Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors
Open accessAbstract
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 mouse 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 in 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 as follows: the oxytocin (mOTR) and vasopressin V1a (mV1aR) and V1b (mV1bR) subtypes. These three receptors were transiently expressed in vitro for binding and intracellular signaling assays, and then a homology model of the mOTR structure was constructed 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 [Thr(4)Gly(7)]OT (TGOT) is remarkably selective for the mOTR and, like the endogenous OT ligand, activates Gq and Gi and recruits β-arrestins. Finally, we report three antagonists that exhibit remarkably high affinities and selectivities at mOTRs. These highly selective pharmacological tools will contribute to the investigation of the specific physiologic and pathologic roles of mOTR for the development of selective OT-based therapeutics.
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Some OTR antagonists, such as atosiban, can activate selective Gi pathways.
“some OTR antagonists, such as atosiban, can activate selective Gi pathways (36, 38).”
From Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice (2018) · cites this paper as [36]
OT facilitates OTR coupling to several different G-proteins and β-arrestins.
“OT facilitates OTR coupling to several different G-proteins and β-arrestins, allowing for multiple degrees of freedom for effects on neural activity (36, 37).”
From Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice (2018) · cites this paper as [36]
Atosiban activates Gi-mediated pathways in vitro and in vivo.
“Interestingly, the OTR ligand atosiban, considered to be an OTR antagonist, actually activates Gi-mediated pathways in vitro (36, 38) and in vivo (57).”
From Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female California mice (2018) · cites this paper as [36]
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- Authors
- Busnelli, M., Bulgheroni, E., Manning, M., Kleinau, G., & Chini, B.
- Affiliations
- University of Milan (IT)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 346
- Issue
- 2
- Pages
- 318-327
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC3716315
- OpenAlex
- W1999029335
- Cited by
- 102
- References
- 47
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 13 · 2021: 11 · 2020: 10 · 2019: 9 · 2018: 6 · 2017: 11 · 2016: 10 · 2015: 5 · 2014: 3 · 2013: 2
- FWCI
- 9.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- oxytocin receptor, vasopressin V1a receptor, vasopressin V1b receptor, oxytocin, vasopressin, receptor agonists, receptor antagonists, ligand selectivity, β-arrestin recruitment, social behavior, mouse model
- MeSH terms
- beta-Arrestins, Amino Acid Sequence, Animals, Brain, Chlorocebus aethiops, Humans, Models, Molecular, Molecular Sequence Data, Oxytocin, Radioligand Assay, Structure-Activity Relationship, Vasopressins, Receptors, Vasopressin, Receptors, Oxytocin, GTP-Binding Protein alpha Subunits, Gi-Go, Arrestins, COS Cells, GTP-Binding Protein alpha Subunits, Gq-G11, Mice, HEK293 Cells, Antidiuretic Hormone Receptor Antagonists
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