Lamotrigine treatment during amygdala-kindled seizure development fails to inhibit seizures and diminishes subsequent anticonvulsant efficacy

PURPOSE: Lamotrigine (LTG) is an anticonvulsant that is currently in use for the treatment of various seizure disorders and that shows promise in the treatment of affective illness. LTG is also effective in the suppression of amygdala-kindled seizures. Because many drugs show a differential efficacy profile as a function of the phase of kindling evolution, we evaluated LTG for its potential antiepileptogenic effects on the development of amygdala-kindled seizures. METHODS: In two separate studies, LTG (5 or 15 mg/kg versus vehicle) was administered before each daily amygdala stimulation (biphasic square wave pulses, 100 pulse pairs per second for a total of 0.5 second, 1-millisecond pulse width) at an intensity of 50 microA over the AD threshold. Seizure development was assessed, as well as the effect of this pretreatment on subsequent efficacy of LTG on completed kindled seizures. RESULTS: LTG at 5 mg/kg failed to block seizure development. At 15 mg/kg, LTG paradoxically enhanced seizure development and produced running fits in four of the nine animals tested. Animals previously treated with either dose of LTG during kindling development showed a diminished response to the anticonvulsant effects of LTG on fully kindled seizures compared with the vehicle-treated controls. CONCLUSIONS: Although LTG possesses potent anticonvulsant effects on completed amygdala-kindled seizures, it is either without effect (5 mg/kg) or facilitates (15 mg/kg) the initial phase of kindling development. In addition, exposure to LTG during kindled seizure development leads to a reduced subsequent response to the drug in fully kindled animals. These observations parallel those with carbamazepine and suggest that different stages of kindling (epileptogenesis versus fully manifest seizures) may have different underlying neural mechanisms that require distinct pharmacotherapies.