Barbiturates allosterically inhibit GABA antagonist and benzodiazepine inverse agonist binding

Barbiturates and the related depressant drugs, etazolate and etomidate, inhibited both the binding of [³H]bicuculline methochloride (BMC) to γ-aminobutyric acid (GABA) receptor sites and the binding of [³H]β-carboline-3-carboxylic acid methyl ester (βCCM) to benzodiazepine receptor sites in mammalian brain. These concentration-dependent effects were chemically specific and stereospecific in a manner correlating with the activity of barbiturates to enhance GABA responses in neurons and to enhance GABA and benzodiazepine receptor agonist binding in vitro. The barbiturate inhibition of [³H]BMC binding involved a decrease in affinity which at high concentrations of barbiturates results in an effective complete loss of detectable binding. The maximal inhibition of [³H]βCCM binding involved a more modest decrease in affinity (increase in K_D from 1.35 to 1.85 nM). The barbiturate inhibitions of both ligands could be reversed by picrotoxin, suggesting an indirect action at previously defined picrotoxin/barbiturate modulatory sites on the GABA-benzodiazepine receptor/chloride ion channel complex.