Cited by 539Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyOlfactory and Sensory Function Studies

The DOI matches its Crossref record; 332 of the 350 references it cites were found in a registry or an index; 1 of the 182 sources its claims cite were checked for support.

Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior

Open access
Dumais, Kelly M., Veenema, Alexa H.·2016·Frontiers in Neuroendocrinology

Abstract

The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species- specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that brain vasopressin (VP) and oxytocin (OT) systems differ by sex in region- and species-specific ways, with VP/V1aR often higher in males and OT synthesis often higher in females but OTR often higher in males. It also presents new rat data showing male-biased V1aR binding in 8 of 21 forebrain regions and argues these systems regulate social behavior sex-specifically.

Key findings

  • VP synthesis, fiber projections, and V1aR binding are generally higher in males across species; new Wistar rat data show males had higher V1aR binding in 8/21 forebrain regions: SSc (p<0.01), PC (p<0.001), BNSTmp (p<0.01), LOT (p<0.001), AVthal (p<0.001), tubLH (p=0.001), StigH (p<0.01), and DG (p<0.001), with no sex differences in the remaining 13 regions.
  • OT synthesis shows fewer sex differences than VP; when present, OT-immunoreactivity is typically higher in females, whereas OTR binding is often higher in males. In Wistar rats, males had higher OTR binding in 9/15 forebrain regions, with the largest difference in posterior BNST (almost three times higher than females); deer mice showed male-biased OTR binding in 8/20 regions except CA1.
  • VP and OT receptor distributions are distinct and largely non-overlapping in rodent brain, suggesting complementary or opposing functional roles in sex-specific social behavior.
  • Sex-specific behavioral effects are reported for VP in partner preference, social recognition, social play, and aggression, and for OT in social avoidance, social recognition, partner preference, social play, and social interest; human intranasal VP/OT and AVPR1A/OXTR variants also show sex-specific associations.

Methods

  • Narrative review of rodent and human literature on VP and OT synthesis, receptors, and social behavior, including tables summarizing sex differences across species.
  • New data: V1aR autoradiography in Wistar rats using a 125I linear V1aR antagonist, comparing males and females across 21 forebrain regions; additional comparisons examined non-estrus vs. estrus females and nulliparous vs. primiparous females at three weeks post-weaning.
  • Main analysis: statistical comparisons of receptor binding densities, with reported p-values; OTR findings draw on prior specific-ligand autoradiography in rats and deer mice.

Limitations

  • Stated: comprehensive analysis of sex differences in VP/OT systems is lacking in common laboratory species; many studies analyzed only a few brain regions, used too few animals per sex, or used nonselective ligands; human and non-human primate data are limited; functional significance of sex differences remains largely unknown; no studies directly compared brain VP or OT release between males and females; plasma OT measurement methods need improvement.
  • Evident from the text: many behavioral conclusions rely on separate studies in males or females rather than within-sex comparisons; the new rat V1aR data are from one strain/species and cannot establish causality; prior V1aR sex-comparison studies often did not report female estrus phase.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.yfrne.2015.04.003

Cites

332 of 332 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

114 Not checked yet · 49 Own interpretation · 32 No basis given · 7 Own result · 1 Partly supported · accuracy not yet measured

Verify all 179 references — free account
  • Probably not a substantial claim. 8
  • It may state two separate claims as one. 49
  • The quote only partly states this claim. 1
54 of 54
  • The paper relies on this without support.

    VP and OT do not pass the blood brain barrier.

    “Although VP and OT do not pass the blood brain barrier”
1 of 1

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

3 of 3

Citations

Cites

  • The Rat Brain in Stereotaxic Coordinates

    Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · cited 1×

    “The right column depicts representative rat brain images adapted from The Rat Brain Atlas (Paxinos & Watson, 1998).”
  • Oxytocin increases trust in humans

    Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U., & Fehr, E. (2005) · Nature · doi:10.1038/nature03701 · Cited by 3,690 · cited 2×

    “The first studies to report intranasal OT effects in humans were done in males only, showing a role for OT in trust and in the processing of socially relevant information (Kosfeld et al., 2005; Zak et al., 2007; Domes et al., 2007; Guastella et al., 2008a; Guastella et al., 2008b; Di Simplicio et al., 2009).”
    Background
  • The oxytocin receptor system: structure, function, and regulation

    Gimpl, G., & Fahrenholz, F. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.629 · Cited by 3,089 · cited 6×

    “…neurons in the PVN, SON, and accessory nucleus of the hypothalamus (Ross et al., 2009, Knobloch et al., 2012) project centrally, where OT can modulate the activity of many brain regions via binding to the widely distributed OT receptor (OTR; Jard et al., 1987; Gimpl and Fahrenholz, 2001).”
    BackgroundInfluential
  • Hypothalamic integration: organization of the paraventricular and supraoptic nuclei

    Swanson, L. W., & Sawchenko, P. E. (1983) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.06.030183.001413 · Cited by 1,991 · cited 2×

    “…Fliers et al., 1985; Weirda et al., 1991; Meynen et al., 2007) or LH, AH, and MPOA (hamsters, gerbils, voles, naked mole rats: Brownstein et al., 1980; Dierickx, 1980; Rhodes et al., 1981; Swanson and Sawchenko, 1983; Wang et al., 1996; Rosen et al., 2008; Xu et al., 2010; Wang et al., 2013).”
    Background
  • Policy: NIH to balance sex in cell and animal studies

    Clayton, J. A., & Collins, F. S. (2014) · Nature · doi:10.1038/509282a · Cited by 1,816 · cited 3×

    “…potential of the OT system to restore social dysfunction in sex-biased psychiatric disorders (Guastella et al., 2010a; Meyer-Lindenberg et al., 2011; Cochran et al., 2013), and recent initiatives from the NIH requiring the inclusion of both sexes in preclinical research (Clayton & Collins, 2014).”
    Background
  • Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine

    Meyer-Lindenberg, A., Domes, G., Kirsch, P., & Heinrichs, M. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3044 · Cited by 1,688 · cited 5×

    “This may further gain momentum because of the potential of the OT system to restore social dysfunction in sex-biased psychiatric disorders (Guastella et al., 2010a; Meyer-Lindenberg et al., 2011; Cochran et al., 2013), and recent initiatives from the NIH requiring the inclusion of both sexes in preclinical research (C…”
    BackgroundInfluential
  • Sniffing neuropeptides: A transnasal approach to the human brain

    Born, J., Lange, T., Kern, W., McGregor, G. P., Bickel, U., & Fehm, H. L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-849 · Cited by 1,356 · cited 1×

    “Furthermore, intranasal VP administration in humans was associated with an increase in VP concentration in cerebrospinal fluid (Born et al., 2002).”
    Background
  • Oxytocin improves “mind-reading” in humans

    Domes, G., Heinrichs, M., Michel, A., Berger, C., & Herpertz, S. C. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.07.015 · Cited by 1,298 · cited 1×

    “…studies to report intranasal OT effects in humans were done in males only, showing a role for OT in trust and in the processing of socially relevant information (Kosfeld et al., 2005; Zak et al., 2007; Domes et al., 2007; Guastella et al., 2008a; Guastella et al., 2008b; Di Simplicio et al., 2009).”
    Background
  • Social amnesia in mice lacking the oxytocin gene

    Ferguson, J. N., Young, L. J., Hearn, E. F., Matzuk, M. M., Insel, T. R., & Winslow, J. T. (2000) · Nature Genetics · doi:10.1038/77040 · Cited by 1,130 · cited 2×

    “Here, impaired social recognition was found in male OTR KO mice (Takayanagi et al., 2005; Lee et al., 2008; Macbeth et al., 2009), male OT KO mice (Ferguson et al., 2000; Macbeth et al., 2009), and female OT KO mice (Choleris et al., 2003; Choleris et al, 2006).”
    Background
  • Evoked axonal oxytocin release in the central amygdala attenuates fear response

    Knobloch, H. S., Charlet, A., Hoffmann, L. C., Eliava, M., Khrulev, S., Cetin, A. H., Osten, P., Schwarz, M. K., Seeburg, P. H., Stoop, R., et al. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.030 · Cited by 1,049 · cited 2×

    “Moreover, OT synthesized in parvocellular neurons of the PVN (Buijs, 1978; Buijs and Swaab, 1979; Sofroniew, 1980; Sofroniew, 1983) and magnocellular neurons in the PVN, SON, and accessory nucleus of the hypothalamus (Ross et al., 2009; Knobloch et al., 2012) project centrally,where OT canmodulate the activity ofmany…”
    Background

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Metadata

Authors
Dumais, K. M., & Veenema, A. H.
Affiliations
Boston College (US)
Corresponding author
Dumais, Kelly M.
Venue
Frontiers in Neuroendocrinology
Publisher
Elsevier BV
Published
2016-01
Volume
40
Pages
1-23
ISSN
0091-3022 (ISSN-L)
OpenAlex
W318497691
Cited by
520
References
350
Citations by year
2026: 41 · 2025: 54 · 2024: 41 · 2023: 37 · 2022: 42 · 2021: 72 · 2020: 43 · 2019: 53 · 2018: 61 · 2017: 43 · 2016: 26
FWCI
7.07
Type
journal article
Language
en
Open access
Locations
  • Frontiers in Neuroendocrinology (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIMH (F31MH100891, R15MH102807, R01MH102456)
  • NSF IOS (1253386)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
Keywords
vasopressin, oxytocin, vasopressin V1a receptor, oxytocin receptor, sex differences, social behavior, neuropeptides, sexually dimorphic gene expression, brain region-specific expression, rodent models, neuropsychiatric disorders, social dysfunction
MeSH terms
Animals, Arginine Vasopressin, Humans, Oxytocin, Sex Characteristics, Social Behavior, Vasopressins, Receptors, Oxytocin

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