Abstracts

Rationale: Today’s newest antiseizure medications (ASMs) are intelligently designed through drug discovery programs that combine technologies in medicinal chemistry and several seizure/epilepsy models. Unfortunately, ASM-induced psychiatric/behavioral side effects are common (~17% of new ASM prescriptions), and preclinical efforts to systematically screen for intolerability are currently quite limited. ASMs also increase the risk of neurocognitive deficits following prenatal exposure in a drug- and dose-specific manner, but standardized methods to assess behavioral teratogenicity have largely been ignored. Here, we employ an advanced instrumented home-cage monitoring system in mice to compare the psychopharmacology of two water soluble ASMs, valproic acid (VPA) and levetiracetam (LEV).

Methods: We applied Noldus Phenotyper home-cages to non-invasively examine how enterally administered VPA and LEV (dissolved in sweetened drinking water) differentially impact the spontaneous behavior of adult C57BL/6J mice following (i) 4 weeks of drug exposure (n≥ 20), and (ii) prenatal exposure applied throughout the entirety of pregnancy (n≥ 30).

Results: In adult mice at ~500-600mg/kg/d, neither ASM significantly changed measures of horizontal activity, ultradian periodicity or behaviorally defined “sleep” compared with controls. VPA-treated mice displayed hyperphagia and increased wheel-running, which was not observed in LEV-treated mice that exhibited higher sucrose preference and a blunted sheltering response during the light spot test. When applied to breeder pairs, neither ASM impacted litter size or sex ratios, but VPA breeders displayed longer pairing-to-gestation times. As adults, prenatal VPA (but not LEV) exposure produced mild hypophagia, increased total daily “sleep,” with more frequent but shorter active states.

Conclusions: Our data demonstrate that experimenter-free instrumented home cage chambers can reveal unique psychopharmacological profiles for ASMs with distinct mechanisms of action, providing protocols for the screening of pipeline ASM candidates and models that may predict ASM side effects. In ongoing experiments, we extend this analysis to a third water soluble ASM (lacosamide), and explore the effects of ASM polytherapy and dose dependence.

Funding: Please list any funding that was received in support of this abstract.: VK receives support from the NIH (1K08NS110924-01), an AES Junior Investigator Award (2020-2021), The Mike Hogg Fund, and seed funding from Baylor College of Medicine’s Office of Research.