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

Researchers studied whether a medication called fenofibrate could help improve social difficulties in rats with autism-like behaviors. The treatment worked well in male rats, improving their social behavior and brain chemistry. Female rats showed fewer autism-like problems to begin with and responded differently to treatment. This suggests that autism may affect males and females differently at the brain level, which could explain why we see different symptoms and treatment responses between boys and girls with autism.

This preclinical study examined whether PPAR-α activation could improve social difficulties in a rat model of autism using prenatal valproic acid exposure. Male rats treated with the PPAR-α agonist fenofibrate showed restored social behavior and normalized endocannabinoid signaling in key brain regions (nucleus accumbens and medial prefrontal cortex). Specifically, treatment increased N-palmitoyl ethanolamine levels and normalized fatty-acid amide hydrolase levels. Female rats showed minimal autism-like deficits and different endocannabinoid patterns, with decreased N-oleoyl ethanolamine levels and divergent treatment responses.

The findings suggest sex-specific differences in endocannabinoid system functioning may contribute to different autism presentations between males and females, with potential therapeutic implications for social reward processing.

Results suggest potential therapeutic value of PPAR-α modulators for social difficulties in autism, particularly for males. Findings support the importance of considering sex differences in autism research and treatment development. However, human clinical trials are needed before any therapeutic recommendations can be made.

Animal model findings may not translate directly to humans. Sample size not reported, limiting statistical power assessment. Study focused on short-term treatment effects without long-term follow-up. VPA model may not capture full complexity of human autism spectrum conditions.

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.