted from the Meyer-Overton hypothesis) can produce convulsions. The nonimmobilizer flurothyl [di-(2,2,2,-trifluoroethyl)ether] blocks the action of -aminobutyric acid on -aminobutyric acid_A receptors, whereas the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N, also called F6) does not. 2N can block the action of acetylcholine on nicotinic acetylcholine receptors. We examined the relative capacities of these compounds to cause convulsions in mice having and lacking the ß2 subunit of the acetylcholine receptor. The partial pressure causing convulsions in half the mice (the 50% effective concentration [EC₅₀]) was the same as in control mice. For the knockout mice, the EC₅₀ for flurothyl was 0.00170 ± 0.00030 atm (mean ± SD), and for 2N, it was 0.0345 ± 0.0041 atm. For the control mice, the respective values were 0.00172 ± 0.00057 atm and 0.0341 ± 0.0048 atm. The ratio of the 2N to flurothyl EC₅₀ values was 20.8 ± 3.5 for the knockout mice and 21.7 ± 7.0 for the control mice. These results do not support the notion that acetylcholine receptors are important mediators of the capacity of 2N or flurothyl to cause convulsions. However, we also found that both nonimmobilizers inhibit rat 4ß2 neuronal nicotinic acetylcholine receptors at EC₅₀ partial pressures (0.00091 atm and 0.062 atm for flurothyl and 2N, respectively) that approximate those that produce convulsions (0.0015 atm and 0.04 atm).

IMPLICATIONS: The results from the present study provide conflicting data concerning the notion that acetylcholine receptors mediate the capacity of nonimmobilizers to produce convulsions.