Prenatal exposure to valproic acid reduces social responses and alters mRNA levels of opioid receptor and pre-pro-peptide in discrete brain regions of adolescent and adult male rats

Abstract

Altered social behaviours are a hallmark of several psychiatric and developmental disorders. Clinical and preclinical data have demonstrated that prenatal exposure to valproic acid (VPA), an anti-epileptic and mood stabiliser, is associated with impaired social responses, and thus provides a useful model for the evaluation of neurobiological mechanisms underlying altered social behaviours. The opioid system is widely recognised to regulate and modulate social behaviours, however few studies have examined if the endogenous opioid system is altered in animal models of social impairment. The present study examined social behavioural responses of adolescent and adult male rats prenatally exposed to VPA, and the expression of mRNA encoding opioid receptors and pre-pro-peptides in discrete brain regions. Adolescent and adult rats prenatally exposed to VPA spent less time engaging in social behaviours in the direct social interaction test and exhibited reduced sociability and social novelty preference in the 3-chamber sociability test, compared to saline-treated counterparts. The VPA-exposed adolescent rats exhibited significantly reduced kappa opioid receptor (oprk1) and pre-pro-dynorphin (pdyn) mRNA expression in the cerebral cortex, and reduced oprk1 and nociceptin/orphanin FQ (oprl1) mRNA expression in the hypothalamus. Adult rats prenatally exposed to VPA exhibited decreased mRNA expression of oprk1 and pdyn in hypothalamus, reduced pro-opiomelanocortin(pomc) in the striatum and an increase in delta opioid receptor (oprd1) mRNA in the amygdaloid cortex, when compared to saline-treated counterparts. Mu opioid receptor (oprm1) mRNA expression did not differ between saline and VPA-exposed rats in any region examined. The data demonstrate that impaired social behaviours in adolescent and adult rats prenatally exposed to VPA is accompanied by altered mRNA expression of opioid receptors and pre-pro-peptides in a region specific manner. In particular, both adolescent and adult VPA-exposed rats exhibit reduced oprk1-pdyn mRNA expression in several brain regions, which are associated with deficits in social behavioural responding in the model.

Keywords: Behaviour; Dynorphin; Kappa; Opioid receptors; Social; Valproic acid.