PPAR-α activation in a model of autism modulates social reward and endocannabinoid signaling selectively in male rats

: Social difficulties in autism spectrum disorder (ASD), including reduced sensitivity and responsiveness to the rewarding value of social stimuli (social anhedonia), may arise from dysregulation of dopaminergic and endocannabinoid (eCB) pathways. We examined whether social reward processing was restored in male and female rats prenatally exposed to valproic acid (VPA) by PPARαs activation which modulates dopaminergic and eCB transmission. After 4-week administration of the PPARα agonist fenofibrate (FBR), social interaction and social reward sensitivity were assessed, and levels of eCBs and related markers measured in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). In VPA-exposed male rats, FBR administration reinstated social behavior, increased N-palmitoyl ethanolamine (PEA) levels in the NAc and normalized fatty-acid amide hydrolase (FAAH) levels in the NAc and mPFC. In contrast, VPA-exposed female rats showed very subtle ASD-like social deficits, different patterns of eCB alterations, with decreased N-oleoyl ethanolamine (OEA) levels in both regions, and divergent responses to FBR. Overall, these findings suggest that FBR modulation of the eCB system contribute to improving social behavior in VPA-exposed male rats. Moreover, differences in eCB signaling in male and female rats may play a role in the development of sex-divergent phenotype following prenatal VPA exposure.