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 Ca 2+ channels could explain the differences in the sensitivity of CBZ and VPA .