Pharmacological properties of the GABA(A) receptor complex from brain regions of (hypoemotional) Roman high- and (hyperemotional) low-avoidance rats

Abstract

The pharmacological properties of benzodiazepine binding sites of the gamma-aminobutyric acid (GABA)A receptor complex from cortical, hippocampal and cerebellar membranes of Roman high-avoidance (RHA/Verh) and Roman low-avoidance (RLH/Verh) rats were investigated. No major differences between the two lines were found in the binding parameters of [3H]flunitrazepam (a non-selective agonist). [3 H]zolpidem (a Type I selective agonist) or [3 H]ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a]-[1,4]benzodiazepine- 3-carboxylate (Ro15-4513) (a partial inverse agonist). Neither the Kd values nor the Bmax for these ligands differed between RHA/Verh and RLA/Verh rats in any of the brain regions studied. As a result, the proportion of Type I binding sites in cortical and hippocampal membranes of RHA/Verh and RLA/Verh rats or the 'diazepam-sensitive' and the 'diazepam-insensitive' binding sites in cerebellar membranes, calculated from the [3H]flunitrazepam and [3H]zolpidem maximal binding sites or from [3H]Ro15-4513 binding (in the absence or in presence of diazepam), respectively, was also similar. Furthermore, there were no differences between the two rat lines in the allosteric interactions between GABA and the benzodiazepine binding sites (labeled with [3H]flunitrazepam) in all three areas tested or the Type I binding sites (labeled with [3H]zolpidem) in the hippocampus. In contrast, RLA/Verh rats showed a significant reduction in the allosteric interactions between GABA and [3H]zolpidem binding sites in the cortex. As a whole, these results indicate the absence of generalized between-line differences in the GABA(A) receptor complex showing, at the same time, the existence of some specific differences in allosterism within the GABA(A) complex. These differences may contribute to the divergent emotional responses which characterize the RHA/Verh and RLA/Verh rat lines.