D-Cycloserine ameliorates social alterations that result from prenatal exposure to valproic acid

Prenatal exposure to valproic acid (VPA) alters rodent social interactions in a dose-dependent way: exposure to a high dose of VPA (>500 mg/kg) mid-gestation decreases social interactions whereas a moderate dose of VPA (350 mg/kg) increases peer-directed social behavior. The moderate dose also decreases expression of the mRNA for serine in amygdala and orbitofrontal cortex. In this study, we examined whether d-cycloserine could ameliorate VPA-induced alterations in ultrasonic vocalizations (USVs), social interactions, and locomotor activity. Pregnant Sprague Dawley rats were given intraperintoneal injections of VPA (200mg/kg each) on gestational days 12, 12.5 and 13; controls were injected with saline. Offspring received a subcutaneous injection of saline or d-cycloserine (32 or 64 mg/kg) either acutely (1h prior to testing) or repeatedly (once per day for four days). Social interactions were assessed during late adolescence, and USVs were recorded concomitantly. Male and female rats that were exposed to VPA demonstrated more locomotor activity than control animals during habituation to the testing chamber. VPA-exposed males showed increased play fighting. d-Cycloserine normalized the VPA-induced increase in play fighting in males and also increased social motivation in females. When the pair contained a VPA-exposed rat, significantly fewer USVs were emitted and 16% of the vocalizations were of a novel waveform. These effects were not seen in pairs containing VPA-exposed animals that were treated with d-cycloserine. Overall, these findings are consistent with data from other laboratories suggesting that d-cycloserine may be a promising pharmacotherapeutic compound for improving social behavior disorders.