Tolerance to the anticonvulsant effects of clobazam in mice.

Tolerance to the anticonvulsant effects of clobazam has been studied in three murine models of epilepsy: pentylenetetrazole- and N-methyl-D,L-aspartic acid-induced seizures and audiogenic-induced seizures in the DBA/2 strain. Tolerance occurred most rapidly in the pentylenetetrazole model but the development of tolerance could be reduced by increasing the dose interval. Tolerance to the protective effects of clobazam occurred more readily to the first tonic seizure than to the full tonic clonic seizure. The development of tolerance could not be attributed to smaller concentrations of clobazam in brain or to increasing concentrations of the metabolite. Although slower to develop, tolerance to clobazam did occur in the N-methyl-D,L-aspartate model. However, tolerance to the protection from the full tonic clonic seizure in DBA/2 mice could not be detected, even when the dose of clobazam was reduced to the smallest dose that acutely protected most of the mice. In contrast, the protection given by clobazam to the induction of the wild-run in DBA/2 mice, did exhibit tolerance. Studies on the mechanism of tolerance to the anticonvulsant activity of benzodiazepines must take account of the seizure model used and the dose and interval between doses.