Abstract

α-Chloralose is widely used as an anesthetic in the laboratory due to its minimal effects on autonomic and cardiovascular systems, yet little is known about its mechanism of action. We examined the effects of α-chloralose on γ-aminobutyric acid type A (GABA_A) receptor activity because recent studies have shown that several classes of general anesthetics modulate the function of this receptor. GABA_A receptor activity was assayed by measuring the GABA-induced current in Xenopus oocytes expressed with human GABA_A receptor alpha-1,beta-1 and gamma-2L subunits. α-Chloralose produced a concentration-dependent potentiation of the GABA-induced current with an EC₅₀ value of 49 μM and a maximal effect of 239% of control. Membrane current was not affected by α-chloralose in the absence of GABA. α-Chloralose (100 μM) increased the affinity for GABA 5-fold and produced a small (17%) increase in the efficacy of GABA. Measurement of the reversal potentials for the α-chloralose response suggested that the effect is mediated through increased Cl⁻ conductance. Studies of α-chloralose interactions with other allosteric modulators determined that α-chloralose binds to a site on the GABA_A receptor complex distinct from the benzodiazepine, neurosteroid and barbiturate sites. Chloral hydrate, trichloroethanol and urethane also augmented GABA-induced currents. α-Chloralose had no effect on the hydroxytryptamine-induced currents in oocytes expressed with the 5-hydroxytryptamine₃ receptor. These data extend the number of classes of anesthetics that allosterically modulate GABA_A receptor activity and indicate that GABA_Areceptors may be a common site of action for diverse classes of general anesthetics.