Introduction: Autism spectrum disorder (ASD) is a complex, behaviorally defined disorder of the immature brain as a result of genetic and environmental risk factors, such as prenatal exposure to valproic acid (VPA). This syndrome is known for its high prevalence. On the other hand, postnatal manipulations have been shown to affect brain development, cortical neuroscience, and pituitary-adrenal activity. In early handling (EH) procedure, pups are removed from their mother on a daily basis from birth to lactation, are physically touched, and exposed to the (a) new environment. In the present study, the effect of EH on anxiety-like behaviors in rats exposed preand post-natally to valproic acid was investigated.

Methods: Pregnant Wistar rats were randomly separated into six groups which are prenatal saline, Prenatal VPA, Prenatal VPA + EH and postnatal saline, Postnatal VPA, Postnatal VPA + EH. VPA administration was performed either on ED12.5 (600 mg/kg, i.p.) or PD 2-4 (400 mg/kg, s.c.). In the groups receiving EH, pups underwent physical handling from PD 1 to 21. On postnatal day 21 all offspring were weaned and the behavioral tests were performed on 30 and 31 days of age. Elevated plus maze and open field tests were used to investigate anxiety-like behaviors.

Results: The results revealed that intraperitoneal injection of valrpoic acid (600 mg.kg) during pregnancy significantly reduced OAT% in males (p 0.01) and females in a non-significant manner (p 0.05). Compared with the postnatal VPA group, no significant change was reported in the EPM performance of postnatal VPA + EH group in neither of sexes (p 0.05).

Conclusion: The findings of this study suggest that injections of valproic acid during pregnancy lead to anxietylike behaviors in male offspring, which EH can improve (attenuate) to some extent. VPA injections on the second to the fourth day of infancy did not have a profound effect on anxiety level. Further behavioral studies need to be