Background and Purpose Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behaviours. Multiple studies have highlighted the potential of oxytocin (OT) to ameliorate behavioural abnormalities in animal models and subjects with ASD. Clinical trials, however, yielded disappointing results. Our study aimed at challenging hypotheses accounting for such negative results by assessing the behavioural effects of different regimens of OT administration in the Oprm1 null mouse model of ASD. Experimental Approach We assessed the effects of intranasal OT injected once at different doses and time points following administration, or chronically, on ASD-related behaviours in Oprm1+/+ and Oprm1-/- mice. We then tested whether pairing intranasal OT injection with social experience would influence its outcome on ASD-like core symptoms, and measured gene expression in several regions of the reward/social circuit. Key Results Acute intranasal OT improved social behaviour in Oprm1-/- mice at a moderate dose (0.3 IU) shortly after administration (5 min). Effects on non-social behaviours were limited. Chronic OT at this dose maintained beneficial effects in Oprm1 null mice but was deleterious in wild-type mice. Finally, improvements in the social behaviour of Oprm1-/- mice were greater and longer lasting when OT was administered in a social context, while the expression of OT and vasopressin receptor genes, as well as marker genes of striatal projection neurons, was suppressed. Conclusions and implications Our results highlight the importance of considering dosage and social context when evaluating the effects of OT treatment 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.