Development of tolerance to the anticonvulsant effect of diazepam in amygdala-kindled rats

The anticonvulsant long-term efficacy of diazepam was studied in amygdala-kindled rats. The drug was administered three times daily at doses of 5 mg/kg i.p. for 2 weeks in fully kindled animals. The severity of the kindled seizures was markedly reduced throughout the period of treatment, while tolerance developed to the effect of diazepam on seizure latency and duration and, less marked, on duration of amygdala afterdischarges. Concomitant determination of plasma concentrations of diazepam and its major metabolite, desmethyldiazepam, showed that diazepam increased during the 2 weeks of treatment, suggesting that the observed tolerance was not metabolic but functional in nature. After cessation of treatment, there was no clear indication for withdrawal symptoms except a significant increase in kindled seizure duration after 2 days. The data demonstrate that amygdala-kindled rats are a useful model to study the long-term efficacy of anticonvulsant drugs.