Sex dependent alterations of resveratrol on social behaviors, nociceptive reactivity and anxiety-like behaviors in VPA-induced autistic-like model in rats

Background and Aim : Autism spectrum disorders (ASDs) 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 has attached public attention by its high prevalence. A large body of evidence suggests that VPA may have a significant effect on pain threshold. Pain is defined as an unpleasant sensation which is implicated in virtually all human and animal diseases, and usually produced by physical, chemical, and biological stimuli, or some combination of these. According to neuro-protective effects, anti-inflammatory and antioxidant resveratrol (RSV), The present study was designed to clarify the effects of resveratrol (RSV) on social behavioral alterations, anxiety-like behaviors and nociceptive reactivity in valproic acid (VPA)-induced autistic-like model in rats.Methods : Pregnant Wistar rats were randomly separated in five groups. Animals received saline, DMSO, VPA, RSV and RSV+VPA. VPA was administered (600mg/kg, i. p.) on embryonic day 12.5 and pretreatment by resveratrol (3.6 mg/kg, s. c.) was applied on E6.5 until E18.5. All offspring were weaned on postnatal day 21 and the experiments were done in male and female rats on day 60. Social interaction, elevated plus maze (EPM), open field, hot plate and tail-flick tests were set out to assess social deficits, anxiety-like behavior and pain threshold. SI (sociability index), SNI (Social novelty index) and Latency time were calculated as the standard indices of social behaviors and pain threshold, respectively.Results : The results indicated that systemic intraperitoneal administration of VPA (600 mg/kg) significantly decreased SI and SNI in social interaction test (SIT), indicating the social impairments caused by VPA. RSV (3.6 mg/kg, s. c.) could reverse VPA-induced social deficits in male rats, but not in female group. VPA administration resulted in significant increase in latency time in the hot plate and tail flick tests in male rats, whereas had no such dramatic effect in females. RSV administration in combination with VPA non significantly decreased latency time compared to the valproic acid group in male rats. It is important to note that RSV by itself had no significant effect on SI, SNI and latency time in female and male rats. In addition, valproic acid administration increased anxiety-like behaviors, which could be improved at least in part by resveratrol. Conclusion : It can be concluded that valproic acid produces autistic-like behaviours and increases pain threshold in male rats which may be improved at least in part by resveratrol administration. Further studies, which better elucidate the molecular mechanisms involved in valproic acid and resveratrol-induced effects, will need to be undertaken.

کلیدواژه ها:

Valproic acid ، Resveratrol ، Autistic-like behavior ، Anxiety-like behavior ، Social interaction ، Pain ، Rat