Behavioral effects of diazepam in the murine plus-maze: Flumazenil antagonism of enhanced head dipping but not the disinhibition of open-arm avoidance

Although it is widely believed that benzodiazepines reduce anxiety through positive allosteric modulation of the GABA(A)-chloride channel complex, thi s is not the only mechanism through which agents of this class can modify C NS function. Furthermore, a significant number of reports of apparent fluma zenil blockade of diazepam anxiolysis in animal models have paid limited at tention to possible intrinsic behavioral actions of the antagonist per se. In the present study, ethological methods were employed to assess in detail the effects of diazepam, flumazenil, and their combination on the behavior of male DBA/2 mice in the elevated plus-maze paradigm. In two experiments, diazepam (1.5 mg/kg) alone reduced open-arm avoidance and increased head d ipping, whereas flumazenil (10-40 mg/kg) alone was without significant beha vioral effect. However, with the sore exception of head dipping, prior admi nistration of flumazenil (10 and 40 mg/kg) failed to block the behavioral e ffects of diazepam under present test conditions. These findings imply that the anxiolytic effects of diazepam in the mouse plus-maze are not mediated through flumazenil-sensitive benzodiazepine receptors and that alternate m echanisms must be considered. (C) 1999 Elsevier Science Inc.