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Cited by 265Neuroendocrine regulation and behaviorOlfactory and Sensory Function StudiesHuman-Animal Interaction Studies

Chronic intranasal oxytocin causes long-term impairments in partner preference formation in male prairie voles

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Bales, Karen L., Perkeybile, Allison M., Conley, Olivia G., Lee, Meredith H., Guoynes, Caleigh D., Downing, Griffin M., Yun, Catherine R., Solomon, Marjorie +2 more·2013·Biological Psychiatry
DOI 10.1016/j.biopsych.2012.08.025PMC PMC3556198
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Abstract

Background Oxytocin (OT) is a hormone shown to be involved in social bonding in animal models. Intranasal OT is currently in clinical trials for use in disorders such as autism and schizophrenia. We examined long-term effects of intranasal OT given developmentally in the prairie vole (Microtus ochrogaster), a socially monogamous rodent, often used as an animal model to screen drugs that have therapeutic potential for social disorders.Methods We treated voles with one of three dosages of intranasal OT, or saline, from day 21 (weaning) through day 42 (sexual maturity). We examined both social behavior immediately following administration, as well as long-term changes in social and anxiety behavior after treatment ceased. Group sizes varied from 8 to 15 voles (n = 89 voles total).Results Treatment with OT resulted in acute increases in social behavior in male voles with familiar partners, as seen in humans. However, long-term developmental treatment with low doses of intranasal OT resulted in a deficit in partner preference behavior (a reduction of contact with a familiar opposite-sex partner, used to index pair-bond formation) by male voles.Conclusions Long-term developmental treatment with OT may show results different to those predicted by short-term studies, as well as significant sex differences and dosage effects. Further animal study is crucial to determining safe and effective strategies for use of chronic intranasal OT, especially during development.

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Written from the paper’s full text.

TL;DR

Chronic developmental intranasal oxytocin produced acute pro-social effects in male prairie voles but long-term deficits in partner preference formation at low and medium doses, while females did not show this partner-preference deficit. Effects were sex- and dose-dependent, and the paper cautions that chronic intranasal OT during development may not be safe or effective based on short-term pro-social findings.

Key findings

  • Acute intranasal OT in males increased contact with a familiar cage-mate at any dosage compared with saline (F3,227 = 3.48, p = 0.017); social approach was also affected, with low dosages inhibiting approach (F3,227 = 2.97, p = 0.033), and autogrooming was dose-dependently reduced (F3,227 = 2.74, p = 0.044). OT had no acute effects on social behavior in female voles.
  • After chronic treatment from day 21 to day 42, male voles treated with low or medium intranasal OT showed impaired partner preference formation, with a significant reduction in time spent with the female pair-mate (F3,20 = 3.12, p = 0.048); females did not show this deficit.
  • In two-way partner preference analysis, males showed a significant treatment by stimulus animal interaction (F3 = 3.03, p = 0.037), while females showed a significant effect of stimulus animal (F1 = 15.97, p < 0.001) but no treatment effect (F3 = 0.10, p = 0.961) or interaction (F3 = 0.59, p = 0.622).
  • Anxiety-related tests did not indicate increased anxiety from OT; elevated plus-maze showed no effects, and in the open field females treated with low or medium OT crossed fewer lines than saline-treated females (F3,26 = 3.66, p = 0.025).

Methods

  • Subjects were prairie voles (Microtus ochrogaster; n = 89 total, group sizes 8–15), weaned at day 20 and treated intranasally once daily from day 21 through day 42 with saline or oxytocin at Low (0.08 IU/kg), Medium (0.8 IU/kg), or High (8.0 IU/kg) doses.
  • Acute behavioral observations were conducted twice weekly after OT administration; after treatment ended, adult tests within two weeks included alloparental care, elevated plus-maze, open field, juvenile affiliation, and partner preference testing (6-hr cohabitation for females, 24-hr for males, followed by a three-chamber partner/stranger choice test).
  • Data were analyzed with mixed model ANOVAs in SAS 9.2, with sexes considered separately, treatment as fixed factor, ID or litter within pair as random factors, significance at p < 0.05, two-tailed; partner preference data were also analyzed with stimulus animal (partner vs. stranger) and treatment as factors.

Limitations

  • Stated in the paper: the between-subjects design and use of different developmentally appropriate tests at each age prevented longitudinal assessment of changes in the same behaviors; future work is needed on additional developmental ages, adult treatment effects, mechanisms, and replication of suggestive female pup-contact findings.
  • Stated in the paper: some behaviors were presented in tables but not statistically analyzed, and the low-dose female pup-contact pattern was described as suggestive rather than significant.
  • Evident from the text: group sizes were small (8–15 per group), some reported effects were trends or non-significant (e.g., male approach-startles F3,24 = 2.42, p = 0.091), and treatment was limited to days 21–42, so effects of continuing OT into adulthood were not tested.

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Crossref · 10.1016/j.biopsych.2012.08.025

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 72 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In female prairie voles, chronic intranasal oxytocin treatment with low or medium doses reduced line-crosses in the open field compared to saline.

    “Females showed a treatment effect of OT on line-crosses (F3,26 = 3.66, p = 0.025), a measure of emotionality (47). In post-hoc tests, females treated with either low or medium OT treatments crossed fewer lines than females treated with saline (Table 5).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In saline-treated prairie voles, males spent more time in contact with the partner than females in the partner preference test.

    “In the partner preference test, there were sex differences in saline-treated animals in time spent in contact with the partner (F1,21 = 11.09, p = 0.045), with males spending more time with the partner (Figure 3).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Acute intranasal oxytocin administration had no effects on social behavior in female prairie voles.

    “OT administration had no effects on acute social behavior in female voles (Table 1).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Acute intranasal oxytocin treatment increased social contact with a familiar cage-mate in male prairie voles at any dosage compared to saline.

    “Treatment with OT resulted in acute increases in social behavior in males with familiar partners, as seen in humans.”
    • Also stated in: § Acute Behavioral Observations · plain
      “Male voles increased contact with the cage-mate when they received OT of any dosage compared to saline (F3,227 = 3.48, p = 0.017).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Chronic intranasal oxytocin did not affect anxiety-like behavior in the elevated plus-maze in prairie voles.

    “Elevated plus-maze tests did not indicate any effects of intranasal OT on anxiety (Table 3), nor were there sex differences in saline-treated animals.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 28
  • Classified as probably not a substantial claim. 35

  • May combine two claims.

    Findingown data

    Male prairie voles treated with chronic intranasal oxytocin showed a significant reduction in time spent with the female pair-mate, while time spent with a stranger or in the empty cage did not differ by treatment.

    “Males showed a significant reduction in time spent with the female pair-mate (F3,20 = 3.12, p = 0.048). Time spent with the stranger did not differ significantly by treatment, nor did time spent in the empty cage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Male prairie voles treated with low or medium dosages of chronic intranasal oxytocin later showed deficits in formation of a partner preference, tested approximately two weeks after cessation of treatment, while females did not.

    “However, long-term developmental treatment with low doses of intranasal OT resulted in a deficit in partner preference behavior (a reduction of contact with a familiar opposite-sex partner, used to index pair-bond formation) by males.”
    • Also stated in: § Behavioral Testing Following Long-term Treatments · plain
      “Male voles that were treated with low or medium dosages of chronic intranasal OT later showed deficits in formation of a partner preference, tested approximately two weeks after the cessation of OT treatment (Figure 3), while females did not.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In male prairie voles, acute intranasal oxytocin affected social approach, with low dosages inhibiting approach compared to saline.

    “Social approach was also significantly affected by OT in males, although effects varied by dosage, with low dosages inhibiting approach (F3,227 = 2.97, p = 0.033; Table 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Acute intranasal oxytocin dose-dependently reduced autogrooming in male prairie voles, with the highest dosage reducing it the most.

    “Autogrooming following administration was significantly and dose-dependently reduced in males (F3,227 = 2.74, p = 0.044), with males receiving the highest dosage of OT autogrooming the least.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In saline-treated prairie voles, males autogroomed more and spent less time in social contact than females.

    “When considering the saline treatment only, there was a sex difference in autogrooming (F1,181 = 5.08, p = 0.026) and a trend for a sex difference in contact (F1,181 = 3.64, p = 0.058, Table 1); saline-treated males autogroomed more and spent less time in social contact than saline-treated females.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Low-dose OT-treated male prairie voles showed less interest in a strange juvenile.

    “While not statistically analyzed here, other behaviors measured suggest that males treated with low OT also showed less interest in a strange juvenile (Table 4)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Multiple measures of anxiety across the adult tests indicated either no difference between OT- and saline-treated animals, or a reduction in emotionality in OT-treated animals.

    “Multiple measures of anxiety across the adult tests indicated either no difference between OT- and saline-treated animals, or a reduction in emotionality in OT-treated animals”
    Quote in the paperSubstantial claim

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

    Findingnone given

    Acute administration had pro-social effects in the context of interactions with a familiar partner.

    “It is important to note that acute administration did have pro-social effects in the context of interactions with a familiar partner.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In healthy subjects, intranasal oxytocin alters pro-social feelings, social communication, emotional recognition, self-perception, and social interactions with offspring.

    “Generally, in healthy subjects pro-social feelings, including generosity and trust (6–8), social communication and emotional recognition (9,10), self-perception (11), and social interactions with offspring are altered by OT(12).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [6] Kosfeld, 2005, Oxytocin increases trust in humans, Nature source

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    • cites [7] Zak, 2008, The neurobiology of trust, Sci Am source

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    • cites [8] Barraza, 2009, Empathy toward strangers triggers oxytocin release and subsequent generosity, Ann N Y Acad Sci source

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    • cites [9] Domes, 2010, Effects of intranasal oxytocin on emotional face processing in women, Psychoneuroendocrinology source

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    • cites [10] Domes, 2007, Oxytocin attenuates amygdala responses to emotional faces regardless of valence, Biol Psychiatry source

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    • cites [11] Cardoso, 2012, Acute intranasal oxytocin improves self-perceptions of personality, Psychopharmacology (Berl) source

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

    Premisecitation

    Oxytocin is associated with maternal behavior and adult pair-bond formation (partner preference) behavior in rodents.

    “Oxytocin (OT), a neuropeptide hormone found exclusively in mammals, is associated with maternal behavior (1,2) and adult pair-bond formation (partner preference) behavior (3,4) in rodents.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [1] Pedersen, 1979, Induction of maternal behavior in virgin rats after intracerebroventricular administration of oxytocin, Proc Natl Acad Sci U S A source

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    • cites [2] Neumann, 1993, Oxytocin and vasopressin release within the supraoptic and paraventricular nuclei of pregnant, parturient and lactating rats: A microdialysis study, Neuroscience source

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    • cites [3] Williams, 1994, Oxytocin centrally administered facilitates formation of a partner preference in female prairie voles (Microtus ochrogaster), J Neuroendocrinol source

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    • cites [4] Cho, 1999, The effects of oxytocin and vasopressin on partner preferences in male and female prairie voles (Microtus ochrogaster), Behav Neurosci source

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    Premisecitation

    Many neuropeptides cross the blood-brain barrier when given intranasally.

    “Born and colleagues (5) showed that many neuropeptides crossed the blood-brain barrier when given intranasally.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Born, 2002, Sniffing neuropeptides: A transnasal approach to the human brain, Nat Neurosci source

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    Premisecitation

    Oxytocin can produce opposing effects at different dosages.

    “OT (like other peptides) can produce opposing effects at different dosages (19–22).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [19] Bales, 2007, Oxytocin has dose-dependent developmental effects on pair-bonding and alloparental care in female prairie voles, Horm Behav source

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    • cites [20] Carter, 2008, Early experience and the developmental programming of oxytocin and vasopressin

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    • cites [21] Kramer, 2003, Developmental effects of oxytocin on stress response: Single versus repeated exposure, Physiol Behav source

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    • cites [22] Kramer, 2007, The organizational effects of oxytocin on the central expression of estrogen receptor alpha and oxytocin in adulthood, BMC Neurosci source

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

    Premisecitation

    In individuals with autism, intranasal oxytocin increases emotion recognition and feelings of trust and willingness to interact socially.

    “In individuals with autism, intranasal OT was shown to increase emotion recognition (13) and to increase feelings of trust and willingness to interact socially (16).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Guastella, 2010, Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders, Biol Psychiatry source

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    • cites [16] Andari, 2010, Promoting social behavior with oxytocin in high-functioning autism spectrum disorders, Proc Natl Acad Sci U S A source

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

    Premisecitation

    Acute oxytocin administration reveals few safety concerns.

    “Acute OT administration reveals few safety concerns (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] MacDonald, 2011, A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research, Psychoneuroendocrinology source

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

    Premisecitation

    A single intraperitoneal oxytocin administration on postnatal day 1 led to long-term effects on partner preference in both male and female prairie voles, which differed depending on dose.

    “In voles, we found a single intraperitoneal OT administration postnatal day 1, led to long-term effects on partner preference in both male and female prairie voles, which differed depending on dose (19, 20).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Bales, 2007, Oxytocin has dose-dependent developmental effects on pair-bonding and alloparental care in female prairie voles, Horm Behav source

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    • cites [20] Carter, 2008, Early experience and the developmental programming of oxytocin and vasopressin

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

    Premisecitation

    In schizophrenic patients, intranasal oxytocin increased emotion recognition at 20 IU and decreased it at 10 IU.

    “In schizophrenic patients, intranasal OT increased emotion recognition at one dose (20 IU) and decreased emotion recognition at a different dose (10 IU) (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Goldman, 2011, Divergent effects of two different doses of intranasal oxytocin on facial affect discrimination in schizophrenic patients with and without polydipsia, Psychopharmacology (Berl) source

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

    Premisecitation

    The prairie vole is the premier animal model for the neurobiology of social bonding and is increasingly used to screen drugs with therapeutic potential for social disorders such as autism.

    “The prairie vole (Microtus ochrogaster), a socially monogamous rodent native to the American Midwest (24), is the premier animal model for the neurobiology of social bonding (25) and increasingly used to screen drugs that have therapeutic potential for social disorders such as autism (26,27).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] McGraw, 2010, The prairie vole: An emerging model organism for understanding the social brain, Trends Neurosci source

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    • cites [26] Modi, 2012, The oxytocin system in drug discovery for autism: Animal models and novel therapeutic strategies, Horm Behav source

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    • cites [27] Millan, 2012, Cognitive dysfunction in psychiatric disorders: Characteristics, causes, and the quest for improved therapy, Nat Rev Drug Disc source

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

    Premisecitation

    In prairie voles, oxytocin has extensive sex-specific effects, although in both sexes it is intimately involved in social behavior.

    “In prairie voles, OT has been shown to have extensive sex-specific effects, although in both sexes it is intimately involved in social behavior.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [3] Williams, 1994, Oxytocin centrally administered facilitates formation of a partner preference in female prairie voles (Microtus ochrogaster), J Neuroendocrinol source

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    • cites [30] Insel, 1998, Oxytocin, vasopressin, and the neuroendocrine basis of pair bond formation, Prog Brain Res

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    • cites [31] Carter, 1992, Oxytocin and social bonding, Ann N Y Acad Sci source

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    • cites [32] Ross, 2009, Characterization of the oxytocin system regulating affiliative behavior in female prairie voles, Neuroscience source

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    • cites [33] Lim, 2004, Vasopressin-dependent neural circuits underlying pair bond formation in the monogamous prairie vole, Neuroscience source

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

    Premisecitation

    Intranasal oxytocin is currently in clinical trials and has been identified as a treatment for developmental disorders involving social dysfunction, including autism spectrum disorders, social anxiety, and schizophrenia.

    “Intranasal OT, currently the subject of multiple clinical trials (clinicaltrials.gov), has been identified as a treatment for developmental disorders involving social dysfunction, including autism spectrum disorders (13), social anxiety (14), and schizophrenia (15).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites clinicaltrials.gov

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    • cites [13] Guastella, 2010, Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders, Biol Psychiatry source

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    • cites [14] Hall, 2012, Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome, Psychoneuroendocrinology source

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    Interpretationcitation

    The acute increase in pro-social behavior, specifically time spent in contact, in male prairie voles following intranasal oxytocin resembles findings in many human studies.

    “The acute effects of intranasal OT that we found here resemble those found in many human studies, consisting of an increase in pro-social behavior and engagement (specifically time spent in contact in males)(13,15,64–66).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [13] Guastella, 2010, Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders, Biol Psychiatry source

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    • cites [15] Pedersen, 2011, Intranasal oxytocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia, Schizophr Res source

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    • cites [64] Guastella, 2008, Oxytocin increases gaze to the eye region of human faces, Biol Psychiatry source

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    • cites [65] Guastella, 2009, A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder, Psychoneuroendocrinology source

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    • cites [66] Feifel, 2010, Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients, Biol Psychiatry source

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

    Premisecitation

    In Fragile X patients, 24 IU intranasal oxytocin increased eye gaze but did not affect cortisol, while 48 IU affected cortisol but not eye gaze.

    “In Fragile X patients, one dose (24 IU) increased eye gaze but did not affect cortisol, while a higher dose (48 IU) affected cortisol but not eye gaze (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Hall, 2012, Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome, Psychoneuroendocrinology source

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    Premisecitation

    Pair-bond formation is a social cognitive process involving social recognition and social reward and models a human attachment relationship more closely than social interactions of adult mice or rats.

    “Pair-bond formation is a social cognitive process that involves both social recognition and social reward (27–29) and models a human attachment relationship far more closely than do the social interactions of adult mice or rats.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Millan, 2012, Cognitive dysfunction in psychiatric disorders: Characteristics, causes, and the quest for improved therapy, Nat Rev Drug Disc source

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    • cites [28] Modi, 2011, D-cycloserine facilitates socially reinforced learning in an animal model relevant to autism spectrum disorders, Biol Psychiatry source

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    • cites [29] Aragona, 2009, Dopamine regulation of social choice in a monogamous rodent species, Front Behav Neurosci source

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    Premisecitation

    Some data suggest women may be more responsive to oxytocin than men, but a recent meta-analysis indicated data are insufficient to analyze gender differences even in trust and facial recognition.

    “Some data suggest that women may be more responsive to OT than males (41), but a recent meta-analysis indicated data are insufficient to analyze gender differences even in the best studied areas, trust and facial recognition (40).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] van Ijzendoorn, 2012, A sniff of trust: Meta-analysis of the effects of intranasal oxytocin administration on face recognition, trust to in-group, and trust to out-group, Psychoneuroendocrinology source

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    • cites [40] Cardoso, 2012, Coping style moderates the effect of intranasal oxytocin on the mood response to interpersonal stress, Exp Clin Psychopharmacol source

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  • May combine two claims.

    Premisecitation

    With sustained stimulation, oxytocin receptors can undergo desensitization and internalization, leading to physiological tolerance.

    “With sustained stimulation OT receptors can undergo desensitization and internalization (18) leading to physiological tolerance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Gimpl, 2001, The oxytocin receptor system: Structure, function, and regulation, Physiol Rev source

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    Premisecitation

    Female prairie voles seem more resilient to developmental manipulations of the oxytocin system, typically responding only at higher doses of oxytocin.

    “Females seem more resilient to developmental manipulations, typically responding only at higher dose of OT (19,39).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Bales, 2007, Oxytocin has dose-dependent developmental effects on pair-bonding and alloparental care in female prairie voles, Horm Behav source

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    • cites [39] Carter, 2003, Developmental consequences of oxytocin, Physiol Behav source

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    Premisecitation

    Male prairie voles appear to facilitate infant care behavior through either the oxytocin or arginine vasopressin system.

    “Males appear to facilitate infant care behavior through either the OT or AVP system (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Bales, 2004, Both oxytocin and vasopressin may influence alloparental behavior in male prairie voles, Horm Behav source

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

    Premisecitation

    After single developmental manipulations of the oxytocin system, male prairie voles appear more responsive to lower doses of oxytocin, which induce changes in partner preference, sexual behavior and reproductive potential, responses to infants, and AVP receptors.

    “Single developmental manipulations of the OT system males appear to be more responsive to lower doses of OT which induce changes in partner preference (20,35), sexual behavior and reproductive potential (36), responses to infants (37), and AVP receptors (38).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [20] Carter, 2008, Early experience and the developmental programming of oxytocin and vasopressin

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    • cites [35] Bales, 2003, Developmental exposure to oxytocin facilitates partner preferences in male prairie voles (Microtus ochrogaster), Behav Neurosci source

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    • cites [36] Bales, 2004, Effects of neonatal oxytocin manipulations on male reproductive potential in prairie voles, Physiol Behav source

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    • cites [37] Bales, 2004, Sex differences and effects of manipulations of oxytocin on alloparenting and anxiety in prairie voles, Dev Psychobiol source

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

    Premisecitation

    Oxytocin is primarily responsible for pair-bonding in female voles, while arginine vasopressin is responsible for pair-bonding in males.

    “OT is primarily responsible for pair-bonding in female voles, with the related peptide arginine vasopressin (AVP) responsible for pair-bonding in males (3,30–33).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [3] Williams, 1994, Oxytocin centrally administered facilitates formation of a partner preference in female prairie voles (Microtus ochrogaster), J Neuroendocrinol source

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    • cites [30] Insel, 1998, Oxytocin, vasopressin, and the neuroendocrine basis of pair bond formation, Prog Brain Res

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    • cites [31] Carter, 1992, Oxytocin and social bonding, Ann N Y Acad Sci source

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    • cites [32] Ross, 2009, Characterization of the oxytocin system regulating affiliative behavior in female prairie voles, Neuroscience source

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    • cites [33] Lim, 2004, Vasopressin-dependent neural circuits underlying pair bond formation in the monogamous prairie vole, Neuroscience source

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

    Premisecitation

    Adult male prairie voles are responsive to oxytocin but require higher dosages than females to induce a partner preference.

    “Adult males are also responsive to OT, but require higher dosages than females to induce a partner preference (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cho, 1999, The effects of oxytocin and vasopressin on partner preferences in male and female prairie voles (Microtus ochrogaster), Behav Neurosci source

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

    Interpretationown data

    Low-dose OT-treated female prairie voles showed similar patterns of behavior with pups, suggesting lower motivation to socially interact.

    “Similar patterns of behavior with low-dose OT in female interactions with pups (Table 2), which do suggest lower motivation to socially interact”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The results of this study suggest that starting children off at lower dosages of intranasal OT is not safer.

    “In particular, many parents may believe that starting their children off at lower dosages of any treatment, including intranasal OT, is safer. The results of the current study suggest otherwise.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The behavioral effects of chronic intranasal oxytocin in prairie voles are relevant to human intranasal oxytocin treatment.

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

    Study design and conductnone given

    Initial order of treatment for cage-mates was randomized and then alternated on subsequent test days.

    “Initial order of treatment for cage-mates was randomized, and then alternated on subsequent test days.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    Context may be important for long-term effects of OT in order to generate specific effects in humans and animals.

    “Context may be important for long-term effects of OT (for example, pairing OT administration with specific environments or social learning tasks) in order to generate specific effects in humans and animals (81).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Bartz, 2011, Social effects of oxytocin in humans: Context and person matter, Trends Cogn Sci

      Not checked in the free run.

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

    Study design and conductreasoning

    The between-subjects design used in this study avoided design issues associated with re-testing.

    “While this avoided design issues associated with re-testing”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Medium and low dosages of chronic intranasal oxytocin changed social behavior, primarily partner preferences in males, in a potentially detrimental fashion.

    “In particular, our medium and low dosages (medium = similar to that used in human studies, while low = an order of magnitude lower) changed social behavior, primarily partner preferences in males, in a potentially detrimental fashion (Figure 3).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Sex differences in responses to OT are pervasive in both adult voles and in single-dose developmental studies.

    “While sex differences in responses to OT are pervasive in both adult voles (3,72) and in single-dose developmental studies (37,38,73)”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [3] Williams, 1994, Oxytocin centrally administered facilitates formation of a partner preference in female prairie voles (Microtus ochrogaster), J Neuroendocrinol source

      Not checked in the free run.

    • cites [72] Insel, 1995, A gender-specific mechanism for pair bonding: Oxytocin and partner preference formation in monogamous voles, Behav Neurosci source

      Not checked in the free run.

    • cites [37] Bales, 2004, Sex differences and effects of manipulations of oxytocin on alloparenting and anxiety in prairie voles, Dev Psychobiol source

      Not checked in the free run.

    • cites [38] Bales, 2007, Neonatal oxytocin manipulations have long-lasting, sexually dimorphic effects on vasopressin receptors, Neuroscience source

      Not checked in the free run.

    • cites [73] Bales, 2003, Sex differences and developmental effects of oxytocin on aggression and social behavior in prairie voles (Microtus ochrogaster), Horm Behav source

      Not checked in the free run.

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

    Premisecitation

    High-dose OT might saturate OT receptors and subsequently bind to vasopressin receptors, to which OT also has binding affinity and which can cause differing and sometimes opposite behavioral effects.

    “In other words, high dose OT might saturate OT receptors and subsequently bind to vasopressin receptors, to which OT also has binding affinity and which can cause differing and sometimes opposite behavioral effects (18,38,76,77).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [18] Gimpl, 2001, The oxytocin receptor system: Structure, function, and regulation, Physiol Rev source

      Not checked in the free run.

    • cites [38] Bales, 2007, Neonatal oxytocin manipulations have long-lasting, sexually dimorphic effects on vasopressin receptors, Neuroscience source

      Not checked in the free run.

    • cites [76] Carter, 2009, Consequences of early experience and exposure to oxytocin and vasopressin are sexually dimorphic, Dev Neurosci source

      Not checked in the free run.

    • cites [77] Heinrichs, 2008, Neuropeptides and social behavior: Effects of oxytocin and vasopressin in humans, Prog Brain Res source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Short-term administration may be safer or more effective than chronic administration.

    “Short-term administration may be safer or more effective than chronic administration, although ideally long term learning effects would be demonstrated.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The behavioral effects of chronic intranasal oxytocin in prairie voles are relevant to human intranasal oxytocin treatment.

  • May combine two claims.

    Interpretationown data

    The observed changes in social behavior in male prairie voles do not reflect a difference in general social motivation, because time spent alone did not differ between treatment groups.

    “The observed changes in social behavior do not reflect a difference in general social motivation, as time spent alone did not differ between treatment groups.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Developmental treatments can have particular ramifications to receptor binding and up- or down-regulation of peptide production.

    “Developmental treatments can have particular ramifications to receptor binding and up- or down-regulation of peptide production (38,54,74,75).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [38] Bales, 2007, Neonatal oxytocin manipulations have long-lasting, sexually dimorphic effects on vasopressin receptors, Neuroscience source

      Not checked in the free run.

    • cites [54] Greenberg, 2012, Is it all in the family? The effects of early social structure on neural-behavioral systems of prairie voles (Microtus ochrogaster), Neuroscience source

      Not checked in the free run.

    • cites [74] Bales, 2011, Are behavioral effects of early experience mediated by oxytocin?, Front Psychiatry source

      Not checked in the free run.

    • cites [75] Bales, 2012, Developmental experiences and the oxytocin receptor system, Horm Behav source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    The changes in partner preference behavior observed in this study are species-atypical.

    “these changes in partner preference behavior are clearly species-atypical”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    All subjects were sex- and pairing-naive.

    “All subjects were thus sex- and pairing- naive.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All behavioral scorers were trained against one primary observer and to 95% or greater reliability on all behaviors before scoring actual sessions.

    “All behavioral scorers (for this and other tests) were trained against one primary observer (or in the case of recorded tests, against a recording previously scored by a primary observer). All observers were trained to 95% or greater reliability on all behaviors before they were allowed to score actual sessions.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The apparent direction of changes in female behavior towards pups is clearly less nurturing.

    “the apparent direction of changes in female behavior towards pups is clearly less nurturing.”
    Quote in the paperNot a substantial claim
44 of 44

  • The paper relies on this without support.

    No studies have examined long-term effects of intranasal oxytocin exposure.

    “However, no studies have examined long-term effects of intranasal OT exposure.”

  • The paper relies on this without support.

    Few human intranasal oxytocin studies have examined dose-response curves.

    “In addition, few human intranasal OT studies have examined dose-response curves.”

  • The paper relies on this without support.

    Prairie voles are evolutionarily adapted for social bonding and have neural substrates for social bonding that non-monogamous species might lack.

    “Prairie voles are evolutionarily adapted for this type of social behavior, and therefore have neural substrates for social bonding that non-monogamous species might lack.”

  • The paper relies on this without support.

    The behavioral effects of chronic intranasal oxytocin in prairie voles are relevant to human intranasal oxytocin treatment.

    “While manipulations of OT hold great promise for treatment of disorders involving social deficits, the results of this study should sound a cautionary note.”
    “The results of the current study suggest otherwise.”
4 of 4

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?

  • Chronic exposure to exogenous oxytocin can lead to a dampening of the short-term improvement effect and to even counterproductive results.

    “However, first indications exist that chronic exposure to exogenous oxytocin can lead to a dampening of this effect and to even counterproductive results (Bales et al., 2013; but see Young, 2013).”

    From Endogenous peripheral oxytocin measures can give insight into the dynamics of social relationships: a review (2014) · cites this paper as Bales et al., 2013

  • In male voles, a long-term developmental treatment with low doses of intranasal oxytocin resulted in a deficit in partner preference behavior.

    “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 [139]

  • A rodent study showed negative finding such as deficit in partner preference behavior after long-term development treatment with lower doses of oxytocin.

    “A rodent study showed negative finding such as deficit in partner preference behavior after long-term development treatment with lower doses of oxytocin.58”

    From Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial (2016) · cites this paper as [58]

  • Male prairie voles administered low, medium, and high doses of intranasal oxytocin daily from postnatal day 21 to 42 display increases in social contact during the treatment window.

    “Male prairie voles administered low, medium, and high doses of intranasal Oxt daily during the approximate time between weaning and sexual maturity, from PND21 until 42, display increases in social contact during the treatment window”

    From Oxytocin during Development: Possible Organizational Effects on Behavior (2015) · cites this paper as [43]

  • Male prairie voles given low and medium doses of intranasal oxytocin from postnatal day 21 to 42 increase their preference for strangers when tested from postnatal day 43 to 60.

    “and those given low and medium doses increase their preference for strangers when tested from PND43–60 (43).”

    From Oxytocin during Development: Possible Organizational Effects on Behavior (2015) · cites this paper as [43]

The citation lists haven’t been fetched yet

References 84 · Cited by 265

Research works printed but not linked: 1

  1. DeVries, 1999, Sex differences in temporal parameters of partner preference in prairie voles (Microtus ochrogaster), Can J Zool, 77, 885, 10.1139/z99-054 · DOI · Paper page

Authors
Bales, K. L., Perkeybile, A. M., Conley, O. G., Lee, M. H., Guoynes, C. D., Downing, G. M., Yun, C. R., Solomon, M., Jacob, S., & Mendoza, S. P.
Affiliations
  • University of California, Davis (US)
  • University of Illinois Chicago (US)
Corresponding author
Bales, Karen L.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2013-08
Volume
74
Issue
3
Pages
180-188
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2012.08.025
PMC
PMC3556198
OpenAlex
W1997981295
Cited by
265
References
84
Citations by year
2026: 16 · 2025: 7 · 2024: 10 · 2023: 14 · 2022: 14 · 2021: 31 · 2020: 9 · 2019: 12 · 2018: 25 · 2017: 33 · 2016: 24 · 2015: 31 · 2014: 23 · 2013: 15
FWCI
33.20
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (P51OD011107)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD071998, R21HD060117, R01HD071998, HD060117)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Human-Animal Interaction Studies
Keywords
oxytocin, intranasal administration, Microtus ochrogaster, mate preferences, pair bonding, social monogamy, long-term behavioral effects, anxiety-like behavior, sex differences, autism spectrum disorder, schizophrenia, social bonding
MeSH terms
Administration, Intranasal, Age Factors, Analysis of Variance, Animals, Animals, Newborn, Arvicolinae, Dose-Response Relationship, Drug, Exploratory Behavior, Female, Male, Oxytocin, Pair Bond, Sexual Behavior, Animal, Sex Characteristics, Social Behavior Disorders, Time Factors, Maze Learning, Models, Animal

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.

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