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Cited by 540Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyOlfactory and Sensory Function Studies

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
DOI 10.1016/j.yfrne.2015.04.003PMC PMC4633405
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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.

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.

Claims the paper makes

0 of 182 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    VP-immunoreactivity is consistently higher in males compared to females.

    “This is in contrast with VP synthesis in the brain, where VP-immunoreactivity is consistently higher in males compared to females”
    Quote in the paperSubstantial claim
  • Findingnone given

    There is a lack of sex differences in OT synthesis in the brain in most species analyzed.

    “Overall, we can conclude that there is a lack of sex differences in OT synthesis in the brain in most species analyzed.”
    Quote in the paperSubstantial claim
  • Findingnone given

    VP within the BNST/MeA is modulated by gonadal hormones.

    “VP within the BNST/MeA is modulated by gonadal hormones”
    Quote in the paperSubstantial claim
  • Findingnone given

    When sex differences in VP and OT systems are present, they are highly brain region- and species-specific.

    “when sex differences are present, they are highly brain region- and species- specific.”
    Quote in the paperSubstantial claim
  • Findingnone given

    VP system parameters (VP and V1aR) are typically higher in males.

    “VP system parameters (VP and V1aR) are typically higher in males”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 8
  • May combine two claims. 49
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Comparative analysis of V1aR binding between males and females of other rodent species is very limited.

    “Comparative analysis of V1aR binding between males and females of other rodent species is very limited”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    VP synthesis, VP innervation in the brain, and VP plasma concentrations generally seem to be higher in males than females.

    “VP synthesis, VP innervation in the brain, and VP plasma concentrations generally seem to be higher in males than in females.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    ICV administration of the specific V1aR antagonist d(CH2)5[Tyr(Me)2]AVP reduced social play behavior in male juvenile rats, while increasing social play behavior in female juvenile rats.

    “ICV administration of the specific V1aR antagonist d(CH2)5[Tyr(Me)2]AVP) reduced social play behavior in male juveniles, while increasing social play behavior in female juveniles (Veenema et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Veenema et al., 2013 source

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  • May combine two claims.

    Findingcitation

    OT administered into the LS decreased social play behavior in female, but not male, juvenile rats.

    “OT administered into the LS decreased social play behavior in females, but not in males (Bredewold et. al, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bredewold et. al, 2014

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingreasoning

    Given robust sex differences in VP synthesis, it is surprising that only a few comparative studies investigate behavioral effects of VP in males and females.

    “Given the robust and well-known sex differences in VP synthesis, it is surprising that there are only a few comparative studies investigating the behavioral effects of VP in males and females.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    There are fewer and inconsistent sex differences in OT synthesis, yet several studies compare effects of OT on social behavior in males and females.

    “In contrast, there are fewer and inconsistent sex differences in OT synthesis, yet there are several studies comparing the effects of OT on social behavior in males and females.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    V1aR blockade in the LS increased social investigation of a familiar over a novel stimulus rat in both male and female juvenile rats, but with a stronger effect in males.

    “we showed that V1aR blockade in the LS increased social investigation of a familiar over a novel stimulus rat in both male and female juvenile rats, but with a stronger effect in males (Veenema et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Veenema et al., 2012 source

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  • May combine two claims.

    Premisecitation

    V1aR has been implicated in pair bonding, maternal care, aggression, social recognition, and social play.

    “V1aR has been implicated in pair bonding, maternal care, aggression, social recognition, and social play”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bielsky et al., 2004 source

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    • cites Egashira et al., 2004 source

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    • cites Lim et al., 2004b

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  • May combine two claims.

    Premisecitation

    VP and OT are implicated in the etiology of schizophrenia, autism, depression, and borderline personality disorder, which show sex biases in prevalence, symptom severity, and treatment response.

    “VP and OT have been implicated in the etiology of psychiatric disorders, such as schizophrenia (Jobst et al., 2014), autism (Yang et al., 2010; Xu et al., 2013; LoParo and Waldman, 2014), depression (Yuen et al., 2014), and borderline personality disorder (Bertsch et al., 2013), disorders which show sex biases in prevalence, symptom severity, and treatment responses.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Jobst et al., 2014 source

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    • cites Yang et al., 2010; Xu et al., 2013; LoParo and Waldman, 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Yuen et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Male Siberian hamsters had higher V1R binding in ventromedial, medial tuberal, and ventral premammillary hypothalamic nuclei on a long photoperiod, and in ventral premammillary hypothalamus on a short photoperiod, compared to females.

    “male Siberian hamsters had higher V1R binding in the ventromedial, medial tuberal, and ventral premammillary hypothalamic nuclei when on a long photoperiod light cycle, and in the ventral premammillary hypothalamus when on a short photoperiod light cycle, compared to females”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dubois-Dauphlin et al., 1991

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    Premisecitation

    V1aR and V1bR are expressed in the brain and are the most well-known mediators of VP effects on social behavior.

    “V1aR and V1bR are both expressed in the brain and are the most well-known mediators of the effects of VP in the brain on social behavior.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bielsky et al., 2004 source

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    • cites Egashira et al., 2004 source

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    • cites Lim et al., 2004b

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  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Sex differences in VP could have a dual function: contributing to sex differences in some behaviors while preventing sex differences in others.

    “It has been proposed that these consistent sex differences in VP could have a dual function, namely contributing to sex differences in some behaviors while preventing sex differences in other behaviors”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites De Vries & Boyle, 1998

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    • cites De Vries, 2004 source

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    Premisecitation

    In chimpanzees, males with DupB+/− had lower dominance and higher conscientiousness than females with DupB+/−, while DupB−/− carriers showed no effect.

    “while there was no effect in DupB−/− carriers, males with the DupB+/− allele had lower dominance and higher conscientiousness scores than females with the DupB+/−”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hopkins et al., 2012 source

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  • May combine two claims.

    Interpretationcitation

    Sex differences in OTR binding are both brain region- and species-specific.

    “Similar to the VP receptor, sex differences in OTR binding are both brain region- and species-specific (Tables 5–7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The VP system regulates social behaviors in rodents and humans, often in sex-specific ways.

    “Taken together, the VP system has been shown to regulate social behaviors in both rodents and humans often in sex-specific ways.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A single neonatal i.p. injection of OT on postnatal day 1 facilitated partner preference in both male and female adult prairie voles, but required high or low dose in males and an intermediate dose in females.

    “a single neonatal intraperitoneal (i.p.) injection of OT on postnatal day 1 facilitated partner preference in both male and female adult prairie voles, but required a high (12μg) or low (3μg) dose in males and an intermediate dose (6μ) in females”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bales & Carter, 2003a

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    • cites Bales et al. 2007b

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    Interpretationreasoning

    Prepulse inhibition may reflect social cognition in addition to attention and memory, and AVP1A gene variants may partly regulate this.

    “Prepulse inhibition may therefore be a reflection of not only attention and memory, but also social cognition, which may be partially regulated by AVP1A gene variants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ICV V1aR antagonist impaired partner preference formation in male prairie voles, but had no effect in females.

    “intracerebroventricular (ICV) V1aR antagonist impaired partner preference formation in males (Winslow et al., 1993), but there was no effect in females (Insel & Hulihan, 1995).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Winslow et al., 1993 source

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    • cites Insel & Hulihan, 1995

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  • May combine two claims.

    Premisecitation

    Neonatal OT increased V1aR binding in the ventral pallidum and cingulate cortex of adult male prairie voles, but decreased V1aR binding in the same regions of adult females.

    “neonatal OT increased V1aR binding in the ventral pallidum and cingulate cortex of adult males, but decreased V1aR binding in the same regions of adult females”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bales et al., 2007a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In chimpanzees, males with the DupB−/− allele needed more social cues to orient than males with DupB+/−, while females showed no effect.

    “while there was no effect in females, males with the DupB−/− allele (which is the shorter bp version and lacks RS3) needed more social cues to elicit an orienting response than males with the DupB+/−”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hopkins et al., 2014

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  • May combine two claims.

    Premisecitation

    The first studies to report intranasal OT effects in humans were done in males only, showing a role for OT in trust and processing of socially relevant information.

    “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”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kosfeld et al., 2005 source

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    • cites Zak et al., 2007 source

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    • cites Domes et al., 2007

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    Premisecitation

    The effects of OT on partner preference in female prairie voles could be located in the nucleus accumbens and prefrontal cortex, but these studies did not include males.

    “the effects of OT on partner preference in females could be located in the nucleus accumbens and in the prefrontal cortex, but these studies did not include males”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Young et al., 2001 source

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    • cites Liu and Wang, 2003 source

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  • May combine two claims.

    Interpretationreasoning

    These studies suggest a role of OT in social recognition in both sexes, but also suggest possible sex differences in sensitivity to exogenous OT, with a lack of effect in females.

    “Together, these studies suggest a role of OT in social recognition in both sexes, but also suggest that there might be sex differences in the sensitivity to exogenous OT, with a lack of an effect in females.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Intranasal OT facilitated kinship recognition in women, but not men.

    “facilitated kinship recognition in women, but not men (Fischer-Shofty et al., 2013)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fischer-Shofty et al., 2013 source

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  • May combine two claims.

    Premisecitation

    OT impaired accurate emotion perception ability in women, but not men.

    “OT impaired accurate emotion perception ability in women, but not men (Lynn et al., 2014)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lynn et al., 2014

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  • May combine two claims.

    Premisecitation

    ICV OT administration facilitated partner preference formation in female, but not male, prairie voles.

    “ICV OT administration facilitated partner preference formation in female (Williams et al., 1994; Insel and Hulihan, 1995), but not in male (Winslow et al., 1993) prairie voles.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Williams et al., 1994 source

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    • cites Insel and Hulihan, 1995

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    • cites Winslow et al., 1993 source

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  • May combine two claims.

    Interpretationcitation

    Initial work in prairie voles indicated a sex-specific role of the OT system in partner preference formation, suggesting the OT system may be more important for partner preference in females than males.

    “Initial work in prairie voles indicated a sex-specific role of the OT system in partner preference formation, suggesting that the OT system may be more important for partner preference in females compared to males.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    It is likely that the endogenous OT system plays a similar role in social recognition in both sexes, but males may be more sensitive to enhancing effects of exogenous OT, while females may have reached a ceiling effect.

    “It is therefore likely that the endogenous OT system plays a similar role in social recognition in both sexes, but that males may be more sensitive to the enhancing effects of exogenous OT, while females have perhaps reached a ceiling effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ICV OT reversed social defeat-induced social avoidance in male, but not female, rats.

    “ICV OT reversed social defeat-induced social avoidance in male (Lukas et al., 2011b), but not in female (Lukas and Neumann, 2014) rats.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Lukas et al., 2011b

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    • cites Lukas and Neumann, 2014

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  • May combine two claims.

    Interpretationreasoning

    These findings suggest the OT system is involved in partner preference in both sexes, but females may be more sensitive to exogenous OT.

    “These findings suggest that the OT system is involved in partner preference in both sexes, but that females may be more sensitive to exogenous OT.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    These results may suggest the OT system is involved in modulating salience and/or valence of social stimuli differently in males and females, possibly via activation of different neural circuits.

    “These results may suggest that the OT system is involved in modulating the salience and/or valence of social stimuli differently in males and females, possibly via the activation of different neural circuits.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    This underscores complexity of OTR function and may provide a mechanism to explain how OTR can be involved in different social behaviors by inducing brain region-specific effects.

    “This underscores not only the complexity of the function of the OTR but may also provide a mechanism to explain how the OTR can be involved in such different social behaviors, namely by inducing brain region-specific effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    These findings were surprising given typically pro-social effects of OT, although recent studies suggest a role for the OTR in the LS in reducing pro-social behaviors and enhancing anxiety in rodents.

    “These findings were a bit surprising, given the typically pro-social behavior effects of OT, although recent studies suggest a role for the OTR in the LS in reducing pro-social behaviors and enhancing anxiety in rodents”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Olazábal and Young, 2006

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    • cites Beery et al., 2008 source

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    • cites Guzman et al., 2013 source

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  • May combine two claims.

    Interpretationreasoning

    These studies highlight the importance of emotional valence in the role of OT in perception and recognition of social stimuli, and how this may differ in men and women.

    “These studies highlight the importance of emotional valence in the role of OT in perception and recognition of social stimuli, and how this may differ in men and women.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ICV OT improved social recognition in male, but not female, rats.

    “ICV OT improved social recognition in male (Benelli et al., 1995), but not in female (Engelmann et al., 1998) rats.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Benelli et al., 1995 source

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    • cites Engelmann et al., 1998 source

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    Premisecitation

    Reduced positive affect and reward dependence were found in men only among carriers of the A allele in rs53576.

    “whereas reduced positive affect (Lucht et al., 2009) and reward dependence (Tost et al., 2010) were found in men only.”
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    • cites Lucht et al., 2009 source

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    • cites Tost et al., 2010 source

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    Premisecitation

    Genetic studies of SNPs in the OTR gene provide evidence for involvement of the OTR in various social behaviors in humans, and potential sex-specific effects on human social behavior.

    “Genetic studies of single nucleotide polymorphisms (SNPs) in the OTR gene provide evidence for the involvement of the OTR in various social behaviors in humans (for reviews see Meyer-Lindenberg et al., 2011; Ebstein et al., 2012), and potential sex-specific effects on human social behavior.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Meyer-Lindenberg et al., 2011 source

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    • cites Ebstein et al., 2012 source

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    Premisecitation

    Sex differences in VP neurons and plasma VP concentrations have also been found in humans.

    “Sex differences in VP neurons and plasma VP concentrations have also been found in humans”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Share et al., 1988 source

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    • cites Asplund & Aberg, 1991

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    • cites Van Londen et al., 1997 source

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    Premisecitation

    A meta-analysis of rs53576 and rs2254298 did not reveal any sex effects or any general effects in the social behavior domain.

    “a meta-analysis of the most commonly studied SNPs rs53576 and rs2254298 did not reveal any sex effects or any general effects in the social behavior domain (Bakermans-Kranenburg and van IJzerdoorn, 2014)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bakermans-Kranenburg and van IJzerdoorn, 2014

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  • May combine two claims.

    Premisecitation

    Intranasal OT increased caudate/putamen response in males, whereas it decreased this response in females.

    “Intranasal OT increased the caudate/putamen response in males, whereas it decreased this response in females (Rilling et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rilling et al., 2014 source

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  • May combine two claims.

    Interpretationreasoning

    These studies overall suggest a correlation between OTR SNPs and differences in social processing, social behaviors, and social functioning in both sexes, with some important sex differences.

    “these studies overall suggest a correlation between OTR SNPs and differences in social processing, social behaviors, and social functioning in both sexes, with some important sex differences”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Although not statistically significant in a comparison between sexes, OT lowered rates of cooperation with computer partners following defection in women only.

    “Although not statistically significant in a comparison between sex, OT lowered rates of cooperation with computer partners following defection in women only (Rilling et al., 2012; 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Rilling et al., 2012 source

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    • cites [2014]

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  • May combine two claims.

    Interpretationreasoning

    For these species, studies only analyzed a few brain regions or had few subjects per sex, which might explain the limited brain regions in which sex differences in V1aR binding were found.

    “For these species, studies only analyzed a few brain regions or had only a few subjects per sex, which might explain the limited brain regions in which sex differences in V1aR binding were found”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Dubois Dauphin et al., 1996 source

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    • cites Dubois-Dauphlin et al., 1991

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    • cites Delville & Ferris, 1995

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The fewer sex differences in OT and OTR could be due to the lack of comprehensive analysis of sex differences in the OT system across species.

    “The latter could be due to the lack of comprehensive analysis of sex differences in the OT system across species.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Because some sex-specific effects were dose-dependent and required a higher dose in one sex, such effects may result from sex differences in sensitivity to VP or OT systems.

    “Because some of these sex-specific effects were dose-dependent and required a higher dose in one sex (i.e., role of VP on partner preference in prairie voles with higher doses required in females; Cho et al., 1999), this further suggests that such sex-specific effects may be the result of sex differences in sensitivity to VP or OT systems.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cho et al., 1999 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In most cases discussed, VP and OT systems seem to modulate several social behaviors in a similar direction, but may do so by acting at distinct brain regions.

    “in most cases discussed, VP and OT systems seem to modulate several social behaviors in a similar direction (i.e., VP and OT systems both facilitate social recognition, pair bonding, and aspects of social cognition), but they may do so by acting at distinct brain regions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These two studies generated different social behaviors and different effects of manipulation of the VP system.

    “Yet, this generated different social behaviors and different effects of manipulation of the VP system.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Partner preference formation in prairie voles is modulated by the VP system acting in the LS and ventral pallidum and by the OT system acting in the NAc and prefrontal cortex.

    “partner preference formation in prairie voles is modulated by the VP system acting in the LS and ventral pallidum (Liu et al., 2001; Pitkow et al., 2001; Lim & Young, 2004) and by the OT system acting in the NAc and prefrontal cortex (Young et al., 2001; Liu and Wang, 2003).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Liu et al., 2001 source

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    • cites Pitkow et al., 2001 source

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    • cites Young et al., 2001 source

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  • May combine two claims.

    Interpretationreasoning

    The direction of sex-specific behavioral actions of VP and OT systems can be variable, may be specific to a certain aspect of social behavior, and may depend on the species.

    “the direction of sex-specific behavioral actions of the VP and OT systems can be variable, may be specific to a certain aspect of social behavior, and may depend on the species.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Species-specific social organizations may explain why sex differences in VP and OT systems are so highly species-specific.

    “We have recently suggested that this may depend on species-specific social organizations (Dumais & Veenema, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dumais & Veenema, 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Interpretationreasoning

    This could imply that VP and OT systems may modulate social behaviors in a similar way by activating distinct neural circuits.

    “This could imply that VP and OT systems may modulate social behaviors in a similar way by activating distinct neural circuits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Social behaviors may be regulated by a synchrony of activity of OT and VP acting at distinct brain regions, and a balance of OT and VP activity is necessary for modulation of a wide range of social behaviors.

    “This suggests that social behaviors may be regulated by a synchrony of activity of OT and VP acting at distinct brain regions, and that a balance of OT and VP activity is necessary for the modulation of a wide range of social behaviors (Neumann & Landgraf, 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Neumann & Landgraf, 2012

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These sex differences were highly species-specific, suggesting a role for species-specific sex differences in social organization.

    “These sex differences were highly species-specific, suggesting a role for species-specific sex differences in social organization.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    The functional significance of sex differences in VP and OT systems is still largely unknown and in need of further research.

    “We conclude that the functional significance of sex differences in VP and OT systems is still largely unknown, and in need of further research.”
    Quote in the paperNot a substantial claim
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

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Extracellular OT release in the pBNST was higher in adult male rats compared to adult female rats when exposed to a juvenile conspecific.

    “extracellular OT release in the pBNST was higher in adult male rats compared to adult female rats when exposed to a juvenile conspecific (Dumais et al., 2016)”

    From Quantitative mapping reveals age and sex differences in vasopressin, but not oxytocin, immunoreactivity in the rat social behavior neural network (2017) · cites this paper as Dumais et al., 2016

    Section 2.b (Oxytocin; page unavailable) says that potential sex differences in brain OT release remain unclear because rat studies of region-specific release examined one sex only. Section 3.b reports higher oxytocin *receptor binding* in the posterior BNST of male rats, not higher extracellular OT release during exposure to a juvenile conspecific. (LLM, conf=0.86)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Sex differences in the vasopressin system have their origins in development and are androgen-dependent.

    “Sex differences in the vasopressin system also have their origins in development and are androgen-dependent (De Vries & Panzica, 2006; Dumais & Veenema, 2016).”

    From Developmental origins of sex differences in the neural circuitry of play (2020) · cites this paper as Dumais & Veenema, 2016

  • Sex differences in the OXTR system are documented, suggesting findings in males may not generalize to females.

    “Sex differences in the OXTR system are documented,11, 12, 13 suggesting that findings in males may not generalize to females.”

    From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [11]

  • In the mammalian brain, OTRs and V1aRs are robustly expressed in many regions, but their distributions often differ.

    “In mammalian brain OTRs and V1aRs are robustly expressed in many regions but their distributions often differ [9; 21; 22] (Figure 3).”

    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 [9]

  • The behavioral effects of vasopressin are mediated primarily by V1aR and V1bR, while vasopressin acts on V2 to regulate fluid homeostasis in the kidney.

    “The behavioral effects of AVP are mediated primarily by V1aR (or Avpr1a) and V1bR (16,37,38,49,68), while AVP acts on V2 to regulate fluid homeostasis in the kidney (69).”

    From Oxytocin, Vasopressin, and Social Behavior: From Neural Circuits to Clinical Opportunities (2022) · cites this paper as [49]

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.

  • V1R hormonal regulation is described in opposite ways

    Minor

    The paper says the OTR, unlike the V1R, is modulated by gonadal hormones. Earlier, it explicitly says V1R binding depends on gonadal hormones and describes effects of gonadectomy on V1aR binding.

  • Olfactory bulb is added to the reported male-higher OTR regions

    Minor

    The paper attributes higher male OTR binding in the olfactory bulb to its Wistar rat findings. Its earlier enumeration of all nine regions with higher male OTR binding does not include the olfactory bulb.

  • Studies reporting OTR sex differences are classified as finding none

    Minor

    The general discussion groups studies of ICR mice, singing mice, and tuco-tuco among those that did not find OTR sex differences. The receptor section explicitly reports sex differences in each of those species.

3 of 3

Cites

Flagged first, then by citations

18 of the 350 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Dumais, K. M., & Veenema, A. H.
Affiliations
Boston College (US)
Corresponding author
Dumais, Kelly M.
ORCID
Venue
Frontiers in Neuroendocrinology
Publisher
Elsevier BV
Published
2016-01
Volume
40
Pages
1-23
ISSN
0091-3022 (ISSN-L)
DOI
10.1016/j.yfrne.2015.04.003
PMC
PMC4633405
OpenAlex
W318497691
Semantic Scholar
574d709e73a149f815895751a2ba2c3bda879881
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 · 2015: 6
FWCI
7.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroendocrinology (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIMH (F31MH100891, R15MH102807, R01MH102456)
  • NSF IOS (1253386)
Topics
  • Social Sciences › Psychology › Social Psychology › 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

About these checks

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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