Dose-dependent memory effects and cerebral volume changes after in utero exposure to valproate in the rat

Purpose: Recent clinical studies raised concern of a cognitive teratogenicity of the major antiepileptic drug valproate. To investigate possible cerebral correlates, we established a forced self-application schedule by diluting valproate in the drinking water of pregnant Wistar rats. Methods: After application of medium (MD) and high doses (HDs) with mean daily intakes of about 470 and 720 mg/kg during the entire pregnancy, we analyzed effects on offspring performance in a series of behavioral paradigms as well as brain volumetric changes bymagnetic resonance imaging (MRI). Results: While high dosages with peak serum concentrations slightly above 100 mu g/ml induced early decrements in general activity and deficits in learning and memory, medium dosages led to improved watermaze performance in 30-day-old rats. MRI analyses indicated increased hippocampal volumes in the MD condition, whereas in the HD condition significantly decreased cortical and brainstem volumes were registered. Cortical volume reduction was correlated with spatial acuity in the watermaze. Conclusions: The results indicate that effects of valproate in utero on offspring cognitive capabilities might depend on total drug load differentially affecting cerebral development during adolescence in the rat.