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.The inspiration to understand drug-resistant or pharmacoresistant or intractable epilepsy began nearly two decades ago and has included defining refractory epilepsy, the early identification of the phenomenon, therapeutic attention and attempt to develop new experimental models. It is well evident that even after the discovery of new anti-epileptic drugs (AEDs), onethird of epilepsy patients are resistant to therapy [1][2][3]. The experimental animal is said to be drug-resistant if persistent seizure activity prevails after monotherapy with at least two current AEDs at the maximum doses [4,5]. In the late 1990s and early 2000s, several drug-resistant models that fulfilled these criteria were developed. Models such as the 6 Hz psychomotor seizure model in mice, the lamotrigine (LTG)-resistant kindled model in rats, the In Utero methylazoxymethanol (MAM) exposed rats, the phenytoin (PHT)-resistant kindled rats, the phenobarbitone (PB)-resistant kindled rats and the Pilocarpine (PL)-resistant model in rats have marked their existence as drug-resistant models. Each one of these models has a unique mechanism, expressing a unique type of human epilepsy [4,6]. Out of this set of models, the LTG-resistant kindled model is one of the most recently and widely investigated for the kindling process and drug resistance [7][8][9]. The kindling process depicts epileptogenesis that could be achieved from stimulation either by a low-intensity electric current at the amygdala or by the administration of a subconvulsive dose of a CNS stimulant such as pentylenetetrazole (PTZ), picrotoxin or strychnine once daily or every other day over a period of time to induce a permanent alteration in the epileptogenic sensitivity of the brain [10][11][12]. The LTG-resistant model was originally conc...
