Tolerance to the anticonvulsant effects of lamotrigine on amygdala kindledseizures: Cross-tolerance to carbamazepine but not valproate or diazepam

Using an amygdala-kindled seizure paradigm, we evaluated the acute and chro nic anticonvulsant effects of lamotrigine (LTG). Lamotrigine produced dose- dependent inhibitory effects on seizure stage, afterdischarge (AD), and sei zure duration. Lamotrigine (15 mg/kg) also increased the afterdischarge and seizure thresholds. Following repeated LTG administration and stimulation at 48-h intervals, tolerance developed to LTG's (15 mg/kg) anticonvulsant e ffects, and cross-tolerance was observed to the anticonvulsant effects of c arbamazepine (CBZ, 15 mg/kg). In a separate group of kindled rats, CBZ (15 mg/kg) was repeatedly administered to induce tolerance. This led to a parti al cross-tolerance to LTG, manifesting as an increased rate of tolerance de velopment to LTG, and seizures following the first injection in some animal s, which were not observed in CBZ-nontolerant controls. When these rats wer e made fully tolerant to LTG and then exposed to higher doses of LTG (30 an d 50 mg/kg), no anticonvulsant effects were observed. In contrast, higher d oses of CBZ (30 mg/kg) did restore efficacy in CBZ-tolerant animals. Cross- tolerance from LTG to valproate and diazepam was not observed, although cro ss-tolerance from CBZ to valproate has been reported previously. These data suggest that LTG has both shared and distinct anticonvulsant mechanisms fr om those of CBZ on amygdala-kindled seizures. The implications of these res ults for clinical therapeutics remain to be evaluated. (C) 2000 Academic Pr ess.