Comparison of abstinence syndromes precipitated by flumazenil and PK 11195 in female diazepam-dependent rats.

Abstract

The abilities of the central (CBR) and the peripheral (PBR) benzodiazepine receptor antagonists, flumazenil (FLU) and PK 11195 (PK), to precipitate an abstinence syndrome in diazepam (DZ)-dependent rats have been evaluated. Female rats were exposed for 5 weeks to DZ slowly released from SC implanted silastic capsules (90 mg/capsule per week) and thereafter they were challenged in weekly intervals with IV injections of FLU (10, 20, 40 mg/kg) or PK (5, 10, 20 mg/kg), respectively. The maximum abstinence scores tended to increase with the dose of FLU but not with the dose of PK. Although FLU and PK precipitated some common abstinence signs, there were marked differences between these antagonists. FLU evoked dose-related tonic-clonic and clonic convulsions (five out of six rats), whereas PK (10 mg/kg) induced convulsions in only one rat (out of five); tachypnea tended to increase with the dose of both FLU and PK; twitches and jerks, backing and writhing had a significant regression on the dose of FLU; rearing tended to decrease with the dose of PK whereas FLU-evoked head bobbing and PK-evoked twitches and jerks had inverse U-shaped dose-response curves. In comparison to FLU, similar doses of PK (10 and 20 mg/kg) induced a lower precipitated abstinence score (P < 0.05) and a less intense tachypnea (P < 0.05). The data indicate that the chronic continuous exposure to DZ (and/or its active metabolites) affects both CBR and PBR in the rat; however, the abstinence syndromes produced by the CBR and PBR antagonists, FLU and PK, differ in overall intensities and in the diversity of evoked abstinence signs.