Differences between the tolerance characteristics of two anticonvulsant benzodiazepines in the amygdaloid-kindled rat

The characteristics of the development of tolerance to the anticonvulsant e ffects of chronic treatment by dipotassium clorazepate and diazepam using a mygdaloid-kindled rats were investigated. Dipotassium clorazepate (5 mg/kg) or diazepam (5 mg/kg) were intraperitoneally administered for 10 consecuti ve days. Tolerance to the anticonvulsant effect of dipotassium clorazepate developed in seizure stage on day 6, after-discharge duration on day 7 and seizure latency on day 4. In contrast, tolerance to the effects of diazepam developed more rapidly in seizure stage on day 4, after-discharge duration on day 4 and seizure latency on day 3. Thus tolerance to the anticonvulsiv e effect of dipotassium clorazepate developed relatively slower than that t o diazepam. All rats had stage 5 convulsions 24 hr after cessation of the a dministration of dipotassium clorazepate and diazepam. Concomitant determin ations of plasma concentrations of the main metabolite of dipotassium clora zepate and diazepam, desmethyldiazepam, showed no statistical difference du ring treatment, suggesting that the developed tolerance was not metabolic b ut functional. (C) 2001 Elsevier Science Inc. All rights reserved.