POTENTIATION OF GAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTOR-MEDIATED CHLORIDE CURRENTS BY NOVEL HALOGENATED COMPOUNDS CORRELATES WITH THEIR ABILITIES TO INDUCE GENERAL-ANESTHESIA

The Meyer-Overton hypothesis, predicting that the potency of an anesth etic correlates with its affinity for lipid, is a cornerstone of moder n anesthetic theory. Several halogenated compounds were recently found to deviate from this prediction, whereas others did not. We tested th e abilities of enflurane and five of these compounds to potentiate gam ma-aminobutyric acid (GABA)(A) receptor responses in Xenopus oocytes e xpressing alpha 1 beta 2 or alpha 1 beta 2 gamma 2S GAB(A) receptors. Enflurane and the anesthetic 1-chloro-1,2,2-trifluorocyclobutane (F3) strongly potentiated chloride currents produced by 5 mu M GABA with bo th alpha 1 beta 2 and alpha 1 beta 2 gamma 2S receptors. This potentia tion decreased as the GABA concentration was raised. The transitional compound (less potent than predicted by its lipid solubility) 2-bromoh eptafluoropropane produced modest enhancement, whereas three nonanesth etics (neither causing anesthesia in vivo nor decreasing the requireme nt for known anesthetics), 1,2-dichlorohexafluorocyclobutane, 2-chloro heptafluoropropane, and 2,3-chlorooctafluorobutane, did not affect GAB A(A) receptor currents. Although all five compounds were predicted to be anesthetics by the Meyer-Overton hypothesis, only F3 behaved as an anesthetic in vivo, and only F3 markedly potentiated GABA(A) receptor responses in oocytes. These results strongly implicate the GABA(A) rec eptor in general anesthesia. Fluorescence polarization studies showed that anesthetics (enflurane and F3), but not nonanesthetics (1,2-dichl orohexafluorocyclobutane and 2,3-chlorooctafluorobutane), disordered m embrane lipids. Thus, for the compounds studied, actions on both GABA( A) receptor function and lipid order distinguish between anesthetics a nd nonanesthetics.