Abecarnil enhances recovery from diazepam tolerance

Treatment with diazepam (25 mg/kg; p.o., twice-daily for 17 days) induced t olerance to the anticonvulsant effect of diazepam against bicuculline-induc ed convulsions in mice. Cross-tolerance was observed to the anticonvulsant action of clonazepam, imidazenil but not abecarnil. While substitution of c lonazepam (12 mg/kg; p.o., twice-daily for 15 days) for diazepam did not af fect tolerance to diazepam, substitution of imidazenil (17 mg/kg; p.o., twi ce-daily for 15 days) for diazepam significantly increased sensitivity to t he anticonvulsant effect of diazepam, although tolerance was not abolished. Tolerance to diazepam progressively decreased either after suspension of d iazepam administration or replacement treatment with abecarnil (20 mg/kg; p .o., twice-daily). Complete recovery of diazepam efficacy was detected afte r 8 and 15 days of administration of abecarnil and vehicle, respectively. B inding experiments using [H-3]-flumazenil showed that K-d values did not di ffer among treatment groups. A significant decrease in B-max (-42%) was obs erved in the cortex of diazepam-tolerant mice whether or not also treated w ith imidazenil and clonazepam. Conversely, chronically diazepam-treated mic e, that further received abecarnil for either 8 or 15 days or vehicle for 1 5 days showed B-max values similar to those of vehicle-treated mice never e xposed to diazepam. Results suggest that repeated abecarnil administration to diazepam-tolerant mice can facilitate re-adaptation of receptors to the diazepam-free state. It is proposed that replacement therapy with abecarnil after long-term treatment with conventional benzodiazepines (BDZs) may pro vide a novel approach for reducing tolerance to their anticonvulsant effect s. (C) 1999 Elsevier Science Ltd. All rights reserved.