The nonpeptide oxytocin receptor agonist WAY 267,464: receptor-binding profile, prosocial effects and distribution of c-Fos expression in adolescent rats
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Previous research suggests that the nonpeptide oxytocin receptor (OTR) agonist WAY 267,464 may only partly mimic the effects of oxytocin in rodents. The present study further explored these differences and related them to OTR and vasopressin 1a receptor (V(1a) R) pharmacology and regional patterns of c-Fos expression. Binding data for WAY 267,464 and oxytocin were obtained by displacement binding assays on cellular membranes, while functional receptor data were generated by luciferase reporter assays. For behavioural testing, adolescent rats were tested in a social preference paradigm, the elevated plus-maze (EPM) and for locomotor activity changes following WAY 267,464 (10 and 100 mg/kg, i.p.) or oxytocin (0.1 and 1 mg/kg, i.p.). The higher doses were also examined for their effects on regional c-Fos expression. Results showed that WAY 267,464 had higher affinity (K(i) ) at the V(1a) R than the OTR (113 versus 978 nm). However, it had no functional response at the V(1a) R and only a weak functional effect (EC(50) ) at the OTR (881 nm). This suggests WAY 267,464 is an OTR agonist with weak affinity and a possible V(1a) R antagonist. Oxytocin showed high binding at the OTR (1.0 nm) and V(1a) R (503 nm), with a functional EC(50) of 9.0 and 59.7 nm, respectively, indicating it is a potent OTR agonist and full V(1a) R agonist. WAY 267,464 (100 mg/kg), but not oxytocin, significantly increased the proportion of time spent with a live rat, over a dummy rat, in the social preference test. Neither compound affected EPM behaviour, whereas the higher doses of WAY 267,464 and oxytocin suppressed locomotor activity. WAY 267,464 and oxytocin produced similar c-Fos expression in the paraventricular hypothalamic nucleus, central amygdala, lateral parabrachial nucleus and nucleus of the solitary tract, suggesting a commonality of action at the OTR with the differential doses employed. However, WAY 267,464 caused greater c-Fos expression in the medial amygdala and the supraoptic nucleus than oxytocin, and lesser effects in the locus coeruleus. Overall, our results confirm the differential effects of WAY 267,464 and oxytocin and suggest that this may reflect contrasting actions of WAY 267,464 and oxytocin at the V(1a) R. Antagonism of the V(1a) R by WAY 267,464 could underlie some of the prosocial effects of this drug either through a direct action or through disinhibition of oxytocin circuitry that is subject to vasopressin inhibitory influences.
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Preclinical studies have found that oxytocin may regulate social-emotional functioning.
“Preclinical studies have found that the neuropeptide, oxytocin, may regulate socialemotional functioning (Dölen et al., 2013;Hicks et al., 2012;Lim and Young, 2006;Lukas et al., 2011;Onaka et al., 2012).”
From Meta-analysis of the effects of intranasal oxytocin on interpretation and expression of emotions (2017) · cites this paper as Hicks et al., 2012
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The oxytocin receptor: from intracellular signaling to behavior
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Self-citation
- Authors
- Hicks, C., Jorgensen, W., Brown, C., Fardell, J., Koehbach, J., Gruber, C. W., Kassiou, M., Hunt, G. E., & McGregor, I. S.
- Affiliations
- The University of Sydney (AU)
- Medical University of Vienna (AT)
- Corresponding author
- McGregor, I. S.
- ORCID
- Venue
- Journal of Neuroendocrinology
- Publisher
- Wiley
- Published
- 2012-06-19
- Volume
- 24
- Issue
- 7
- Pages
- 1012-1029
- ISSN
- 0953-8194 (ISSN-L)
- 1365-2826
- PMC
- PMC3399775
- OpenAlex
- W1594116056
- Cited by
- 73
- References
- 101
- Citations by year
- 2025: 1 · 2024: 4 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 10 · 2016: 4 · 2015: 6 · 2014: 9 · 2013: 8 · 2012: 3
- FWCI
- 12.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- oxytocin receptor agonists, oxytocin, vasopressin 1a receptor, receptor binding affinity, prosocial behavior, social preferences, Fos expression, paraventricular nucleus, central amygdala, lateral parabrachial nucleus, nucleus tractus solitarius, locomotor activity, adolescent rats
- MeSH terms
- Age Factors, Animals, Behavior, Animal, Benzodiazepines, Cells, Cultured, Drug Evaluation, Preclinical, Humans, Male, Protein Binding, Pyrazoles, Social Behavior, Tissue Distribution, Gene Expression, Proto-Oncogene Proteins c-fos, Rats, Wistar, Receptors, Oxytocin, Rats, HEK293 Cells
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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