CoChat
Sign Up
Cited by 199Neuroendocrine regulation and behaviorOlfactory and Sensory Function StudiesNeuropeptides and Animal Physiology

Chronic and acute intranasal oxytocin produce divergent social effects in mice

Open access
Huang, Huiping, Michetti, Caterina, Busnelli, Marta, Managò, Francesca, Sannino, Sara, Scheggia, Diego, Giancardo, Luca, Sona, Diego +4 more·2014·Neuropsychopharmacology
DOI 10.1038/npp.2013.310PMC PMC3957104
Open this paper in CoChat — free accountOpen PDF

Abstract

Intranasal administration of oxytocin (OXT) might be a promising new adjunctive therapy for mental disorders characterized by social behavioral alterations such as autism and schizophrenia. Despite promising initial studies in humans, it is not yet clear the specificity of the behavioral effects induced by chronic intranasal OXT and if chronic intranasal OXT could have different effects compared with single administration. This is critical for the aforementioned chronic mental disorders that might potentially involve life-long treatments. As a first step to address these issues, here we report that chronic intranasal OXT treatment in wild-type C57BL/6J adult mice produced a selective reduction of social behaviors concomitant to a reduction of the OXT receptors throughout the brain. Conversely, acute intranasal OXT treatment produced partial increases in social behaviors towards opposite-sex novel-stimulus female mice, while on the other hand, it decreased social exploration of same-sex novel stimulus male mice, without affecting social behavior towards familiar stimulus male mice. Finally, prolonged exposure to intranasal OXT treatments did not alter, in wild-type animals, parameters of general health such as body weight, locomotor activity, olfactory and auditory functions, nor parameters of memory and sensorimotor gating abilities. These results indicate that a prolonged over-stimulation of a 'healthy' oxytocinergic brain system, with no inherent deficits in social interaction and normal endogenous levels of OXT, results in specific detrimental effects in social behaviors.

AI snapshot

Written from the paper’s full text.

TL;DR

Chronic intranasal oxytocin in wild-type C57BL/6J adult male mice selectively reduced social behaviors and decreased brain oxytocin receptor binding, whereas acute intranasal oxytocin produced context-dependent social effects. The authors conclude that prolonged over-stimulation of a healthy oxytocinergic system can have detrimental social effects.

Key findings

  • Chronic intranasal OXT reduced social behavior toward opposite-sex novel females and same-sex cagemates: body sniffing frequency F(2,43)=5.69, p<0.05 and duration F(2,43)=10.14, p<0.0005; total social behavior frequency F(2,43)=3.10, p<0.05 and duration F(2,43)=8.08, p<0.005; male-male total social duration F(2,23)=3.32, p=0.05.
  • Chronic OXT decreased OXTR binding across brain regions; the higher dose caused greater reductions in lateral septum (−25% vs −9%), anterior olfactory nucleus (−21% vs −9%), and amygdala (−18% vs −8%), and increased V1aR binding in lateral septum (+18% for 0.15 IU, +31% for 0.3 IU).
  • Acute intranasal OXT increased social behavior toward opposite-sex novel females (anogenital sniffing frequency F(2,14)=8.05, p<0.005; total social frequency F(2,14)=4.09, p<0.05 for 0.3 IU), did not alter interactions with familiar male cagemates, and reduced exploration of unfamiliar males (social duration treatment × trial F(6,111)=3.49, p=0.003).
  • Chronic OXT did not alter body weight, olfactory abilities, temporal order object recognition memory, acoustic startle, or prepulse inhibition; locomotor activity showed only slight, time-point-specific distance reductions.

Methods

  • Adult male C57BL/6J mice (12–20 weeks) received intranasal OXT at 0.15 or 0.3 IU/5 ml or saline; chronic treatment was twice daily for 7–21 days and tested 1 h after the last dose, while acute treatment was a single dose tested 5 min later.
  • Behavioral assays included male-female social interaction with ultrasonic vocalizations, male-male cagemate interaction, olfactory testing, locomotor activity, temporal order object recognition, acoustic startle/prepulse inhibition, and habituation/dishabituation social memory; separate cohorts underwent brain autoradiography for OXTR and V1aR.
  • Analyses used one- or two-way ANOVAs with Newman-Keuls post hoc tests, significance at p<0.05; sample sizes varied by experiment (e.g., chronic male-female Ns=14 VEH, 16 OXT 0.15 IU, 16 OXT 0.3 IU; autoradiography Ns=7 per group).

Limitations

  • The paper states that the significance of the brain receptor modulations and their underlying neurobiological mechanisms remain for future study, and that the experimental setting was not specifically designed to investigate sexual behaviors but rather a male’s approach toward a sexually receptive female.
  • Evident from the text: findings are restricted to wild-type C57BL/6J male mice, so generalizability to females, other strains, disease models, and humans is not established.
  • Evident from the text: some acute effects were partial or trend-level, and several experiments used small samples (e.g., acute groups Ns=6), which may limit robustness of the behavioral conclusions.

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

Integrity signals

Registry

Crossref · 10.1038/npp.2013.310

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 43 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Chronic intranasal OXT treatment in wild-type C57BL/6J adult mice produced a reduction of OXT receptors throughout the brain.

    “here we report that chronic intranasal OXT treatment in wild-type C57BL/6J adult mice produced a selective reduction of social behaviors concomitant to a reduction of the OXT receptors throughout the brain.”
    • Also stated in: § Chronic Intranasal OXT Treatment Decreased OXT Receptors in the Brain · plain
      “As shown in Figure 3, mice treated with OXT had a significant decrease in OXTR-binding sites in all of the regions considered.”
    • Also stated in: § Chronic Intranasal OXT Treatment Decreased OXT Receptors in the Brain · boosted
      “These results clearly show that chronic intranasal OXT treatment reduced OXTRs throughout the brain whereas having much less impact on V1aR vasopressin receptors.”
    Quote in the paperSubstantial claim
  • Findingown data

    Prolonged exposure to intranasal OXT treatments did not alter, in wild-type animals, parameters of general health such as body weight, locomotor activity, olfactory and auditory functions.

    “Finally, prolonged exposure to intranasal OXT treatments did not alter, in wild-type animals, parameters of general health such as body weight, locomotor activity, olfactory and auditory functions, nor parameters of memory and sensorimotor gating abilities.”
    • Also stated in: § Chronic Intranasal OXT Treatment did not Affect Body Weight, General Olfactory and Locomotor Abilities · plain
      “Thus, chronic intranasal OXT treatment did not alter the body weight of mice, up to 21 days of administration (Supplementary Figure 3).”
    • Also stated in: § Chronic Intranasal OXT Treatment did not Affect Body Weight, General Olfactory and Locomotor Abilities · hedged
      “Hence, these results indicate that the social behavioral deficits found in C57BL/6J mice chronically treated with intranasal OXT were not dependent on alterations of body weight, olfactory abilities or gross locomotor activity.”
    Quote in the paperSubstantial claim
  • Findingown data

    Prolonged exposure to intranasal OXT treatments did not alter, in wild-type animals, parameters of memory and sensorimotor gating abilities.

    “Finally, prolonged exposure to intranasal OXT treatments did not alter, in wild-type animals, parameters of general health such as body weight, locomotor activity, olfactory and auditory functions, nor parameters of memory and sensorimotor gating abilities.”
    • Also stated in: § Chronic Intranasal OXT Treatment did not Alter Temporal Order Object Recognition Memory Functions · hedged
      “These results suggest that chronic intranasal OXT treatment did not alter object memory abilities that depend on intact mPFC, hippocampus and PRH in wild-type C57BL/6J mice.”
    • Also stated in: § Acoustic Startle and Prepulse Inhibition are Unaltered by Chronic Intranasal OXT Treatment · hedged
      “These results indicate that chronic intranasal OXT treatment did not alter reactivity to stressful events or sensorimotor gating abilities in healthy C57BL/6J mice.”
    Quote in the paperSubstantial claim
  • Findingown data

    Acute intranasal OXT treatment decreased social exploration of same-sex novel stimulus male mice.

    “Conversely, acute intranasal OXT treatment produced partial increases in social behaviors towards opposite-sex novel-stimulus female mice, while on the other hand, it decreased social exploration of same-sex novel stimulus male mice, without affecting social behavior towards familiar stimulus male mice.”
    Quote in the paperSubstantial claim
  • Findingown data

    Acute intranasal OXT treatment did not affect social behavior towards familiar stimulus male mice.

    “Conversely, acute intranasal OXT treatment produced partial increases in social behaviors towards opposite-sex novel-stimulus female mice, while on the other hand, it decreased social exploration of same-sex novel stimulus male mice, without affecting social behavior towards familiar stimulus male mice.”
    Quote in the paperSubstantial claim
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 16
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingown data

    Chronic intranasal OXT treatment did not affect body weight, general olfactory and locomotor abilities.

    “Chronic Intranasal OXT Treatment did not Affect Body Weight, General Olfactory and Locomotor Abilities”
    • Also stated in: § Chronic Intranasal OXT Treatment did not Affect Body Weight, General Olfactory and Locomotor Abilities · hedged
      “Hence, these results indicate that the social behavioral deficits found in C57BL/6J mice chronically treated with intranasal OXT were not dependent on alterations of body weight, olfactory abilities or gross locomotor activity.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Chronic intranasal OXT treatments of 7, 15 and 21 days produced the same decrease in social interactions.

    “The time of testing was based on preliminary pilot studies showing that chronic intranasal OXT treatments of 7, 15 and 21 days produced the same decrease in social interactions (data not shown).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Both OXT 0.15 and 0.3 IU groups showed no significant differences in the frequency of all nonsocial behaviors including standing/walking alone, digging, grooming, rearing, and wall rearing, compared with the VEH group.

    “Both OXT 0.15 and 0.3 IU groups showed no significant differences in the frequency and duration of all nonsocial behaviors including standing/ walking alone”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    VEH-treated mice showed a characteristic decline (p<0.01) in the time spent investigating the same stimulus male, with a full recovery following the introduction of a new unfamiliar male (p<0.001).

    “As expected, VEH-treated mice showed a characteristic decline (po0.01) in the time spent investigating the same stimulus male, with a full recovery following the introduction of a new unfamiliar male (po0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    C57BL/6J male mice chronically treated with intranasal OXT decreased social interaction behaviors towards opposite-sex novel-stimulus female mice as well as towards same-sex familiar cagemates.

    “C57BL/6J male mice chronically treated with intranasal OXT decreased social interaction behaviors towards opposite-sex novel-stimulus female mice as well as towards same-sex familiar cagemates.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Both OXT 0.15 and 0.3 IU groups showed no significant differences in the duration of all nonsocial behaviors including standing/walking alone, digging, grooming, rearing, and wall rearing, compared with the VEH group.

    “Both OXT 0.15 and 0.3 IU groups showed no significant differences in the frequency and duration of all nonsocial behaviors including standing/ walking alone”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Prolonged exposure to intranasal OXT treatments did not alter, in wild-type animals, parameters of general health, such as body weight, gross locomotor activity, olfactory and auditory functions, nor parameters of memory and sensorimotor gating abilities.

    “Finally, prolonged exposure to intranasal OXT treatments did not alter, in wild-type animals, neither parameters of general health, such as body weight, gross locomotor activity, olfactory and auditory functions, nor parameters of memory and sensorimotor gating abilities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Almost no aggressive/fighting behaviors were observed, with no OXT treatment (F(2,37)=1.14, p=0.33) or OXT treatment × trial interaction effects (F(6,111)=1.15, p=0.34).

    “Almost no aggressive/fighting behaviors were observed (ie, VEH group: 1 mouse out of 13; OXT 0.15-IU group: 1 out of 14; OXT 0.3-IU group: 1 out of 13) with no OXT treatment (F (2,37) ¼ 1.14, p ¼ 0.33) or OXT treatment  trial interaction effects (F (6,111) ¼ 1.15, p ¼ 0.34).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The neuropeptide oxytocin (OXT) has been strongly implicated in social behaviors including social recognition, social approach, pair bonding, paternal care and maternal behavior.

    “The neuropeptide oxytocin (OXT) has been strongly implicated in social behaviors including social recognition, social approach, pair bonding, paternal care and maternal behavior (Lim et al, 2005;Sala et al, 2011;Winslow and Insel, 2002).”
    • Also stated in: § Chronic Intranasal OXT Treatment Decreased Male-Female Social Interaction · boosted
      “The OXT system has been extensively involved in the modulation of social-related behaviors (Bielsky and Young, 2004;Sala et al, 2012;Sala et al, 2011;Winslow and Insel, 2002).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Lim et al, 2005 source

      Not checked in the free run.

    • cites Sala et al, 2011 source

      Not checked in the free run.

    • cites Winslow and Insel, 2002 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Intranasal administration of vasopressin (AVP) and of OXT increases the intracerebral concentration of these peptides in rats and mice, not only in the cerebrospinal fluid but also in selected brain regions.

    “Intranasal administration of vasopressin (AVP) and of OXT have been reported, in rats and mice, to increase the intracerebral concentration of these peptides, not only in the cerebrospinal fluid but also in selected brain regions (Born et al, 2002;Neumann et al, 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Born et al, 2002 source

      Not checked in the free run.

    • cites Neumann et al, 2013 source

      Not checked in the free run.

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

    Premisecitation

    In patients with schizophrenia, an adjunctive 3-week treatment with intranasal OXT significantly improves Positive and Negative Syndrome Scale (PANSS) total scores and verbal memory measures of the California Verbal Learning Test.

    “Furthermore, in patients with schizophrenia, an adjunctive 3-week treatment with intranasal OXT has been found to significantly improve Positive and Negative Syndrome Scale (PANSS) total scores (Feifel et al, 2010) and verbal memory measures of the California Verbal Learning Test (Feifel et al, 2012a).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Feifel et al, 2010 source

      Not checked in the free run.

    • cites Feifel et al, 2012a

      Not checked in the free run.

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

    Premisecitation

    Central effects are observed in humans after intranasal administration of OXT/AVP.

    “Whatever the mechanism(s) involved, there is no doubt that central effects are observed in humans after intranasal administration (Veening and Olivier, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Veening and Olivier, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The role of the OXT system has been investigated in rodent models, but uniquely using OXT-related mutant mice and giving OXT through intracerebroventricular (ICV), intraperitoneal (IP) and subcutaneous (SC) injections.

    “The role of the OXT system has been investigated in rodent models, but uniquely using OXT-related mutant mice and giving OXT through intracerebroventricular (ICV), intraperitoneal (IP) and subcutaneous (SC) injections (Bielsky and Young, 2004;Jin et al, 2007;Popik et al, 1996;Sala et al, 2012;Sala et al, 2011;Takayanagi et al, 2005;Winslow and Insel, 2002).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bielsky and Young, 2004 source

      Not checked in the free run.

    • cites Jin et al, 2007 source

      Not checked in the free run.

    • cites Popik et al, 1996 source

      Not checked in the free run.

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

    Premisecitation

    Acute intranasal OXT seems to produce no negative side effects in both healthy volunteers and subjects with developmental or mental health difficulties when delivered in doses of 18-40 IU.

    “Acute intranasal OXT seems to produce no negative side effects in both healthy volunteers and subjects with developmental or mental health difficulties when delivered in doses of 18-40 IU (MacDonald et al, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites MacDonald et al, 2011 source

      Not checked in the free run.

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

    Premisecitation

    In subjects diagnosed with autism, a single intranasal administration of OXT might improve, at least temporarily, emotion recognition abilities in the Reading the Mind in the Eyes test and the patients' ability to process socially relevant cues in a computer-based game.

    “Moreover, in subjects diagnosed with autism, a single intranasal administration of OXT might be able to improve, at least temporarily, emotion recognition abilities in the Reading the Mind in the Eyes test and the patients' ability to process socially relevant cues in a computer-based game (Andari et al, 2010;Green and Hollander, 2010;Guastella et al, 2010).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Andari et al, 2010 source

      Not checked in the free run.

    • cites Green and Hollander, 2010 source

      Not checked in the free run.

    • cites Guastella et al, 2010 source

      Not checked in the free run.

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

    Study design and conductnone given

    Experimenters were blind to the mouse treatments during testing and behavioral scoring.

    “Experimenters were blind to the mouse treatments during testing and behavioral scoring.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All procedures were approved by the Italian Ministry of Health (permit n. 230/2009-B) and strictly adhere to the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

    “All procedures were approved by the Italian Ministry of Health (permit n. 230/2009-B) and strictly adhere to the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In agreement with the previous experiment, acute intranasal OXT treatment did not alter social exploration of a familiar male, whereas it reduced exploration of an unfamiliar male.

    “Thus, in agreement with the previous experiment, acute intranasal OXT treatment did not alter social exploration of a familiar male whereas; in contrast, it reduced exploration of an unfamiliar male.”
    • Also stated in: § DISCUSSION · plain
      “reduced social behaviors towards same-sex novel-stimulus male mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The oxytocin receptor is a G protein-coupled receptor and can undergo desensitisation and internalization after agonist application.

    “Indeed, the oxytocin receptor is a G protein-coupled receptor and can undergo desensitisation and internalization after agonist application (Conti et al, 2009;Insel et al, 1992).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Conti et al, 2009 source

      Not checked in the free run.

    • cites Insel et al, 1992 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Chronic intranasal OXT treatment consistently reduced both social behaviors and communication.

    “Concomitantly, chronic intranasal OXT treatment decreased the number of USVs, revealing that this treatment consistently reduced both social behaviors and communication.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The behavioral measures used (e.g., sniffing, following, USVs) validly index social interaction and communication in mice.

  • May combine two claims.

    Interpretationcitation

    Intranasal administration of OXT might act to increase the concentration of OXT beyond endogenous levels in a normal-functioning brain, resulting in desensitisation and hence down-regulation of OXTRs.

    “Thus, intranasal administration of OXT might act to increase the concentration of OXT beyond endogenous levels in a normal-functioning brain resulting in desensitisation and hence, down-regulation of OXTRs.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Conti et al, 2009 source

      Not checked in the free run.

    • cites Insel et al, 1992 source

      Not checked in the free run.

    • Rests on an assumption: The C57BL/6J mice used have a normal-functioning oxytocinergic system with no inherent deficits in social interaction and normal endogenous levels of OXT.

  • Classified as probably not a substantial claim.

    Premisecitation

    Intranasal OXT administration in healthy humans improves social and emotion recognition.

    “improving social and emotion recognition (Domes et al, 2007b;Guastella et al, 2008;Rimmele et al, 2009)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Domes et al, 2007b

      Not checked in the free run.

    • cites Guastella et al, 2008 source

      Not checked in the free run.

    • cites Rimmele et al, 2009 source

      Not checked in the free run.

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

    Premisecitation

    Intranasal OXT administration in healthy humans attenuates activation of the amygdala to social stimuli.

    “attenuating activation of amygdala to social stimuli (Baumgartner et al, 2008;Domes et al, 2007a;Gamer et al, 2010;Kirsch et al, 2005)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Baumgartner et al, 2008 source

      Not checked in the free run.

    • cites Domes et al, 2007a

      Not checked in the free run.

    • cites Gamer et al, 2010 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    A possible reason for the apparent discrepancies between our findings and current evidence from human studies regarding OXT-induced effects in social-related behaviors might be that a prolonged over-stimulation of a 'healthy' oxytocinergic system, with no inherent deficits in social interaction and normal endogenous levels of OXT, might result in detrimental effects.

    “Thus, a possible reason for the apparent discrepancies between our findings and current evidence from human studies regarding OXTinduced effects in social-related behaviors might be that a prolonged over-stimulation of a 'healthy' oxytocinergic system, with no inherent deficits in social interaction and normal endogenous levels of OXT, might result in detrimental effects.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The C57BL/6J mice used have a normal-functioning oxytocinergic system with no inherent deficits in social interaction and normal endogenous levels of OXT.

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

    Premisecitation

    Intranasal OXT administration in healthy humans reduces endocrinal and behavioral responses to social stress and enhances stress-buffering effects of social support.

    “administration in healthy humans have also indicated OXT's modulation of psychosocial functions, such as reducing endocrinal and behavioral responses to social stress, enhancing stress-buffering effects of social support (Heinrichs et al, 2003)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Heinrichs et al, 2003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human studies have prevalently used acute administration of OXT in healthy subjects, whereas prolonged OXT treatments have been adopted only in pathological states presenting social deficits.

    “human studies have prevalently used acute administration of OXT in healthy subjects”
    • Also stated in: § DISCUSSION · plain
      “prolonged OXT treatments have been adopted only in pathological states presenting social deficits”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Baumgartner et al, 2008 source

      Not checked in the free run.

    • cites Feifel et al, 2012a

      Not checked in the free run.

    • cites Tachibana et al, 2013 source

      Not checked in the free run.

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

    Interpretationown data

    The OXT intranasal route of administration in mice might be a valuable tool to preclinically test novel compounds and to better investigate the neural mechanisms of OXT-mediated behaviors in different social settings.

    “Altogether, our results show that the OXT intranasal route of administration in mice might be a valuable tool to preclinically test novel compounds and to better investigate the neural mechanisms of OXT-mediated behaviors in different social settings (eg, differentiating between novel vs familiar and opposite-vs same-sex social interactions).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Intranasal OXT treatment in normal C57BL/6J mice can reliably modulate the oxytocinergic system to selectively alter social behavior; different effects on specific social behaviors are obtained upon chronic or acute intranasal administration.

    “In conclusion, we demonstrated that intranasal OXT treatment in normal C57BL/6J mice can reliably modulate the oxytocinergic system to selectively alter social behavior; most importantly, different effects on specific social behaviors are obtained upon chronic or acute intranasal administration.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    An acute intracerebroventricular injection of OXT in wild-type male mice reduced sociability towards a stranger male subject.

    “an acute intracerebroventricular injection of OXT in wild-type male mice reduced the sociability towards a stranger male subject (Sala et al, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sala et al, 2011 source

      Not checked in the free run.

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

    Premisecitation

    Acute OXT aerosol in male monkeys reduced social vigilance for unfamiliar dominant faces.

    “acute OXT aerosol in male monkeys reduced social vigilance for unfamiliar dominant faces (Ebitz et al, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ebitz et al, 2013 source

      Not checked in the free run.

30 of 30

  • The paper relies on this without support.

    It is not yet clear if chronic intranasal OXT might affect psychiatric-relevant behavioral measures (eg, in social and memory domains), and if chronic intranasal OXT has different effects compared with single administration.

    “Despite these promising initial results, it is not yet clear if chronic intranasal OXT might affect psychiatric-relevant behavioral measures (eg, in social and memory domains), and if chronic intranasal OXT has different effects compared with single administration.”

  • The paper relies on this without support.

    Social alterations are among the most debilitating core features of these mental illnesses, and currently available treatments are not effective in ameliorating these symptoms.

    “This would be particularly important as social alterations are considered among the most debilitating core features of these mental illnesses, and currently available treatments are not effective in ameliorating these symptoms.”

  • The paper relies on this without support.

    C57BL/6J mice is classically used as the background strain for genetically modified mice and animal models of neurodegenerative and neurodevelopmental disorders.

    “This strain of mice is classically used as the background strain for genetically modified mice and animal models of neurodegenerative and neurodevelopmental disorders.”

  • The paper relies on this without support.

    The C57BL/6J mice used have a normal-functioning oxytocinergic system with no inherent deficits in social interaction and normal endogenous levels of OXT.

    “a prolonged over-stimulation of a 'healthy' oxytocinergic system, with no inherent deficits in social interaction and normal endogenous levels of OXT”

  • The paper relies on this without support.

    The behavioral measures used (e.g., sniffing, following, USVs) validly index social interaction and communication in mice.

    “revealing that this treatment consistently reduced both social behaviors and communication.”

  • The paper relies on this without support.

    The doses and timing of acute intranasal OXT (0.15 and 0.3 IU, 5 min before test) are appropriate to produce acute effects on social behavior.

    “5 min after a single intranasal administration of VEH, OXT 0.15 IU or OXT 0.3 IU, male mice were evaluated for interactions with their cagemates in an open-field arena”

  • The paper relies on this without support.

    The habituation/dishabituation social memory test measures social recognition memory.

    “male mice were evaluated in a habituation/dishabituation social memory test.”
7 of 7

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?

  • In mice, chronic oxytocin treatment induced an anxiogenic phenotype.

    “In male voles, a long-term developmental treatment with low doses of OXT IN resulted in a deficit in partner preference behavior (139), and in mice, chronic OXT treatment even induced an anxiogenic phenotype (140).”

    From Dissecting the Role of Oxytocin in the Formation and Loss of Social Relationships (2016) · cites this paper as [140]

  • Chronic intranasal oxytocin from 12 to 23 weeks reduced social behavior in adult male mice when they were tested 1 hour after oxytocin administration.

    “Another study found that chronic intranasal Oxt from 12 to 23 weeks reduced social behavior in adult male mice when they were tested 1 h after Oxt administration (45).”

    From Oxytocin during Development: Possible Organizational Effects on Behavior (2015) · cites this paper as [45]

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.

  • Acute-test sample counts do not match the reported ANOVA degrees of freedom

    Minor

    Figure 4 lists six mice in each of three groups, or 18 total. A three-group one-way ANOVA on all 18 mice would have 15 residual degrees of freedom, whereas the acute-test results consistently report 14; no missing observation is identified.

  • Low-dose IU/kg and mg/kg equivalents disagree

    Minor

    Using the stated conversion of 1 IU to 1.667 mg, the reported 5 IU/kg equals 8.335 mg/kg, not the stated 9.6 mg/kg.

    Reported 9.6 · recomputed 8.335

2 of 2

The citation lists haven’t been fetched yet

References 57 · Cited by 199

Research works printed but not linked: 3

  1. Bales KL, Perkeybile AM, Conley OG, Lee MH, Guoynes CD, Downing GM et al (2012). Chronic intranasal oxytocin causes long-term impairments in partner preference formation in male prairie voles. Biol Psychiatry 15: 00800–00801.
  2. Feifel D, Macdonald K, Cobb P, Minassian A (2012a). Adjunctive intranasal oxytocin improves verbal memory in people with schizophrenia. Schizophr Res 7: 7.
  3. Sala M, Braida D, Donzelli A, Martucci R, Busnelli M, Bulgheroni E et al (2012). Mice heterozygous for the oxytocin receptor gene (Oxtr(+/−)) show impaired social behavior but not increased aggression or cognitive inflexibility: evidence of a selective haploinsufficiency gene effect. J Neuroendocrinol 11: 1365–2826.

Authors
Huang, H., Michetti, C., Busnelli, M., Managò, F., Sannino, S., Scheggia, D., Giancardo, L., Sona, D., Murino, V., Chini, B., Scattoni, M. L., & Papaleo, F.
Affiliations
  • Italian Institute of Technology (IT)
  • Istituto Superiore di Sanità (IT)
  • University of Milan (IT)
  • University of Padua (IT)
Corresponding author
Papaleo, Francesco
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2013-11-04
Volume
39
Issue
5
Pages
1102-1114
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2013.310
PMC
PMC3957104
OpenAlex
W2035561357
Semantic Scholar
479db18b429edd71af891e7f01e6031329fb348a
Cited by
199
References
57
Citations by year
2026: 1 · 2025: 9 · 2024: 14 · 2023: 11 · 2022: 16 · 2021: 23 · 2020: 13 · 2019: 15 · 2018: 14 · 2017: 23 · 2016: 18 · 2015: 27 · 2014: 15
FWCI
30.02
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
intranasal oxytocin, social behavior, oxytocin receptor, social exploration, autism spectrum disorder, schizophrenia
MeSH terms
Administration, Intranasal, Animals, Auditory Perception, Body Weight, Brain, Exploratory Behavior, Habituation, Psychophysiologic, Male, Mice, Inbred C57BL, Motor Activity, Oxytocin, Psychotropic Drugs, Sex Factors, Social Behavior, Time Factors, Time Perception, Receptors, Oxytocin, Recognition, Psychology, Mice, Sensory Gating, Olfactory Perception

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review