The effects of gamma-hexachlorocyclohexane (gamma-HCH) and its alpha, beta and delta isomers on the gamma-aminobutyric acid (GABA) responses of human alpha1beta3gamma2S and alpha6beta3gamma2S GABA(A) receptors expressed in Xenopus oocytes were examined by conventional two-electrode voltage-clamp techniques. Gamma-HCH induced partial inhibition of EC50 GABA responses, whereas the alpha and delta isomers produced potentiation of EC20 GABA currents. In contrast, beta-HCH had no effect on GABA currents, even at concentrations as high as 100 microM. The effects of the active HCH isomers were not influenced by alpha subunit composition because there was no significant difference in either the inhibition or potentiation of alpha1beta3gamma2S or alpha6beta3gamma2S GABA(A) receptors. Delta- and gamma-HCH antagonized picrotoxin inhibition and caused displacement of specific [35S]t-butylbicyclophosphorothionate binding. Delta-HCH potentiation was found to be additive with steroid, loreclezole and lanthanum potentiation, but nonadditive with potentiation by pentobarbital and propofol, which suggested that its activity was linked to the barbiturate site.