Inhibitory effects of anesthetics and ethanol on muscarinic receptors expressed in Xenopus oocytes

Anesthetics (and ethanol) are known to produce amnesia as well as immobilization. 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 these two actions of anesthetic agents. Muscarinic receptors are believed to play a role in memory and learning, and we asked if a specific subtype of these receptors is affected by anesthetics as well as the new nonanesthetic. We investigated the effects of halothane, a novel halogenated anesthetic compound F3 (1-chloro-1,2,2-trifluorocyclobutane) and ethanol on acetylcholine-induced current mediated by a muscarinic m₁ receptor expressed in Xenopus oocytes. We also studied the effects of halogenated nonanesthetic compounds, F6 and F8 (2,3-chlorooctafluorobutane) on muscarinic m₁ receptors. Halothane, F3, F6 and ethanol inhibited muscarinic m₁ receptor-induced Ca²⁺-dependent Cl^- currents at pharmacologically relevant concentrations. F8 had no effect on acetylcholine-induced muscarinic m₁ receptor function. The protein kinase C inhibitor, bisindolylmaleimide I (GF109203X), enhanced the acetylcholine-induced current and the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), inhibited this current. GF109203X abolished the inhibitory effects of halothane, F3 and ethanol on muscarinic m₁ receptors but had no effect on actions of F6. These results demonstrate that anesthetics and a nonanesthetic inhibit the function of muscarinic m₁ receptors and suggest activation of protein kinase C as the mechanism of action of anesthetics and ethanol on these receptors.