Benzodiazepine anticonvulsant action: gamma-aminobutyric acid-dependent modulation of the chloride ionophore.

Brain-specific benzodiazepine receptors are allosterically coupled to chloride ionophore-associated binding sites for sulfur-35-labeled t-butylbicyclophosphorothionate. The specific binding of t-butylbicyclophosphorothionate to fresh unwashed rat cortical membranes is inhibited by nanomolar concentrations of five benzodiazepine agonists but not by the antagonist Ro 15-1788. Their inhibitory potencies in this assay are closely related to their antimetrazol activities. Studies with solubilized receptor-complex preparations establish an absolute requirement for gamma-aminobutyric acid (3 to 10 microM), strongly suggesting that the antagonism of metrazol-induced seizures by the benzodiazepines involves an action on the chloride ionophore mediated through the low affinity gamma-aminobutyric acid receptor.