REPEATED ADMINISTRATION OF FLUMAZENIL DOES NOT ALTER ITS POTENCY IN MODIFYING SCHEDULE-CONTROLLED BEHAVIOR IN CHLORDIAZEPOXIDE-TREATED RHESUS-MONKEYS

Previous reports have suggested that the effects of the benzodiazepine antagonist flumazenil diminish over repeated exposure in subjects tre ated chronically with a benzodiazepine agonist. The current study exam ined whether the frequency of exposure to flumazenil altered its poten cy in decreasing rates of responding in monkeys treated with chlordiaz epoxide (CDP). Three monkeys responded under a multiple fixed ratio (F R10:FR10) schedule of food presentation and stimulus-shock termination (SST). In untreated monkeys, flumazenil (0.1-3.2 mg/kg) had no effect in either component. After 2 weeks of treatment with 32.0 mg/kg per d ay of CDP, flumazenil decreased response rates in the food component, with a dose of 3.2 mg/kg decreasing rates to 10% of control; rates in the SST component were not altered by flumazenil. When flumazenil dose -effect curves were redetermined at 28-, 14-, 7-, 4-, 2- or 1-day inte rvals, then was no further change in the potency of flumazenil in decr easing food-maintained responding. When CDP treatment was terminated, the potency of flumazenil recovered to pre-CDP values within 23 days. These results suggest that dependence develops to CDP, since changes i n the potency of flumazenil co-varied with CDP treatment. Moreover, it does not appear as though results from previous reports, that showed a diminished response to frequently-administered flumazenil, can be ge neralized to all conditions.