Abstract

5-Hydroxytryptamine type 2A receptors (5-HT_2A) are G protein-coupled receptors that increase intracellular Ca²⁺concentrations via activation of phospholipase C-β and elevation of myo-inositol-1,4,5-triphosphate levels. In the central nervous system, these receptors are involved in regulating sleep and alertness. We now report that ethanol inhibited (IC₅₀ = 41 mM) 5-HT_2A receptor-induced Ca²⁺-dependent Cl⁻ currents in Xenopus laevis oocytes. Pharmacologically relevant concentrations of other n-alcohols (propanol to octanol) also inhibited 5-HT responses; however, longer-chain alcohols (decanol, undecanol and dodecanol) had little or no effect. The protein kinase C inhibitor GF109203X and the nonspecific protein kinase inhibitor staurosporine abolished the inhibitory effects of ethanol and octanol on 5-HT_2A receptors. GF109203X enhanced 5-HT_2Areceptor function when administered alone. In addition, the volatile anesthetics halothane and 1-chloro-1,2,2-trifluorocyclobutane decreased 5-HT_2A responses in a concentration-dependent manner. The inhibitory effects of the volatile anesthetics were also attenuated in oocytes treated with GF109203X. The intravenous anesthetics propofol, ketamine, pentobarbital and etomidate did not affect 5-HT_2Areceptor function. The modulation of 5-HT_2Areceptor-dependent current was also investigated using two novel halogenated compounds that do not produce anesthesia. The nonanesthetic compound 2,3-chloro-octafluorobutane had no effects on 5-HT-induced currents; however, the nonanesthetic compound 1,2-dichlorohexafluorocyclobutane had an inhibitory effect at lower concentrations than the predicted anesthetic concentration. Thus, 5-HT_2A receptors are inhibited by alcohols and volatile anesthetics, and these actions are dependent on protein kinase C.