At clinically relevant concentrations, ethers, alcohols, and halogenated alkanes enhance agonist action on the gamma-aminobutyric acid(A) (GABA(A)) receptor, whereas nonhalogenated alkanes do not. Many anesthetics also directly activate and/or inhibit GABA(A) receptors, actions that may produce important behavioral effects; although, the effects of nonhalogenated alkane anesthetics on GABA(A) receptor direct activation and inhibition have not been studied. In this study, we assessed the abilities of two representative nonhalogenated alkanes, cyclopropane and butane, to enhance agonist action, directly activate, and inhibit currents mediated by expressed alpha(1)beta(2)gamma(2L) GABA(A) receptors using electrophysiological techniques. Our studies reveal that cyclopro- pane and butane enhance agonist action on the GABA(A) receptor at concentrations that exceed those required to produce anesthesia. Neither nonhalogenated alkane directly activated nor inhibited GABA(A) receptors, even at concentrations that approach their aqueous saturated solubilities. These results strongly suggest that the behavioral actions of nonhalogenated alkane anesthetics do not result from their abilities to enhance agonist actions, directly activate, or inhibit alpha(1)beta(2)gamma(2L) GABA(A) receptors and are consistent with the hypothesis that electrostatic interactions between anesthetics and their protein binding sites modulate GABA(A) receptor potency.
Implications: When normalized to either their in vivo anesthetic potencies or hydrophobicities, cyclopropane and butane are 1-1.5 orders of magnitude less potent enhancers of agonist action on alpha(1beta2gamma2L) GABA(A) receptors than isoflurane. Additionally, cyclopropane and butane fail to directly activate or inhibit receptors, even at near aqueous saturating concentrations. Thus, it is unlikely that either enhancement or inhibition of the most common GABA(A) receptor subtype in the brain accounts for the behavioral activities of cyclopropane and butane.