FLUNITRAZEPAM HAS AN INVERSE AGONISTIC EFFECT ON RECOMBINANT ALPHA(6)BETA(2)GAMMA(2)-GABA(A) RECEPTORS VIA A FLUNITRAZEPAM-BINDING SITE

gamma-Aminobutyric acid type A (GABA(A)) receptor subtypes containing the alpha(6)-subunit are generally thought to be insensitive to the ac tion of benzodiazepine agonists. We describe the specific binding of t he benzodiazepine agonist flunitrazepam to alpha(6) beta(2) gamma(2)-c ontaining GABA(A) receptors, which has not been observed before and di ffers from previous reports. With the whole-cell voltage-clamp techniq ue, we observed a functional discrimination between alpha(1) beta(2) g amma(2)- and alpha(6) beta(2) gamma(2)-receptors. Different benzodiaze pines had different effects on GABA-evoked chloride currents. The agon ist flunitrazepam had an inverse agonistic effect, whereas the antagon ist flumazenil increased GABA-induced chloride currents. The action of flunitrazepam on the channel activity of alpha(1) beta(2) gamma(2)-re ceptors was opposite to its action on alpha(1) beta(2) gamma(2)-recept ors. We conclude that flunitrazepam can act as either an agonist or an inverse agonist, depending on the GABA(A) receptor configuration.