Cannabinoid Receptors CB1 and CB2 Activation Restores Hippocampal Lipid Profiles and Alleviates Autism‐Like Behaviors in Valproic Acid‐Induced ASD Rats

Objective Emerging evidence suggests lipid metabolism dysregulation contributes to autism spectrum disorders (ASD), with the endocannabinoid system (cannabinoid receptors CB1R/CB2R) implicated in lipid homeostasis. This study investigated whether CB1R/CB2R activation improves hippocampal lipid metabolism and ASD‐like behaviors in a valproic acid (VPA)‐induced ASD rat model. Methods Male offspring from dams exposed to VPA (600 mg/kg, i.p.) received the CB1R agonist ACPA (0.1 mg/kg) or the CB2R agonist AM1241 (3 mg/kg) from postnatal days 21–27. ASD‐like behaviors (marble burying, self‐grooming, social interaction, open‐field tests) and hippocampal lipid profiles (UPLC‐MS/MS) were analyzed. Results VPA‐exposed rats displayed heightened repetitive behaviors, social deficits, and hyperactivity, all significantly alleviated by ACPA and AM1241. Lipidomics revealed marked reductions in hippocampal phosphatidylcholines, lysophosphatidylcholines, fatty acids, sphingomyelins, ceramides, and phosphatidylethanolamines in VPA rats. Both agonists restored lipid levels to near normal, comparable to controls. Conclusions CB1R/CB2R activation ameliorates behavioral abnormalities and rectifies hippocampal lipid dysregulation in VPA‐induced ASD models, highlighting cannabinoid receptors as potential therapeutic targets for ASD‐associated metabolic disturbances.