Acute Dose-Related Effect of Antiseizure Medicines on Open Field Exploration of Male Rats with Established Epilepsy

Abstract

Antiseizure medicines (ASMs) cause both acute and chronic behavioral side effects in individuals with epilepsy. While clinical and preclinical studies often focus on chronic effects, the acute dose-related impact of ASMs on behavior is underreported, especially in rodent temporal lobe epilepsy (TLE) models. Investigating the acute effects of both therapeutic and behaviorally impairing doses may inform clinically relevant adverse effects, such as sedation, hyperactivity, and impaired coordination, which are essential for evaluating drug safety and tolerability. This study investigated the acute effects of anticonvulsant doses of carbamazepine (CBZ), valproic acid (VPA), levetiracetam (LEV), and cenobamate (CNB) on locomotor activity and exploratory behavior in rats 8-13 weeks after kainic acid-induced status epilepticus to elicit confirmed spontaneous recurrent seizures consistent (SRS) with TLE. Behavioral outcomes were quantified using an automated open field task (OFT) in both epileptic and non-epileptic (naive) rats. Our findings revealed that anticonvulsant doses of CNB affected locomotor behavior while other ASMs did not alter exploratory behavior. However, the motor impairing doses of CBZ and CNB equally suppressed exploratory behavior, likely due to sedative effects, in both epileptic and non-epileptic rats. LEV was unique, showing no sedative effects even at high doses, while VPA exhibited an anxiolytic effect in SRS rats and a sedative effect in naive rats at high dose. This study provides essential insight into the efficacy and tolerability profiles of a diversity of FDA-approved ASMs in a clinically relevant TLE model. Thus, SRS may influence ASM tolerability in preclinical TLE models that may inform clinical translation.