Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors.

The neuropeptides oxytocin (OT) and vasopressin (AVP) have been shown to play a central role in social behaviors; as a consequence, they have been recognized as potential drugs to treat neurodevelopmental and psychiatric disorders characterized by impaired social interactions. However, despite the basic and preclinical relevance of mice strains carrying genetic alterations in the OT/AVP systems to basic and preclinical translational neuroscience, the pharmacological profile of mouse OT/AVP receptor subtypes has not been fully characterized. To fill this gap, we have characterized a number of OT and AVP agonists and antagonists at three murine OT/AVP receptors expressed in the nervous system: the oxytocin (mOTR, and vasopressin V1a (mV1aR) and V1b (mV1bR) subtypes. These three receptors were transiently expressed in vitro for binding and intracellular signalling assays, and then a homology model of the mOTR structure was constructed in order to investigate how its molecular features compare with human and rat OTR orthologs. Our data indicate that the selectivity profile of the natural ligands, OT and AVP, is conserved in humans, rats and mice. Furthermore, we found that the synthetic peptide [Thr4Gly7]OT (TGOT) (Lowbridge et al., 1977) is remarkably selective for the mOTR and, like the endogenous OT ligand, activates Gq and Gi, and recruits ?arrestins. Finally, we report three antagonists which exhibit remarkably high affinities and selectivities at mOTRs. These highly selective pharmacological tools will contribute to the investigation of the specific physiological and pathological roles of mOTR for the development of selective OT-based therapeutics.