Evidence That Oxytocin Exerts Anxiolytic Effects via Oxytocin Receptor Expressed in Serotonergic Neurons in Mice
Open accessAbstract
The oxytocin receptor has been implicated in the regulation of reproductive physiology as well as social and emotional behaviors. The neurochemical mechanisms by which oxytocin receptor modulates social and emotional behavior remains elusive, in part because of a lack of sensitive and selective antibodies for cellular localization. To more precisely characterize oxytocin receptor-expressing neurons within the brain, we generated an oxytocin receptor-reporter mouse in which part of the oxytocin receptor gene was replaced with Venus cDNA (a variant of yellow fluorescent protein). Examination of the Venus expression revealed that, in the raphe nuclei, about one-half of tryptophan hydroxylase-immunoreactive neurons were positive for Venus, suggesting a potential role for oxytocin in the modulation of serotonin release. Oxytocin infusion facilitated serotonin release within the median raphe nucleus and reduced anxiety-related behavior. Infusion of a 5-HT 2A/2C receptor antagonist blocked the anxiolytic effect of oxytocin, suggesting that oxytocin receptor activation in serotonergic neurons mediates the anxiolytic effects of oxytocin. This is the first demonstration that oxytocin may regulate serotonin release and exert anxiolytic effects via direct activation of oxytocin receptor expressed in serotonergic neurons of the raphe nuclei. These results also have important implications for psychiatric disorders such as autism and depression in which both the oxytocin and serotonin systems have been implicated.
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Prior studies have suggested that oxytocin is anxiolytic or attenuates measures of fear conditioning.
“The results of a number of other studies have suggested that oxytocin is anxiolytic19–21 or attenuates measures of fear conditioning15–18.”
From Oxytocin enhances observational fear in mice (2017) · cites this paper as [21]
Both OXTR and 5-HT2CR are expressed in dorsal raphe neurons, with their interactions leading to diminished anxiety.
“In relation to functional relevance, both the OXTR and 5-HT2CR are expressed in dorsal raphe neurons with their interactions leading to diminished anxiety (Yoshida et al., 2009).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Yoshida et al., 2009
Both 5-HT2AR and OXTR are located in 5-HT neurons, and 5HT2ARs stimulate oxytocin release from paraventricular hypothalamic neurons.
“both GPCRs are located in 5-HT neurons and 5HT2ARs stimulate oxytocin release from the paraventricular hypothalamic neurons (Zhang et al., 2002; Yoshida et al., 2009).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Yoshida et al., 2009
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Oxytocin enhances observational fear in mice
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Self-citationOxytocin signaling in the medial amygdala is required for sex discrimination of social cues
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Oxytocin׳s role in anxiety: A critical appraisal
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Diversity of oxytocin neurones: Beyond magno‐ and parvocellular cell types?
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Whole-brain wiring diagram of oxytocin system in adult mice
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Roles of Oxytocin Neurones in the Control of Stress, Energy Metabolism, and Social Behaviour
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Self-citationOxytocin mediates entrainment of sensory stimuli to social cues of opposing valence
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Oxytocin and Estrogen Receptor β in the Brain: An Overview
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Oxytocin reduces alcohol cue-reactivity in alcohol-dependent rats and humans
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Role of oxytocin signaling in the regulation of body weight
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Oxytocin and same-sex social behavior in female meadow voles
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Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders
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CD38 and its role in oxytocin secretion and social behavior
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Prosocial effects of oxytocin in two mouse models of autism spectrum disorders
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Links between the neurobiology of oxytocin and human musicality
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Pup exposure facilitates retrieving behavior via the oxytocin neural system in female mice
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Self-citationOxytocin and socioemotional aging: current knowledge and future trends
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Oxytocin: Parallel Processing in the Social Brain?
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Organizational effects of oxytocin on serotonin innervation
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Oxytocin's Fingerprint in Personality Traits and Regional Brain Volume
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Serotonergic neuron regulation informed by <i>in vivo</i> single‐cell transcriptomics
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Region Specific Up-Regulation of Oxytocin Receptors in the Opioid Oprm1−/− Mouse Model of Autism
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Selective localization of oxytocin receptors and vasopressin 1a receptors in the human brainstem
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“A previous mouse study showed that NAcc core had afferent inputs of Oxtr-expressing neurons from PVN, AON, PVT, BLA, central amygdala (CeA), cortical amygdala (CoA), ventral tegmental area (VTA), dorsal raphe nucleus (dRph), ventral subiculum, and ventral hippocampal CA1 (vCA1) by combining the immunostaining of Oxtr-…”
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Self-citationde Oliveira, D. C. G., Chagas, M. H. N., Garcia, L. V., Crippa, J. A. S., & Zuardi, A. W. (2012) · Human Psychopharmacology: Clinical and Experimental · doi:10.1002/hup.2237 · Cited by 39 · see citing works
Breastfeeding experience differentially impacts recognition of happiness and anger in mothers
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Effects of neonatal oxytocin manipulation on development of social behaviors in mice
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Bridging the gap between rodents and humans: The role of non‐human primates in oxytocin research
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“In rodents, OT exerts anxiolytic effects through activation of OXTR-expressing serotonergic neurons in the raphe nuclei (Yoshida et al., 2009).”
BackgroundSelf-citationArai, A., Hirota, Y., Miyase, N., Miyata, S., Young, L. J., Osako, Y., Yuri, K., & Mitsui, S. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.08.022 · Cited by 21 · see citing works
Self-citationOxytocin, a Novel Treatment for Methamphetamine Use Disorder
Edinoff, A. N., Thompson, E., Merriman, C. E., Alvarez, M. R., Alpaugh, E. S., Cornett, E. M., Murnane, K. S., Kozinn, R. L., Shah-Bruce, M., Kaye, A. M., et al. (2022) · Neurology International · doi:10.3390/neurolint14010015 · Cited by 15 · see citing works
“Extensive evidence now supports oxytocin’s role in the complex physiology of addiction and the attenuation of anxiety, inflammatory, and stress responses [39,40].”
Background
- Authors
- Yoshida, M., Takayanagi, Y., Inoue, K., Kimura, T., Young, L. J., Onaka, T., & Nishimori, K.
- Affiliations
- Tohoku University (JP)
- Jichi Medical University (JP)
- Emory University (US)
- The University of Osaka (JP)
- Corresponding author
- Nishimori, Katsuhiko
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-02-18
- Volume
- 29
- Issue
- 7
- Pages
- 2259-2271
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6666325
- OpenAlex
- W2095898364
- Cited by
- 608
- References
- 60
- Citations by year
- 2026: 21 · 2025: 26 · 2024: 42 · 2023: 32 · 2022: 51 · 2021: 60 · 2020: 58 · 2019: 26 · 2018: 34 · 2017: 41 · 2016: 37 · 2015: 40 · 2014: 33 · 2013: 38 · 2012: 20
- FWCI
- 29.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (9876754)
- Japan Society for the Promotion of Science (18380076, 20790194, 20020023, 20590237)
- National Institute of Mental Health (MH-64692, K02MH064692)
- 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, oxytocin receptor, anxiolytic effects, serotonergic neurons, raphe nuclei, serotonin release, 5-HT2A/2C receptors, Venus fluorescent protein, anxiety-like behavior, autism spectrum disorder, depression
- MeSH terms
- Animals, Anxiety Disorders, Bacterial Proteins, Brain, Chimera, Female, Luminescent Proteins, Male, Mice, Inbred C57BL, Mice, Transgenic, Synaptic Transmission, Oxytocin, Raphe Nuclei, Serotonin, Anti-Anxiety Agents, Tryptophan Hydroxylase, Receptors, Oxytocin, Receptor, Serotonin, 5-HT2A, Mice, Gene Knock-In Techniques, Serotonin 5-HT2 Receptor Antagonists
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