Anticonvulsant efficacy of clonazepam and the beta-carboline ZK 93423 during chronic treatment in amygdala-kindled rats.

Amygdala kindling in rats represents an animal model of partial epilepsy with secondary generalization. Benzodiazepines are active against this type of epilepsy in man but their usefulness is limited by the development of tolerance. This study examined the effects of chronic treatment with the benzodiazepine clonazepam and the beta-carboline ZK 93423 (6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester), a full agonist at brain benzodiazepine receptors, on amygdala-kindled seizures in rats. The pharmacokinetics as well as the acute anticonvulsant potency of the drugs were determined prior to the chronic experiments. Based on the data thus obtained clonazepam and ZK 93423 were administered 3 times daily at a dose of 1 or 5 mg/kg i.p., respectively, for 2 weeks. During this treatment period, both compounds significantly reduced seizure severity without indication of tolerance. However, the marked initial effects on seizure duration and/or duration of afterdischarges recorded from the amygdala were attenuated or lost during the 2 weeks of treatment. A pronounced tolerance was also observed with respect to side-effects (sedation, ataxia, muscle relaxation) occurring during treatment. Plasma drug level determinations suggested that the tolerance was of functional nature. The data indicate that, compared to benzodiazepines, the beta-carboline ZK 93423 has no advantage in terms of anticonvulsant potency, side-effects and development of tolerance in the amygdala kindling model of epilepsy.