Background and Purpose: No drugs targeting the core social features of autism spectrum disorder (ASD) have been approved. Although clinical trials with oxytocin (OT) and vasopressin (AVP) have yielded mixed results, targeting their receptors remains the most promising pharmacological strategy for addressing social impairments in ASD. This study aims to identify which receptors and signalling pathways within this family can sustainably improve social impairments. Experimental Approach: We used dose-response and kinetic analyses, along with mathematical modelling, to evaluate OT, AVP, their homologs, and novel synthetic ligands on G protein coupling, β-arrestins recruitment, and internalisation of mouse oxytocin (OTR) and vasopressin (V1A, V1B, V2) receptors in Neuro-2a cells. We tested acute and subchronic administration of OTR agonists and the novel V1A receptor antagonist, alongside OT and AVP, for their effects on social interaction in Fmr1 KO mice, a model exhibiting ASD-like features. Key Results: While OT, AVP and most compounds were non-selective across the four receptors, the OTR agonists TGOT or RO6958375 and the V1A antagonist RO6893074 were selective. TGOT or RO6958375, favouring Gαq signalling, enhanced social interactions in Fmr1 KO mice while showing minimal effects in wild-type mice. In contrast, OT, AVP or RO6893074 exhibited limited efficacy in Fmr1 KO mice. Conclusion and Implications: Selective OTR agonists, unlike OT and AVP, effectively improved social impairments in Fmr1 KO mice after acute and subchronic treatment. These findings highlight the necessity for developing highly selective OTR Gαq-biased agonists to achieve clinical outcomes in ASD.

Autism spectrum disorders (ASD) are diagnosed in 1/100 childbirth worldwide, based on two core symptoms, deficits in social interaction and communication and stereotyped behaviours. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors that mediate the transfer of extracellular signals to convergent intracellular signalling and downstream cellular responses that are dysregulated in ASD. Despite hundreds of GPCRs are expressed in the brain, only 23 GPCRs are genetically associated to ASD according to the Simons Foundation Autism Research Initiative (SFARI) gene database: oxytocin OTR, vasopressin V1A, V1B, metabotropic glutamate mGlu5, mGlu7, GABAB, dopamine D1, D2, D3, serotoninergic 5-HT1B, β2-adrenoceptor, cholinergic M3, adenosine A2A, A3, angiotensin AT2, cannabinoid CB1, chemokine CX3CR1, orphan GPR37, GPR85 and olfactory OR1C1, OR2M4, OR2T10, OR52M1. Here, we review the therapeutical potential of these 23 GPCRs, in addition to 5-HT2A, 5-HT6 and 5-HT7 for their relevance to ASD. We discuss their genetic association with ASD, the effects of their genetic and pharmacological manipulation in animal models and humans, their existing pharmacopeia towards core symptoms of ASD and rank them based on these evidences. Among these 23 GPCRs, we highlight that OTR, V1A, mGlu5, D2, 5-HT2A, CB1, and GPR37 are the best therapeutic targets. We conclude that the dysregulation of GPCRs and their signalling is a convergent pathological mechanism of ASD and their therapeutic potential has only begun as multiple GPCRs could mitigate ASD.