GABAergic modulation of benzodiazepine binding site sensitivity

Abstract

ALTHOUGH neurophysiological, behavioural and biochemical evidence suggests that benzodiazepines (BZ) may affect several neuronal systems within the central nervous system (CNS), recent studies indicate that some of these effects result from a specific interaction with GABAergic transmission¹. The precise mechanism of this interaction remains in doubt, as facilitation of GABAergic transmission², potentiation of GABAergic inhibition^3,4, direct activation of γ-aminobutyric acid (GABA) receptors⁵, and antagonism of GABA-mediated inhibition have all been attributed to the benzodiazepines^6,7. In studies from this laboratory⁸, both the systemic and iontophoretic administration of BZs potentiated an inhibitory response produced by GABA in the dorsal raphe nucleus—suggesting that the potentiation was mediated through a change in the post-synaptic receptor. In addition, direct binding studies using ³H-diazepam have indicated a specific high affinity binding site which may be relevant to the pharmacological actions of BZ in brain⁹. In this study, we show that GABA can modulate the responsiveness of this BZ binding site since the addition of GABA to cortical membranes in vitro results in an increased affinity of the ³H-diazepam binding site for its ligand. This effect is mimicked by the GABA analogue, muscimol¹⁰, and antagonised by the GABA antagonist, (+)bicuculline.