GABA Receptor in Rat Brain: Demonstration of an Antagonist Binding Site

Abstract

A variety of evidence suggests that neurotransmitter receptors in the brain may exist in two interconvertible conformations, an agonist conformation with a selective high affinity for receptor agonists and an antagonist conformation with a selective high affinity for receptor antagonists. This hypothesis can be tested in binding studies using receptor agonists and antagonists as labelled ligands (Snyder and Bennett, 1976). For the GABA receptor, binding studies have so far been performed with GABA agonists as labelled ligands only (Enna et al. 1978). Thus, an attempt was made to identify biochemically the antagonist binding site of the GABA receptor by using the GABA antagonist (+) bicuculline-methiodide as labelled ligand. (+)Bicuculline and its chemically more stable N-methyl-derivative antagonise reversibly and, at low concentrations, rather specifically the synaptic inhibitory action of GABA in the CNS (Johnston et al., 1972) without affecting the uptake or release of GABA or enzymes metabolizing GABA (Beart and Johnston, 1972). Thus, ³H(+)BM should be a suitable ligand for binding studies of the synaptic GABA receptor.