Effects of sodium valproate on development and social behaviour in the Mongolian gerbil

Abstract

Sodium valproate is an anticonvulsant widely prescribed because of its broad spectrum of activity. While acute toxicity from high doses is well recognized, there have been few animal studies of its chronic toxicity at therapeutic dose levels. Sodium valproate given continuously in drinking fluid (600 mg/l) throughout pregnancy and lactation to breeding gerbils caused developmental delay of the self-righting reflex in their pups. Dams ingested 97 mg/kg daily during gestation and 151 mg/kg on average during lactation, a dose in the lower range of anticonvulsant effectiveness. Reproductive performance, birth weights and subsequent growth of the pups remained normal, as did brain weights in adulthood. Drug-treated offspring, continuing to receive valproate as drinking fluid after weaning (600 mg/l; 82 to 111 mg/kg) showed negligible behavioural alteration at 6 weeks of age as assessed by ethological procedures, although behavioural change did occur at 20 weeks in the female animals. These females were characterised by significant enhancement of exploration and scanning during dyadic encounters in an unfamiliar cage, and showed a concomitant reduction of other nonsocial activities. Short-term administration of this dose of the drug did not affect behaviour. These results suggest an increased reactivity to the environment which becomes evident only after long-term treatment with valproate and to which female animals are more susceptible than males. These findings of developmental delay and of modifications to behaviour later in life points to the need for more detailed clinical assessments of the effects of valproate in human patients.