These studies were undertaken to 1) determine whether repeated dosing with the peripheral benzodiazepine antagonist PK 11195 alters its ability to precipitate withdrawal abstinence in diazepam-dependent rats; 2) whether the administration of PK 11195 and the central benzodiazepine antagonist, flumazenil, 3 days apart to the same rat produces an ordering effect in the intensity of withdrawal abstinence; 3) whether there are gender differences in these effects. Age-matched male and female Sprague Dawley rats had capsules implanted weekly that contained approximately equal (mg/kg) doses of diazepam (120 and 90 mg, respectively) or empty capsules (controls). After 5 implants, the maximum precipitated withdrawal score (PAS(MAX)) induced by PK 11195 and/or flumazenil (10 mg/kg/IV, respectively) was measured. Repeated administration of PK 11195 (1x/day for 5 days) induced tolerance with regard to the intensity of the PAS(MAX) and with gender-related differences. When PK 11195 was administered weekly (5 weeks), rather than daily, tolerance did not develop in either sex. The PK 11195- and flumazenil-induced PAS(MAX) was not changed by the order in which they were administered. There were gender differences in that females had a higher PAS(MAX) after flumazenil than after PK 11195 and vocalized more after all treatments than males.