Abstracts

Pharmaco-resistance is a common clinical problem for approximately 25-40% of the patients with partial epilepsy. Lamotrigine (LTG), administered prior to amygdala or pentylenetetrazol (PTZ) kindling, leads to the subsequent development of LTG resistance (Postma et al., Epilepsia. 41(12): 1514-21,2000; Srivastava et al., Epilepsia. 44(42): 2003). However the mechanism underlying this resistance is unclear.
The present study aimed to (1): assess whether LTG-resistant amygdala-kindled rats display subsequent resistance to carbamazepine (CBZ) and sodium valproate(VPA), and (2): to assess whether pharmacokinetics underlie the subsequent resistance to LTG. Two groups of male Sprague Dawley rats were amygdala kindled according to method described by Postma et al. (2000). One hour before each kindling stimulation, rats in the control group received 0.5% methylcellulose and rats in the experimental group received LTG(5mg/kg, i.p.). Treatments were stopped once the control group were fully kindled. One day later, both groups were challenged with a higher dose of LTG (15 mg/kg, i.p.) to verify LTG resistance in the experimental group (i.e., LTG- pretreated rats). The efficacy of CBZ and VPA was then evaluated in both the groups. In a separate set of identical experiments, animals from both vehicle- and LTG-treated groups were sacrificed at one hour and plasma LTG levels determined by high performance liquid chromatography (HPLC). A stable kindled state was established in both vehicle- and LTG-treated animals. Upon subsequent challenge with a higher dose of LTG, the fully kindled seizure of the vehicle-treated rats, but not the LTG-treated rats, was blocked by LTG. HPLC study demonstrated that the observed pharmaco-resistance to LTG could not be accounted for by any depression in plasma LTG level following 15mg/kg dose. Interestingly, CBZ (10, 20, and 40 mg/kg) displayed a dose-dependent anticonvulsant effect in the vehicle kindled group but, was ineffective in the LTG-treated animals. In contrast, VPA (300 mg/kg) effectively blocked the behavioral seizure and decreased the afterdischarge duration in both the groups. The present findings with amygdala kindling confirm our previous findings in the PTZ kindled rats and demonstrate that LTG, when administered at low doses during kindling acquisition, does not prevent the development of kindling but leads to the subsequent development of pharmaco-resistance to LTG and are in agreement with findings of Postma et al., (2000) . In addition, LTG-resistant rats displayed a pharmaco-resistance to CBZ but not to VPA. These findings suggest that the LTG-resistant, amygdala -kindled rat may represent a novel model of pharmaco-resistant epilepsy. Ongoing studies continue to evaluate the mechanism underlying the development of pharmaco-resistance to LTG and CBZ. (Supported by NINDS contract NO1-NS-9-2313)