Tolerance to the Anticonvulsant Effect of Clorazepate and Clonazepam in Mice

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Abstract
The rate of development of tolerance to the benzodiazepines clorazepate and clonazepam against pentetrazole-induced seizures in mice was compared. Treatment with clorazepate (0.1% solution as drinking water) for 21 days led to tolerance beginning at day 7. When mice were treated with clonazepam (0.5 mg/kg twice daily intraperitoneally), tolerance was evident already at the fourth day of treatment. Twenty-four hours after cessation of treatment the seizure threshold was significantly decreased after treatment with both drugs. Clorazepate, a prodrug of the main metabolite of diazepam, desmethyldiazepam, regards further interest for anticonvulsant therapy because of a relatively slow onset of tolerance.