Flumazenil induces benzodiazepine partial agonist-like effects in BALB/c but not C57BL/6 mice

Abstract 

Rationale: Some anxiety disorders may be treated in a different way than normal anxiety. Objective: This study was aimed at investigating the action of the benzodiazepine receptor antagonist flumazenil, compared to that of the benzodiazepine receptor full agonist chlordiazepoxide, in an animal model of generalised anxiety disorder (the BALB/c mouse). Methods: Flumazenil (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) or chlordiazepoxide (5 mg/kg) were administered to BALB/c or C57BL/6 mice subjected to the light/dark test, the elevated plus maze or a passive avoidance step-through paradigm. Results: Chlordiazepoxide and flumazenil (at all doses tested in the elevated plus maze and at the doses of 0.001 and 0.01 mg/kg in the light/dark test) induced a strong anxiolytic effect in BALB/c mice. Flumazenil did not induce anxiolysis in C57BL/6 mice, whatever the behavioral test or the dose used. However, chlordiazepoxide elicited anxiolysis in this strain in both procedures. In the passive avoidance test, chlordiazepoxide was amnesic in both strains but flumazenil had no effect. Conclusion: Flumazenil induces partial agonist-like effects in BALB/c and not in C57BL/6 mice, suggesting a possible benzodiazepine receptor set point shift toward the agonistic direction in some pathological anxiety states such as generalised anxiety disorder.