Coadministration of gabapentin or MK-801 with lamotrigine slows tolerance to its anticonvulsant effects on kindled seizures.

The development of tolerance to therapeutic effects of antiepileptic drugs can be a problem in the treatment of epilepsy, bipolar disorder, and pain syndromes. In the present study, acute treatment with the new antiepileptic drug lamotrigine (LTG, 15 mg/kg) markedly suppressed seizure stage and seizure duration in amygdala-kindled rats; but this antiseizure effect was rapidly lost following 4-8 days of repeated treatment. When gabapentin (GBP, 20 mg/kg) was coadministered with LTG, the ability of LTG to suppress seizure stage, seizure duration, and after-discharge (AD) duration was markedly extended. In addition, GBP coadministration with LTG decreased the number of animals that developed LTG-related running fits (Stage 6 seizures) and lengthened the number of days required to develop running fits or complete tolerance. Neither acute nor repeated treatment with MK-801 (0.3 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, had effects on kindled seizures. However, cotreatment with MK-801 markedly extended the anticonvulsant effects of LTG on the three seizure indices and reduced running fits. These data indicate that cotreatment with either GBP or MK-801 slows tolerance development to the anticonvulsant effects of LTG on kindled seizures. Therapeutic implications of the present study remain to be explored.