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Abstract
Antiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric consequences of AEDs present as: (i) reversible changes in mood, anxiety, anger and/or irritability that often necessitate drug discontinuation, and (ii) autism and/or cognitive/psychomotor delays following fetal exposure. Technical advances in quantifying naturalistic rodent behaviors may provide sensitive preclinical estimates of AED psychiatric tolerability and neuropsychiatric teratogenicity. In this study, we applied instrumented home-cage monitoring to assess how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice and in the adult offspring of VPA-exposed breeder pairs. Through a pup open field assay, we also examined how prenatal VPA exposure impacts early spontaneous exploratory behavior. At 500–600 mg/kg/d, chronic VPA produced hyperphagia and increased wheel-running without impacting sleep, activity and measures of risk aversion. When applied to breeder pairs of mice throughout gestation, VPA prolonged the latency to viable litters without affecting litter size. Two-weeks old VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, hypophagia and increased wheel running, together with subtle alterations in home-cage dyadic behavior. Together, these data illustrate how automated home-cage assessments of spontaneous behavior capture an ethologically centered psychopharmacological profile of enterally administered VPA that is aligned with human clinical experience. By characterizing the effects of pangestational VPA exposure, we discover novel murine expressions of pervasive neurodevelopment. Incorporating such rigorous assessments of psychological tolerability may inform the design of future AEDs with improved neuropsychiatric safety profiles, both for patients and their offspring.
Highlights
For the foreseeable future, orally administered antiepileptic drugs (AEDs) will remain the first line of defense against seizures in patients with epilepsy
The highest incidence of psychiatric and behavioral side effects (PBSEs) occur in patients with medically refractory epilepsy and/or pre-existing psychiatric illness (Chen et al, 2017), itself associated with seizure intractability (Hitiris et al, 2007; Krishnan, 2020)
Rather than aim for a specific plasma or brain concentration, we began by exploring the effects of Valproic acid (VPA) dissolved in drinking water (o.s.) at a dose range of ∼500–600 mg/kg/d, previously demonstrated to provide some seizure protection in rodent models (Frisch et al, 2009; Smeland et al, 2012; De Caro et al, 2019; Citraro et al, 2020)
Summary
For the foreseeable future, orally administered antiepileptic drugs (AEDs) will remain the first line of defense against seizures in patients with epilepsy. Behavioral Consequences of VPA Exposure of anticonvulsant-induced psychiatric and behavioral side effects (PBSEs) should come as no surprise. Such side effects (including alterations in mood, anxiety, irritability, and anger) substantially contribute to disability in epilepsy (Sajobi et al, 2015), and result in suboptimal dosing, poor compliance and/or AED discontinuation in up to 25% of patients (Stephen et al, 2017). The highest incidence of PBSEs occur in patients with medically refractory epilepsy and/or pre-existing psychiatric illness (Chen et al, 2017), itself associated with seizure intractability (Hitiris et al, 2007; Krishnan, 2020). Preclinical assessments of AED “tolerability” in rodents remain largely limited to measures of acute motor “toxicity” (Wilcox et al, 2020) (e.g., rotarod or open field testing) and/or subjectively scored ordinal scales of well-being (e.g., Irwin screen), which may not capture changes in anxiety, mood, motivation or sociability
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