The action radius of oxytocin release in the mammalian CNS: from single vesicles to behavior
Open accessAbstract
The hypothalamic neuropeptide oxytocin (OT) has attracted the attention both of the scientific community and a general audience because of its prosocial effects in mammals, and OT is now seen as a facilitator of mammalian species propagation. Furthermore, OT is a candidate for the treatment of social deficits in several neuropsychiatric and neurodevelopmental conditions. Despite such possibilities and a long history of studies on OT behavioral effects, the mechanisms of OT actions in the brain remain poorly understood. In the present review, based on anatomical, biochemical, electrophysiological, and behavioral studies, we propose a novel model of local OT actions in the central nervous system (CNS) via focused axonal release, which initiates intracellular signaling cascades in specific OT-sensitive neuronal populations and coordinated brain region-specific behaviors.
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In the CNS, OXT is released from dendritic or axonal terminals to specific brain regions to modulate neurotransmitter release, synaptic plasticity, and neural network activity.
“In the CNS, OXT is released from dendritic or axonal terminals to specific brain regions to modulate neurotransmitter release, synaptic plasticity, and neural network activity (Chini et al., 2017; Jurek and Neumann, 2018).”
From Music's context-dependent influence on oxytocin, social bonding, and emotion regulation: a systematic review (2026) · cites this paper as Chini et al., 2017
Endogenous release of OT and AVP in the brain may be the result of neuropeptide release from synaptic and/or non-synaptic regions of neurons.
“The endogenous release of OT and AVP in the brain may be the result of neuropeptide release from synaptic and/or non-synaptic regions of neurons, although the relative roles of these forms of release in different populations of OT and AVP-containing cells are controversial [93; 94; 95; 96].”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [96]
PVN oxytocin cells receive projections from many areas of the brain.
“PVN oxytocin cells receive projections from many areas of the brain”
From Neural circuitry for maternal oxytocin release induced by infant cries (2023) · cites this paper as [11]
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“Additionally, when OXT binds to its receptor it can differentially recruit intracellular G protein-coupled pathways with increasing OXT bioavailability shifting coupling away from the excitatory Gq-protein to the inhibitory Gi- one [37-39].”
BackgroundLinks between the neurobiology of oxytocin and human musicality
Harvey, A. R. (2020) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2020.00350 · Cited by 85 · see citing works
“, 2019), and there is evidence of functionally relevant spillover of oxytocin into the extracellular space beyond traditional synaptic sites (Busnelli and Chini, 2017; Chini et al., 2017; Song and Albers, 2018).”
BackgroundInfluentialThe Monogamy Paradox: What Do Love and Sex Have to Do With It?
Carter, C. S., & Perkeybile, A. M. (2018) · Frontiers in Ecology and Evolution · doi:10.3389/fevo.2018.00202 · Cited by 85 · see citing works
The multiple faces of the oxytocin and vasopressin systems in the brain
Grinevich, V., & Ludwig, M. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.13004 · Cited by 74 · see citing works
Oxytocin and vasopressin: signalling, behavioural modulation and potential therapeutic effects
Rae, M., Lemos Duarte, M., Gomes, I., Camarini, R., & Devi, L. A. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15481 · Cited by 72 · see citing works
“Studies show that OT and V 1A receptors activate G q/11 and G i/o -mediated signalling pathways (Chini et al., 2017; Thibonnier et al., 1998), whereas V 1B receptors activate G s -, G q - and G i/o -mediated signalling (Thibonnier et al., 1998).”
InfluentialThe role of oxytocin in alcohol and drug abuse
King, C. E., Gano, A., & Becker, H. C. (2020) · Brain Research · doi:10.1016/j.brainres.2020.146761 · Cited by 66 · see citing works
Somato‐dendritic vasopressin and oxytocin secretion in endocrine and autonomic regulation
Brown, C. H., Ludwig, M., Tasker, J. G., & Stern, J. E. (2020) · Journal of Neuroendocrinology · doi:10.1111/jne.12856 · Cited by 65 · see citing works
Oxytocin Influences Male Sexual Activity via Non-synaptic Axonal Release in the Spinal Cord
Oti, T., Satoh, K., Uta, D., Nagafuchi, J., Tateishi, S., Ueda, R., Takanami, K., Young, L. J., Galione, A., Morris, J. F., et al. (2021) · Current Biology · doi:10.1016/j.cub.2020.09.089 · Cited by 63 · see citing works
Smith, C. J. W., DiBenedictis, B. T., & Veenema, A. H. (2019) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2019.02.001 · Cited by 59 · see citing works
The modulation of emotional and social behaviors by oxytocin signaling in limbic network
Triana-Del Rio, R., Ranade, S., Guardado, J., LeDoux, J., Klann, E., & Shrestha, P. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1002846 · Cited by 58 · see citing works
“Oxytocin (OT) binds almost exclusively to its membranebound oxytocin receptor (OTR), which is a G-protein coupled receptor that can associate with one of several G proteins that mediate distinct physiological responses downstream of OT-OTR interaction in a cellular context and circuit-specific manner (Tomizawa et al.,…”
BackgroundAn analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray in rats
Iwasaki, M., Lefèvre, A., Althammer, F., Creusot, E. C., Łąpieś, O., Petitjean, H., Hilfiger, L., Kerspern, D., Melchior, M., Küppers, S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36641-7 · Cited by 62 · see citing works
Li, H., Jiang, T., An, S., Xu, M., Gou, L., Ren, B., Shi, X., Wang, X., Yan, J., Yuan, J., et al. (2024) · Neuron · doi:10.1016/j.neuron.2023.12.022 · Cited by 63 · see citing works
The psychophysiology of music-based interventions and the experience of pain
Arnold, C. A., Bagg, M. K., & Harvey, A. R. (2024) · Frontiers in Psychology · doi:10.3389/fpsyg.2024.1361857 · Cited by 64 · see citing works
Neuromodulation of maternal circuits by oxytocin
Valtcheva, S., & Froemke, R. C. (2019) · Cell and Tissue Research · doi:10.1007/s00441-018-2883-1 · Cited by 54 · see citing works
“Although it still remains unexplored which inputs to PVN and what firing patterns of oxytocin neurons are sufficient to trigger oxytocin release in central targets (Chini et al. 2017), there is substantial evidence that they may be different Fig.”
Methylenedioxymethamphetamine (MDMA) in Psychiatry
Schenk, S., & Newcombe, D. A. L. (2018) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000000962 · Cited by 52 · see citing works
The Rostral Agranular Insular Cortex, a New Site of Oxytocin to Induce Antinociception
Gamal‐Eltrabily, M., Monteros-Zúñiga, A. E. D. L., Manzano‐García, A., Martı́nez-Lorenzana, G., Condés‐Lara, M., & González‐Hernández, A. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.0962-20.2020 · Cited by 52 · see citing works
“Indeed, as suggested by Chini et al. (2017), hypothalamic oxytocinergic neurons send long axons to several forebrain regions, and these long axons may release (by en passant boutons) oxytocin in more than one area.”
BackgroundFlattery, C. N. R., Ross, A. P., Sahu, S. P., Siegel, E. R., Dooyema, J. M., Cree, M. A., Stopa, E. G., Young, L. J., Rilling, J. K., Albers, H. E., et al. (2018) · American Journal of Primatology · doi:10.1002/ajp.22875 · Cited by 50 · see citing works
“Axonal release of a single vesicle of OT is estimated to be sufficient for 50% occupancy of OT receptors within a 55 μm radius (Chini et al., 2017).”
BackgroundCasello, S. M., Flores, R. J., Yarur, H. E., Wang, H., Awanyai, M., Arenivar, M. A., Jaime-Lara, R. B., Bravo-Rivera, H., & Tejeda, H. A. (2022) · Frontiers in Neural Circuits · doi:10.3389/fncir.2022.796443 · Cited by 48 · see citing works
Oxytocin—a social peptide? Deconstructing the evidence
Leng, G., Leng, R., & Ludwig, M. (2022) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2021.0055 · Cited by 48 · see citing works
Chronic oxytocin-driven alternative splicing of Crfr2α induces anxiety
Winter, J. J., Meyer, M., Berger, I., Royer, M., Bianchi, M., Kuffner, K., Peters, S., Stang, S., Langgartner, D., Hartmann, F., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01141-x · Cited by 45 · see citing works
“…anxiety-like behavior in mice (Peters et al., 2014) and rats (Slattery and Neumann, 2010), to reduce intracerebral OXTR expression (Huang et al., 2014; Peters et al., 2014), and has been predicted to saturate brain OXTR over the entire course of the chronic OXT treatment (Chini et al., 2017).”
BackgroundThe osmoresponsiveness of oxytocin and vasopressin neurones: Mechanisms, allostasis and evolution
Leng, G., & Russell, J. A. (2018) · Journal of Neuroendocrinology · doi:10.1111/jne.12662 · Cited by 45 · see citing works
Maldonado, P. P., Nuno‐Perez, A., Kirchner, J. H., Hammock, E. A. D., Gjorgjieva, J., & Löhmann, C. (2020) · Current Biology · doi:10.1016/j.cub.2020.10.028 · Cited by 44 · see citing works
Oxytocin Receptor Signaling in Vascular Function and Stroke
McKay, E. C., & Counts, S. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.574499 · Cited by 41 · see citing works
“The OXTR is a widely expressed Gαq protein-coupled receptor (GPCR) that binds its endogenous nonapeptide ligand, oxytocin (OXT), with an affinity of about 1–10 nM (Chini et al., 2017), as well as a structurally similar nonapeptide, vasopressin, with an affinity of about 100 nM–1 μM (Postina et al.”
BackgroundBorie, A. M., Dromard, Y., Guillon, G., Olma, A., Manning, M., Muscatelli, F., Desarménien, M. G., & Jeanneteau, F. (2021) · Journal of Clinical Investigation · doi:10.1172/jci144450 · Cited by 41 · see citing works
“Based on the model of synaptic release of OXT in the brain (33), we assumed axonal secretions of AVP in the LS.”
Method“Less is more”: A dose-response account of intranasal oxytocin pharmacodynamics in the human brain
Martins, D., Brodmann, K., Veronese, M., Dipasquale, O., Mazibuko, N., Schuschnig, U., Zelaya, F. O., Fotopoulou, A., & Paloyelis, Y. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102239 · Cited by 42 · see citing works
Roy, R. K., Althammer, F., Seymour, A. J., Du, W., Biancardi, V. C., Hamm, J. P., Filosa, J. A., Brown, C. H., & Stern, J. E. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109925 · Cited by 37 · see citing works
“Thus, even though not directly tested in this study, we propose that the specificity of the inverse NVC reported here is largely determined by the extent to which dendritically released VP diffuses across the extracellular space (diffusion action radius estimated to be up to 120 μm; Chini et al., 2017) and the presenc…”
BackgroundNeuropeptides and small-molecule amine transmitters: cooperative signaling in the nervous system
Eiden, L. E., Hernández, V. S., Jiang, S. Z., & Zhang, L. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04451-7 · Cited by 36 · see citing works
“In addition, the range of diffusion of neuropeptides from their site of exocytotic release can be considerable [10], and the mechanisms of inactivation by extracellular peptidases not as clearly temporally defined as for ACh inactivation by cholinesterase, glutamate uptake by glia, or biogenic amine removal from the e…”
BackgroundAlthammer, F., Jirikowski, G. F., & Grinevich, V. (2018) · Peptides · doi:10.1016/j.peptides.2018.09.003 · Cited by 35 · see citing works
An oxytocinergic neural pathway that stimulates thermogenic and cardiac sympathetic outflow
Fukushima, A., Kataoka, N., & Nakamura, K. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111380 · Cited by 40 · see citing works
Althammer, F., Muscatelli, F., Grinevich, V., & Schaaf, C. P. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02054-1 · Cited by 34 · see citing works
“Recent studies showed that the traditional views [34] about how OT is released within the brain [5, 35, 36], the way OT”
BackgroundBardo, M. T., Hammerslag, L. R., & Malone, S. G. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108567 · Cited by 32 · see citing works
Oxytocin Effects on Pain Perception and Pain Anticipation
Herpertz, S. C., Schmitgen, M. M., Fuchs, C., Roth, C., Wolf, R. C., Bertsch, K., Flor, H., Grinevich, V., & Boll, S. (2019) · Journal of Pain · doi:10.1016/j.jpain.2019.04.002 · Cited by 30 · see citing works
The Role of Oxytocin in Abnormal Brain Development: Effect on Glial Cells and Neuroinflammation
Knoop, M. S., Possovre, M.-L., Jacquens, A., Charlet, A., Baud, O., & Darbon, P. (2022) · Cells · doi:10.3390/cells11233899 · Cited by 30 · see citing works
“Where synaptic OT release is quick, en passant release is slow and diffusion-based, causing a 60–90 s delay in response [43].”
BackgroundOxytocinergic Feedback Circuitries: An Anatomical Basis for Neuromodulation of Social Behaviors
Lefèvre, A., Benusiglio, D., Tang, Y., Krabichler, Q., Charlet, A., & Grinevich, V. (2021) · Frontiers in Neural Circuits · doi:10.3389/fncir.2021.688234 · Cited by 30 · see citing works
Althammer, F., Eliava, M., & Grinevich, V. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-820107-7.00003-3 · Cited by 32 · see citing works
Bridging the gap between rodents and humans: The role of non‐human primates in oxytocin research
Putnam, P. T., Young, L. J., & Gothard, K. M. (2018) · American Journal of Primatology · doi:10.1002/ajp.22756 · Cited by 28 · see citing works
“Intra-amygdala injections of OT might be more likely to replicate the effect of endogenous OT, as focal increases of OT may better represent the natural mechanisms of OT release in the brain (Chini, Verhage, & Grinevich, 2017).”
BackgroundRole of Oxytocin in Different Neuropsychiatric, Neurodegenerative, and Neurodevelopmental Disorders
Ghazy, A. A., Soliman, O., Elbahnasi, A. I., Alawy, A. Y., Mansour, A. M., & Gowayed, M. A. (2022) · Reviews of physiology, biochemistry and pharmacology · doi:10.1007/112_2022_72 · Cited by 27 · see citing works
New light on cortical neuropeptides and synaptic network plasticity
Smith, S. J., Hawrylycz, M., Rossier, J., & Sümbül, U. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.04.002 · Cited by 26 · see citing works
“NP molecules, once secreted, persist for many minutes in brain interstitial spaces, long enough for paracrine diffusion over distances embracing hundreds of potential target neurons [1, 20, 21, 22, 23].”
Oxytocin for learning calm and safety.
Eckstein, M., de Minas, A. C. A., Scheele, D., Kreuder, A.-K., Hurlemann, R., Grinevich, V., & Ditzen, B. (2019) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2018.06.004 · Cited by 29 · see citing works
Sex-Specific Differences in Oxytocin Receptor Expression and Function for Parental Behavior
Mitre, M., Kranz, T. M., Marlin, B. J., Schiavo, J. K., Erdjument‐Bromage, H., Zhang, X., Minder, J. L., Neubert, T. A., Hackett, T. A., Chao, M. V., et al. (2017) · Gender and the Genome · doi:10.1089/gg.2017.0017 · Cited by 22 · see citing works
Can intranasal oxytocin reduce craving in automated addictive behaviours? A systematic review
Houghton, B., Kouimtsidis, C., Duka, T., Paloyelis, Y., & Bailey, A. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15617 · Cited by 23 · see citing works
“This is not surprising, given that the effects of oxytocin on central intracellular signalling pathways are complex and can vary as a function of the amount of oxytocin that is available extracellularly (Chini et al., 2017).”
BackgroundQuintana, D. S. (2021) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2021.105642 · Cited by 21 · see citing works
Robo2 regulates synaptic oxytocin content by affecting actin dynamics
Anbalagan, S., Blechman, J., Gliksberg, M., Gordon, L., Rotkopf, R., Dadosh, T., Shimoni, E., & Levkowitz, G. (2019) · eLife · doi:10.7554/elife.45650 · Cited by 21 · see citing works
Leng, G., & MacGregor, D. J. (2018) · Mathematical Biosciences · doi:10.1016/j.mbs.2018.07.008 · Cited by 19 · see citing works
“Each vesicle that is released is likely to have a large sphere of action [38], encompassing many potential target neurons.”
BackgroundGigliucci, V., Busnelli, M., Santini, F., Paolini, C., Bertoni, A., Schaller, F., Muscatelli, F., & Chini, B. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1026939 · Cited by 20 · see citing works
“In some conditions, for example in the presence of supraphysiological OXT concentrations, OXT can also activate the highly related vasopressin 1a and 1b receptors (V1aR and V1bR) (Chini et al., 2017).”
BackgroundThe endocrinology of the brain
Leng, G. (2018) · Endocrine Connections · doi:10.1530/ec-18-0367 · Cited by 20 · see citing works
Lemel, L., Nieścierowicz, K., García-Fernández, M. D., Darré, L., Durroux, T., Busnelli, M., Pezet, M., Rébeillé, F., Jouhet, J., Mouillac, B., et al. (2021) · Journal of Lipid Research · doi:10.1016/j.jlr.2021.100059 · Cited by 20 · see citing works
The neurobiology of parenting and infant-evoked aggression
Kaplan, H. S., Horvath, P. M., Rahman, M. M., & Dulac, C. G. (2024) · Physiological Reviews · doi:10.1152/physrev.00036.2023 · Cited by 20 · see citing works
Oxytocin, Vasopressin and Stress: A Hormetic Perspective
Nazarloo, H. P., Kingsbury, M. A., Lamont, H., Dale, C. V., Nazarloo, P., Davis, J. M., Porges, E. C., Cuffe, S. P., & Carter, C. S. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47080632 · Cited by 19 · see citing works
“OT also promotes metabolic health [161,162], cognitive longevity [135,163], and exercise adaptation [161,164].”
Hagiwara, D., Grinevich, V., & Arima, H. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2872-4 · Cited by 18 · see citing works
Neural cell-types and circuits linking thermoregulation and social behavior
Rogers, J. F., Vandendoren, M., Prather, J. F., Landen, J. G., Bedford, N. L., & Nelson, A. C. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105667 · Cited by 20 · see citing works
“Exocytotic release of OT from large dense core vesicles (also called volume transmission) has been documented in the hypothalamus and spinal cord, with effects on both thermogenesis and sexual behavior (Chini et al., 2017; Fukushima et al., 2022; Oti et al., 2021).”
BackgroundNavigating Central Oxytocin Transport: Known Realms and Uncharted Territories
Parmaksiz, D., & Kim, Y. (2024) · The Neuroscientist · doi:10.1177/10738584241268754 · Cited by 20 · see citing works
Marazziti, D., Diep, P.-T., Carter, C. S., & Carbone, M. G. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220727120646 · Cited by 16 · see citing works
Intranasal oxytocin affects the stress response to social isolation in sheep
Damián, J. P., de Soto, L., Espindola, D., Gil, J., & van Lier, E. (2020) · Physiology & Behavior · doi:10.1016/j.physbeh.2020.113282 · Cited by 16 · see citing works
Dorze, C. L., Borreca, A., Pignataro, A., Ammassari‐Teule, M., & Gisquet-Verrier, P. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0714-0 · Cited by 16 · see citing works
Oxytocin modulates local topography of human functional connectome in healthy men at rest
Martins, D., Dipasquale, O., & Paloyelis, Y. (2021) · Communications Biology · doi:10.1038/s42003-020-01610-z · Cited by 15 · see citing works
Early Life Stress, Brain Development, and Obesity Risk: Is Oxytocin the Missing Link?
Colleluori, G., Galli, C., Severi, I., Perugini, J., & Giordano, A. (2022) · Cells · doi:10.3390/cells11040623 · Cited by 15 · see citing works
“Such mismatch, together with the Oxt detection in the cerebrospinal fluid, suggests that cerebral Oxt signaling involves synaptic and volume transmission [65].”
BackgroundImaging neuropeptide effects on human brain function
Lefèvre, A., Hurlemann, R., & Grinevich, V. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2899-6 · Cited by 16 · see citing works
Neurotransmitters in tumors: chemical cross-talk shaping tumor progression
Chen, W., Yu, J., Ge, S., Yuan, T., Ding, X., Yan, B., Ye, L., Wang, Y., & Jia, R. (2025) · Biomarker Research · doi:10.1186/s40364-025-00835-6 · Cited by 14 · see citing works
“Unlike classical neurotransmitters, neuropeptides are cleared slowly from release sites and can diffuse over relatively long distances [119, 120].”
Co-Stimulation of Oxytocin and Arginine-Vasopressin Receptors Affect Hypothalamic Neurospheroid Size
Salehi, M. S., Neumann, I. D., Jurek, B., & Pandamooz, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168464 · Cited by 13 · see citing works
“, intranasal, intravenous, or intracerebroventricular, have been investigated on a behavioral and cellular level [1,48,49].”
BackgroundKageyama, T., Seo, J., Yan, L., & Fukuda, J. (2024) · Scientific Reports · doi:10.1038/s41598-024-55377-y · Cited by 12 · see citing works
Region-Specific KCC2 Rescue by rhIGF-1 and Oxytocin in a Mouse Model of Rett Syndrome
Gigliucci, V., Teutsch, J., Woodbury‐Smith, M., Luoni, M., Busnelli, M., Chini, B., & Banerjee, A. (2021) · Cerebral Cortex · doi:10.1093/cercor/bhab388 · Cited by 12 · see citing works
Ahmed, I. A., Liu, J.-J., Gieniec, K. A., Bair-Marshall, C. J., Adewakun, A. B., Hetzler, B. E., Arp, C. J., Khatri, L., Vanwalleghem, G. C., Seidenberg, A., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.21203/rs.3.rs-2715993/v1 · Cited by 12 · see citing works
“These sources converge on their peripheral targets via diffusion (Chini et al., 2017).”
BackgroundManjila, S. B., Betty, R., & Kim, Y. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1044736 · Cited by 11 · see citing works
“This is a diffusion based slow release of Oxt resulting in 6090s delayed responses (Chini et al., 2017).”
BackgroundOti, T., & Sakamoto, H. (2023) · Journal of Neuroendocrinology · doi:10.1111/jne.13324 · Cited by 9 · see citing works
Schimmer, S., Kania, A., Lefèvre, A., Afordakos, K., Wang, K.-Y., Lebedeva, J., Rozov, A. V., Raftogianni, A., Tiwari, R., Netser, S., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68347-x · Cited by 11 · see citing works
“GiventhecapacityofOTtoact via local diffusion at very low concentrations, OT released from sparse layer-1 afferents could effectively engage OTR + interneurons in layers 2/3 despite the lower local fi ber density 42 .”
Værøy, H., Lahaye, E., Dubessy, C., Bénard, M., Nicol, M., Cherifi, Y., Takhlidjt, S., do Rego, J. L., do-Rego, J.-C., Chartrel, N., et al. (2023) · Discover Mental Health · doi:10.1007/s44192-023-00048-z · Cited by 9 · see citing works
“For instance, oxytocin (OT), a 9 amino acids regulatory peptide produced mainly in the hypothalamus and secreted into the bloodstream and in various regions of the CNS, is known for playing a major role in promoting social interactions and for reducing stress and aggression [5–7].”
BackgroundMartins, D. A., Mazibuko, N., Zelaya, F. O., Vasilakopoulou, S., Loveridge, J., Oates, A., Maltezos, S., Mehta, M. A., Wastling, S. J., Howard, M. A., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/563056 · Cited by 9 · see citing works
“Gs and Gi activation typically result in opposite effects in terms of cellular function (60), meaning that in areas of high density of Gi proteins higher amounts of OT may in fact result on inhibition of neuronal activity or null effects (50, 59).”
BackgroundRethinking the Architecture of Attachment: New Insights into the Role for Oxytocin Signaling
Berendzen, K. M., & Manoli, D. S. (2022) · Affective Science · doi:10.1007/s42761-022-00142-5 · Cited by 9 · see citing works
“…sites, including axons, soma, and dendrites, and its action on neuronal and nonneuronal cells throughout the brain and periphery may account for the functional division of behaviors and physiological processes linked to oxytocin signaling (Chini et al., 2017; Dölen, 2015; Dölen et al., 2013).”
BackgroundPaiva, L., & Leng, G. (2020) · Journal of Neuroendocrinology · doi:10.1111/jne.12841 · Cited by 8 · see citing works
“including the amygdala and the ventromedial nucleus of the hypothalamus where abundant oxytocin receptors are expressed but which contain only sparse oxytocin fibres (23, 45).”
BackgroundChu, T.-H., & Tsai, C.-G. (2026) · Frontiers in cognition · doi:10.3389/fcogn.2025.1678665 · Cited by 8 · see citing works
Pirri, F., & McCormick, C. M. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110409 · Cited by 7 · see citing works
“It reaches target brain regions via synaptic and extrasynaptic pathways (Chini et al., 2017; Ferretti et al., 2019), activating OTRs abundantly expressed in regions associated with the social behavior neuronal network (Johnson and Young, 2017; Marlin and Froemke, 2017; Smith et al., 2019; Stoop,…”
Neuropeptides in control of left–right neural circuits
Kolber, B. J., Neugebauer, V., Thorn, C. A., Froemke, R. C., & Bakalkin, G. Y. (2026) · Trends in Neurosciences · doi:10.1016/j.tins.2025.12.003 · Cited by 7 · see citing works
Oxytocin facilitates human touch-induced play behavior in rats
Hayashi, H., Tateishi, S., Inutsuka, A., Maejima, S., Hagiwara, D., Sakuma, Y., Onaka, T., Grinevich, V., & Sakamoto, H. (2025) · Current Biology · doi:10.1016/j.cub.2025.05.034 · Cited by 6 · see citing works
“19 Recently, our previous work also revealed how oxytocin acts through non-synaptic mechanisms in various central nervous system regions, including the lumbosacral spinal cord, to control male sexual activity.”
Functional role of immunoglobulin G as an oxytocin-carrier protein
Lahaye, E., & Fetissov, S. O. (2024) · Peptides · doi:10.1016/j.peptides.2024.171221 · Cited by 6 · see citing works
“Several in-depth reviews provide a comprehensive picture of oxytocin signaling including gene expression, tissue distribution, and oxytocin receptor (OTR) activation as well as multiple facets of oxytocin actions [1 – 3].”
BackgroundOxytocin neurons in the paraventricular nucleus and fear empathy among male mice
Zhang, L., Chen, H., Li, B., Cao, J., Su, X.-M., Kang, Y., Gao, L., & Jing, Y. (2024) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.230125 · Cited by 6 · see citing works
“35,36 Oxytocin exerts its functions by binding to its receptors.”
BackgroundChini, B. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2923-x · Cited by 6 · see citing works
Fujisaki, M., Nakamura, A., Muroi, Y., & Ishii, T. (2020) · Hormones and Behavior · doi:10.1016/j.yhbeh.2020.104773 · Cited by 6 · see citing works
Long‐range projections of oxytocin neurons in the marmoset brain
Lefèvre, A., Meza, J., & Miller, C. T. (2024) · Journal of Neuroendocrinology · doi:10.1111/jne.13397 · Cited by 5 · see citing works
“However, due to the nature of OT neurotransmission being not strictly synaptic, 47 we considered that any immunoreactive fiber could release OT vesicles and influence surrounding neurons.”
BackgroundEvolution of neuropeptides: From diffusing molecules to modulators of synaptic transmission
Leroy, F., Gimenez, P., Krabichler, Q., & Grinevich, V. (2026) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2026.102920 · Cited by 5 · see citing works
Nakamura, K., Karasawa, K., Yasui, M., & Nuriya, M. (2022) · Analytical Chemistry · doi:10.1021/acs.analchem.2c00452 · Cited by 5 · see citing works
- Authors
- Chini, B., Verhage, M., & Grinevich, V.
- Affiliations
- University of Milan (IT)
- Vrije Universiteit Amsterdam (NL)
- German Cancer Research Center (DE)
- Corresponding author
- Chini, Bice
- Verhage, Matthijs
- Grinevich, Valery
- Venue
- Trends in Pharmacological Sciences
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 38
- Issue
- 11
- Pages
- 982-991
- ISSN
- 0165-6147 (ISSN-L)
- OpenAlex
- W2752945631
- Cited by
- 141
- References
- 71
- Citations by year
- 2026: 17 · 2025: 12 · 2024: 12 · 2023: 9 · 2022: 19 · 2021: 19 · 2020: 21 · 2019: 6 · 2018: 22 · 2017: 4
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Trends in Pharmacological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Pure Amsterdam UMC (submittedVersion)
- VU Research Portal (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Thyssen Foundation
- European Research Council (322966)
- Schaller Research Foundation (1134, 1158)
- Deutsche Forschungsgemeinschaft (3619/701)
- Human Frontiers Science Program
- 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, hypothalamus, neuropeptides, intracellular signaling, prosocial behavior, social behavior, neuropsychiatric disorders, neurodevelopmental disorders
- MeSH terms
- Animals, Axons, Behavior, Central Nervous System, Humans, Oxytocin, Secretory Vesicles
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