FLUMAZENIL BLOCKADE OF ANXIETY FOLLOWING ETHANOL WITHDRAWAL IN RATS

In previous research, the drug flumazenil has been categorized both as a pure benzodiazepine antagonist and as a benzodiazepine partial agon ist. The following studies used an elevated plus maze to test whether flumazenil would exert any antianxiety action in rats. While chlordiaz epoxide (3.0 mg/kg), ethanol (0.75 g/kg), and the atypical benzodiazep ine zolpidem (1.0 mg/kg) all significantly increased time spent on the open arms and percent open arm entries, flumazenil (1-10 mg/kg) alone did not produce any anxiolytic effects on the maze. Withdrawal from c hronic ethanol treatment led to a decrease in open arm time and percen t open arm entries. Flumazenil (3.0 mg/kg) blocked these changes, sugg esting that the effects of flumazenil are at least partially dependent upon the levels of stress or anxiety in the subjects. An anxiolytic a ction of flumazenil was not seen following the central administration of the neuropeptide corticotropin-releasing factor (CRF), which reduce d open arm time on the elevated plus maze. These results support the h ypothesis that the mechanism of action for flumazenil effects on the a nxiety observed during ethanol withdrawal involves antagonism of an en dogenous benzodiazepine inverse agonist, rather than activity as a par tial agonist or blockade of CRF-mediated effects.