Tolerance to the anticonvulsant effects of clonazepam and clobazam in the amygdaloid kindled rat.

A major problem in the treatment of clinical epilepsy with benzodiazepines is the development of tolerance. This is most marked with the 1,5-benzodiazepine, clobazam, but is also noted with the 1,4-benzodiazepine, clonazepam. This study examined the effects of chronic treatment with clobazam, clonazepam and the non-benzodiazepine sodium valproate on the amygdaloid kindled rat with a view to developing an animal model of tolerance. Twice daily intraperitoneal injections of vehicle (1 mL/kg), clonazepam (0.3 mg/kg), clobazam (4.0-8.0 mg/kg) or sodium valproate (200 mg/kg) were given to fully kindled rats for 12 days, in the case of clonazepam and valproate, and for 16 days for clobazam. All rats were stimulated 30-60 minutes (depending on the drug) after the morning dose. The amygdala after-discharge duration (recorded on the EEG) and the seizure stage were determined. While all three drugs initially blocked the kindled seizure, tolerance developed to clonazepam and clobazam but not to valproate. Statistical analysis of the results showed a significant linear trend in the development of tolerance to clonazepam after day 5, but tolerance to clobazam appeared in a more abrupt manner after day 2. The clobazam group were then given a further 2 days of treatment with clonazepam (0.3-0.6 mg/kg) and this blocked the kindled seizures. The amygdaloid kindled rat is a suitable model for studying tolerance to the anticonvulsant effects of benzodiazepines. Further experiments are currently in progress to examine the effectiveness of change-over therapy between clobazam and clonazepam as a means of overcoming tolerance.