Mouse strains selected for differences in sensitivity to a benzodiazepine receptor inverse agonist: pharmacological and behavioural responses

Two strains of mice were selected for their sensitivity (BS strain) or resistance (BR strain) to a convulsant inverse agonist of the benzodiazepine receptor, methyl β-carboline-3-carboxylate or β-CCM. Initial differences between the two strains were observed for a number of biochemical and pharmacological characteristics. The resistant strain was more anxious, less aggressive, more resistant to the convulsant actions of other convulsant compounds acting on the GABA receptor complex, and more resistant to the anxiolytic and sedative effects of benzodiazepines. Standard tests used to test antidepressant compounds showed resistant subjects had a less 'depressed' profile than animals from the sensitive strain. Resistance to seizures can be explained by binding measurements: a possible explanation for the marked decrease in Bmax observed in the resistant strain may be an adaptation of the number of benzodiazepine receptors after β-CCM administration, helping the mice develop resistance to the convulsant agent. But not all behavioural and pharmacological phenomena observed can be easily explained through binding to the benzodiazepine receptor and it is likely that other biochemical processes in the brain are involved.