1,4-Benzodiazepines and Gamma-Aminobutyric Acid: Pharmacological and Biochemical Correlates

Abstract

The high affinity receptors or GABA present in brain interact with an endogenous thermostable inhibitor (GABA modulin) which allosterically modifies GABA binding sites. This is the type of GABA receptor that we term GABA₂ receptor in comparison to GABA₁ receptor which has low affinity for GABA and is not regulated by GABA modulin. The 1,4-benzodiazepines interact competitively with GABA modulin and thereby modify GABA₂ receptor binding. In contrast the occupancy of GABA receptor increases the affinity of 1,4-benzodiazepine receptors for their specific agonist. The GABA modulin and both GABA receptors are located on the membranes of C₆ and NB_2a cells. The NB_2a cell membranes also contain Cl^– ionophore, thus the complete receptor complex is present in the membranes of NB_2a cell clone. It was proposed that the inability of clonazepam to displace ³H-diazepam from specific binding sites characterizes the nonneuronal 1,4-benzodiazepine receptor. This characterization was shown to relate to the properties of other membrane components rather than to the characteristics of the specific benzodiazepine receptors.