Characterization of a Lamotrigine-Resistant Kindled Model of Epilepsy in Mice: Evaluation of Drug Resistance Mechanisms

The aims of this study were to characterize a lamotrigine-resistant kindled model of epilepsy in mice, to study the anticonvulsant effect of carbamazepine (CBZ) and valproic acid (VPA), and to probe into the mechanism for resistance. Swiss albino mice were kindled by a subconvulsive dose of pentylenetetrazole (PTZ, 30 mg/kg, i.p., every other day for 6 weeks). The mice were pre-treated (30 min.) either with a low dose of LTG (5 mg/kg, i.p.) or with vehicle, and the seizures were scored. The acute treatment with LTG (15 mg/kg, i.p.) on the last day blocked seizure in the vehicle-treated group, but the LTG pre-treated group showed resistance. This resistance was extended to CBZ, but not to VPA. The resistant model was successfully replicated in mice with less kindling development time (6 weeks versus 9 weeks 5 days in rats). A highly significant decrease in the level of histamine (p < 0.001) was found, and there were also decreases in serotonin, GABA and AChE levels (p < 0.05). A significantly low level of histamine correlates with drug resistance and indicates involvement of the H1/H3 receptors. It is suggested that the selective action on voltage-gated Na+ and Ca2+ channels could explain the differences in the sensitivity of CBZ and VPA.