Abstracts

Rationale: The lamotrigine-resistant amygdala kindled model has been incorporated into the testing scheme utilized by the Epilepsy Therapy Screening Program (ETSP) to identify compounds with potential efficacy against pharmacoresistant seizures. This model utilizes repeated administration of lamotrigine (LTG) during the kindling process to induce tolerance to LTG. We have previously evaluated various antiseizure medications (ASMs) and found that this model demonstrates pharmacoresistance to some ASMs, including Na⁺ channel blockers. In this model, the same group of kindled animals is used for multiple drug tests, with one week washout periods in between experiments. However, one concern for this testing paradigm is whether drug response shifts after exposure to several compounds. Therefore, we selected several prototype ASMs and administered them as the first and last drug tested within a cohort of LTG-resistant kindled rats.

Methods: Adult male Sprague-Dawley rats were implanted with electrodes and allowed to recover for a week. To establish lamotrigine resistance, implanted animals received daily administration of intraperitoneal (i.p.) LTG (5 mg/kg) prior to stimulation during the kindling acquisition phase (~3 weeks). A higher dose of LTG was used to challenge fully kindled rats and confirm resistance to LTG. Prototype ASMs included LTG, levetiracetam (LEV), gabapentin (GPN), valproic acid (VPA), clobazam (CLB), retigabine (RGB), tiagabine (TGB), and clonazepam (CLZ). Doses used for screening were generally near the maximum tolerated dose, determined in previous studies. ASM testing took place in fully kindled rats before and after testing several other (blinded) compounds (5-10) in the same cohort of animals (N=4-8). Efficacy (# protected from generalized seizure / N) was compared for each ASM (first and last test) by a Fisher’s exact test to determine significance (p < 0.05).