On the Digital Psychopharmacology of Valproic Acid in Mice: Adult and Prenatal Exposure
Abstract number :
141
Submission category :
7. Antiepileptic Drugs / 7D. Drug Side Effects
Year :
2020
Submission ID :
2422489
Source :
www.aesnet.org
Presentation date :
12/5/2020 9:07:12 AM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Catharina Schirmer, Baylor College of Medicine; linh Ton - Rice University; Anney Tuo - Rice University; Miranda Jankovic - Baylor College of Medicine; Paarth Kapadia - Baylor College of Medicine; Vaishnav Krishnan - Baylor College of Medicine;
Rationale:
Antiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric or behavioral consequences of AEDs present as: (i) reversible changes in mood, anxiety and/or irritability that often necessitate discontinuation, and (ii) pervasive cognitive and psychomotor alterations secondary to fetal exposure. Technical advances in visualizing and quantifying higher order patterns of naturalistic rodent behaviors may provide for more sensitive preclinical assessments of AED tolerability and cognitive teratogenicity.
Method:
Using instrumented home-cage monitoring, we assessed how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice (of both sexes), and in the adult offspring of VPA-exposed breeder pairs. Using a pup open field assay, we also clarified how prenatal VPA exposure impacts early spontaneous exploratory behavior.
Results:
At 500-600mg/kg/d, chronic VPA exposure (4 weeks) produced hyperphagia and increased wheel-running without impacting sleep, activity or home-cage measures of risk aversion. When applied to breeder pairs of mice, VPA at this dose prolonged the latency to viable litters without affecting litter size. At two weeks of age, VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, together with hypophagia, increased wheel running and subtle alterations in dyadic behavior.
Conclusion:
Through automated home-cage assessments of mouse behavior, we capture an ethologically sound psychopharmacological profile of enteral VPA that is well-aligned with human clinical experience. By examining mice exposed prenatally to similar doses of VPA, this approach reveals murine manifestations of pervasive neurodevelopment in an enormously popular autism model. Incorporating rigorously validated preclinical assessments of neuropsychiatric tolerability may inform the design and selection of future AEDs (and other neurotherapeutics) with improved psychiatric safety profiles, both for patients and their offspring.
Funding:
:VK receives support from the NIH (1K08NS110924-01), an AES Junior Investigator Award (2020), SK Life Science, and seed funding from Baylor College of Medicine’s Office of Research.
Antiepileptic Drugs