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.
D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D002998:Clonazepam / Q000494:pharmacology; D007476:Ionophores / Q000378:metabolism*; D007700:Kinetics; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D007476:Ionophores; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; C037476:tert-butylbicyclophosphorothionate