We investigated the anticonvulsant and adverse behavioral effects of lamotrigine (LTG), a novel antiepileptic drug (AED), as well as other conventional AEDs on kindled seizures in rats. We also applied an anticonvulsive dose of LTG in vivo to rats in which the hippocampus had been subjected to long-term potentiation (LTP). LTG potently attenuated limbic-kindled seizures in a dose-dependent fashion, at doses at which animals showed no adverse behavioral effects. LTG was effective in preventing kindled seizures for up to 24 h after a single i.p. administration. The anticonvulsant effects of LTG were reversed when the stimulus current was raised to two or three times the generalized seizure-triggering threshold. Among the AEDs examined, valproate and LTG were the only drugs that engendered a potent anticonvulsant effect without concomitant adverse behavioral effects. Although all of the other AEDs exhibited anticonvulsant effects with various potencies, they produced adverse effects such as sedation or motor ataxia. Furthermore, an anticonvulsant dose of LTG did not affect either the induction or maintenance of tetanus-induced LTP in the hippocampus. These results indicate that LTG potently suppresses limbic-kindled seizures by raising the seizure triggering-threshold in the kindling focus at doses that do not affect LTP in the hippocampus.