Flunitrazepam has an inverse agonistic effect on recombinant alpha6beta2gamma2-GABAA receptors via a flunitrazepam-binding site.

gamma-Aminobutyric acid type A (GABAA) receptor subtypes containing the alpha6-subunit are generally thought to be insensitive to the action of benzodiazepine agonists. We describe the specific binding of the benzodiazepine agonist flunitrazepam to alpha6beta2gamma2-containing GABAA receptors, which has not been observed before and differs from previous reports. With the whole-cell voltage-clamp technique, we observed a functional discrimination between alpha1beta2gamma2- and alpha6beta2gamma2-receptors. Different benzodiazepines had different effects on GABA-evoked chloride currents. The agonist flunitrazepam had an inverse agonistic effect, whereas the antagonist flumazenil increased GABA-induced chloride currents. The action of flunitrazepam on the channel activity of alpha6beta2gamma2-receptors was opposite to its action on alpha1beta2gamma2-receptors. We conclude that flunitrazepam can act as either an agonist or an inverse agonist, depending on the GABAA receptor configuration.