GABA A receptor blockers reverse the inhibitory effect of GABA on brain-specific [ 35S]TBPS binding

Abstract

Thirteen sustances previously reported to antagonize the electrophysiological effects of γ-aminobutyric acid (GABA) on neurons also reversed the inhibitory effects of GABA on specific [ 35S]t-butylbicyclophosphorothionate ([ 35S]TBPS) binding to sites on rat brain membranes in vitro with a rank-order of potentcies similar to those found in electrophysiological (R 5135 > pitrazepin > bicuculline> SR 95103 > securinine) confirming the earlier conclusion that GABA inhibits [ 35S]TBPS binding by acting allosterically on relevant GABA A receptors. Pitrazepin is the most potent of a series of mono N-aryl piperazines that block GABA A receptors. The new aryl amino pyridazine GABA derivative SR 95531 was about 3-fold more potent than bicuculline and 39-fold more potent than the structurally related SR 95103. Four known GABA antagonists have the same rank orders of potencies as convulsants and as reversers of GABA's inhibitory action on [ 35S]TBPS binding (bicuculline > securinine > theophylline > caffeine). Reversal of GABA-induced suppression of [ 35S]TBPS binding provides a simple method for further characterizing GABA A receptors linked to TBPS binding sites, and facilitates identification of convulsants and novel, perhaps selective, GABA antagonists.