LIT-001, a non-peptide oxytocin receptor agonist, ameliorates autistic-like behaviors in cannabinoid CB1 receptor knockout mice

Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disability that demonstrates impaired social interactions, social communication deficits, and restrictive/repetitive behaviors. It is reported that children with ASD and some animal models of ASD show the abnormality of endocannabinoid (eCB) system. To determine the causal role of the eCB system in the ASD, we investigated the relationship between the eCB system and ASD-like symptoms, using the cannabinoid CB1 receptor knockout (CB1KO) mice. We found that CB1KO mice demonstrated the reduced sociability and elevated repetitive grooming behaviors which reflect to core symptoms of ASD. Moreover, the CB1KO mice also showed emotional instabilities and resistance to change a learned pattern of behavior. The serum oxytocin, expected as a biomarker for ASD, significantly decreased in CB1KO mice. Moreover, the brain oxytocin also significantly decreased in the hippocampus and hypothalamus of CB1KO mice. Based on the results, we next attempted to recover the autistic-like behaviors in CB1KO mice by activation of oxytocin signaling. Then, LIT-001, a non-peptide oxytocin receptor agonist, ameliorated the reduced sociability and repetitive behaviors in CB1KO mice. These findings suggest that CB1KO mice could have potential as a novel ASD model mouse and provide the possibility of drug development using the non-peptide oxytocin receptor agonist for ASD.