INHIBITORY EFFECTS OF ANESTHETICS AND ETHANOL ON MUSCARINIC RECEPTORSEXPRESSED IN XENOPUS OOCYTES

Anesthetics (and ethanol) are known to produce amnesia as well as immo bilization. Recent identification of a nonimmobilizing (nonanesthetic) agent (F6 or 1,2-dichlorohexafluorocyclobutane) that impairs learning and memory suggests that distinct mechanisms may be responsible for t hese two actions of anesthetic agents. Muscarinic receptors are believ ed to play a role in memory and learning, and we asked if a specific s ubtype of these receptors is affected by anesthetics as well as the ne w nonanesthetic. We investigated the effects of halothane, a novel hal ogenated anesthetic compound F3 (1-chloro-1,2,2-trifluorocyclobutane) and ethanol on acetylcholine-induced current mediated by a muscarinic m(1) receptor expressed in Xenopus oocytes. We also studied the effect s of halogenated nonanesthetic compounds, F6 and F8 (2,3-chlorooctaflu orobutane) on muscarinic m(1) receptors. Halothane, F3, F6 and ethanol inhibited muscarinic m(1) receptor-induced Ca2+-dependent Cl- current s at pharmacologically relevant concentrations. F8 had no effect on ac etylcholine-induced muscarinic m(1) receptor function. The protein kin ase C inhibitor, bisindolylmaleimide I (GF109203X), enhanced the acety lcholine-induced current and the protein kinase C activator, phorbol 1 2-myristate 13-acetate (PMA), inhibited this current. GF109203X abolis hed the inhibitory effects of halothane, F3 and ethanol on muscarinic m(1) receptors but had no effect on actions of F6. These results demon strate that anesthetics and a nonanesthetic inhibit the function of mu scarinic m(1) receptors and suggest activation of protein kinase C as the mechanism of action of anesthetics and ethanol on these receptors. (C) 1997 Elsevier Science B.V.