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Cited by 251Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyNeurotransmitter Receptor Influence on Behavior

Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery

Open access
Song, Zhimin, Albers, H. Elliott·2018·Frontiers in Neuroendocrinology
DOI 10.1016/j.yfrne.2017.10.004PMC PMC5906207
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Abstract

Oxytocin (OT) and arginine-vasopressin (AVP) act in the brain to regulate social cognition/social behavior and in the periphery to influence a variety of physiological processes. Although the chemical structures of OT and AVP as well as their receptors are quite similar, OT and AVP can have distinct or even opposing actions. Here, we review the increasing body of evidence that exogenously administered and endogenously released OT and AVP can activate each other’s canonical receptors (i.e., cross-talk) and examine the possibility that receptor cross-talk following the synaptic and non-synaptic release of OT and AVP contributes to their distinct roles in the brain and periphery. Understanding the consequences of cross-talk between OT and AVP receptors will be important in identifying how these peptides control social cognition and behavior and for the development of drugs to treat a variety of psychiatric disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that oxytocin (OT) and arginine-vasopressin (AVP) can activate each other’s canonical receptors, especially at high concentrations, producing receptor cross-talk in the brain and periphery. It suggests that distinct or opposing effects of OT and AVP often depend more on which receptor is activated than on which peptide is present, with implications for intranasal OT/AVP studies and psychiatric drug development.

Key findings

  • OT and AVP share seven of nine amino acid sequences, differing only at positions 3 and 8; their receptors are structurally similar, with about 25% sequence identity among human OTR, V1aR, V1bR, and V2R and 85% homology between V1aR and OTR.
  • Receptor selectivity is limited: there can be around 10–100-fold differences in selectivity of OTRs and AVP receptors for OT and AVP; AVP has similar affinity for OTRs, V1aRs, and V1bRs, while OT may have higher affinity for OTRs than V1aRs or V1bRs.
  • Cross-talk is supported in both periphery and brain: peripherally administered OT can act via V1aRs for analgesia, locomotor reduction, adjacent lying, and social huddling, while AVP can act via OTRs for uterine contractions and social investigation; centrally, OT can act via V1aRs for flank marking, and both OT and AVP can act via OTRs for social recognition and social reward.
  • In Syrian hamsters, both OT and AVP induce flank marking dose-dependently, but AVP is around 100-fold more potent than OT; selective V1aR, not OTR, agonists/antagonists mediate this effect. Intranasal OT/AVP at commonly used 20–40 IU produces supraphysiological peripheral levels and likely activates OTRs, V1aRs, V1bRs, and V2Rs.

Methods

  • Narrative review; no new experimental data, sample, or primary analysis are reported.
  • The authors synthesize evidence from in vitro and in vivo receptor selectivity assays, behavioral pharmacology with selective OT/AVP receptor agonists and antagonists, genetic manipulations including knockouts, anatomical and electron microscopic studies, and microdialysis/peptide release studies across species.
  • Main analysis is qualitative integration of these findings to assess when exogenous or endogenous OT and AVP may cross-activate each other’s receptors.

Limitations

  • The paper states that much of the discussed data were collected in males despite major sex differences in OT and AVP systems, and that there is no “gold standard” for defining receptor selectivity.
  • The paper states that selectivity estimates come from different assays, limited tissues, and only a few species, and that brain levels of peptide produced by intranasal administration are not well understood.
  • The paper states that little is known about how frequently OT/AVP synapses contain the corresponding receptors, that OT/AVP receptors cannot currently be identified with immunohistochemistry, and that cross-talk following endogenously released peptides remains to be confirmed; evident from the text, this is a narrative rather than systematic review.

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

Integrity signals

Registry

Crossref · 10.1016/j.yfrne.2017.10.004

Cites

138 of 138 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 136 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Studies using recombinant expression systems for human, rat, and mouse OT and AVP receptors have shown that only the human OTR is selective for OT by a standard criterion.

    “For example, studies employing recombinant expression systems to examine selectivity of human, rat, and mouse OT and AVP receptors have shown that only the human OTR is selective for OT using a standard criterion [34; 35] (Table 1).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Manning M Stoev S Chini B Durroux B Mouillac B Guillon G Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents Neumann ID Landgraf R Advances in Vasopressin and Oxytocin: From genes to behavior Elsevier 2008 473 512 18655903 source

      Not checked in the free run.

    • cites [35] Manning M Misicka A Olma A Bankowski K Stoev S Chini B Durroux T Mouillac B Corbani M Guillon G Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics Journal of Neuroendocrinology 24 2012 609 628 22375852 PMC3490377 source

      Not checked in the free run.

  • Interpretationnone given

    OT and AVP can activate each other's canonical receptors, a phenomenon termed cross-talk.

    “Here, we review the increasing body of evidence that exogenously administered and endogenously released OT and AVP can activate each other’s canonical receptors (i.e., cross-talk)”
    • Also stated in: § 1. Introduction · plain
      “Recently, however, there has been increasing evidence that OT and AVP can act on each other’s canonical receptors in potentially important ways.”
    Quote in the paperSubstantial claim
  • Premisecitation

    There can be differences of around 10-100 fold in the selectivity of OTRs and AVP receptors for OT and AVP.

    “Nevertheless, it appears that there can be differences of around 10–100 fold in the selectivity of OTRs and AVP receptors for OT and AVP.”
    • Also stated in: § 4. Receptor cross-talk in response to exogenously administered peptides · hedged
      “Existing data suggest that there are 10–100 fold differences in the selectivity of OT and AVP for OTRs, V1aRs, and V1bRs”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [28] Chini B Mouillac B Ala Y Balestre MN Trumpp-Kallmeyer S Hoflack J Elands J Hibert M Manning M Jard S Tyr115 is the key residue for determining agonist selectivity in the V1a vasopressin receptor EMBO J 14 1995 2176 2182 7774575 PMC398323 source

      Not checked in the free run.

    • cites [29] Hawtin SR Wesley VJ Parslow RA Patel S Wheatley M Critical role of a subdomain of the N-terminus of the V1a vasopressin receptor for binding agonists but not antagonists; functional rescue by the oxytocin receptor N-terminus Biochemistry 39 2000 13524 33 11063589 source

      Not checked in the free run.

    • cites [30] Kimura T Makino Y Saji F Takemura M Inoue T Kikuchi T Kubota Y Azuma C Nobunaga T Tokugawa Y Molecular characterization of a cloned human oxytocin receptor Eur J Endocrinol 131 1994 385 90 7921228 source

      Not checked in the free run.

    • cites [31] Lolait SJ O’Carroll AM Brownstein MJ Molecular biology of vasopressin receptors Ann N Y Acad Sci 771 1995 273 92 8597406 source

      Not checked in the free run.

    • cites [32] Thibonnier M Coles P Thibonnier A Shoham M The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists Annu Rev Pharmacol Toxicol 41 2001 175 202 11264455 source

      Not checked in the free run.

    • cites [33] Song Z McCann KE McNeill JK Larkin TE Huhman KL Albers HE Oxytocin induces social communication by activating arginine-vasopressin V1a receptors and not oxytocin receptors Psychoneuroendocrinology 50C 2014 14 19 PMC4252597 25173438 source

      Not checked in the free run.

  • Interpretationreasoning

    The overall lack of receptor selectivity is not surprising given the high degree of structural homology among these receptors, such as 85% between V1aR and OTR.

    “This overall lack of receptor selectivity is not surprising when one considers that these receptors have a high degree of structural homology (e.g., 85% between V1aR and OTR) (Figure 4).”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Despite similar chemical structures of OT, AVP, and their receptors, the two peptides can have distinct or even opposing roles in many behavioral and physiological functions.

    “Although the chemical structures of OT and AVP as well as their receptors are quite similar, OT and AVP can have distinct or even opposing actions.”
    • Also stated in: § 1. Introduction · boosted
      “Although the chemical structures of OT and AVP as well as their receptors are quite similar, there is substantial evidence that these nonapeptides (i.e., nine amino acid peptides) can have distinct or even opposing roles in the regulation of many behavioral and physiological functions [3; 4; 5; 6; 7].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [3] Neumann ID Landgraf R Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors Trends Neurosci 35 2012 649 659 22974560 source

      Not checked in the free run.

    • cites [4] Legros JJ Inhibitory effect of oxytocin on corticotrope function in humans: are vasopressin and oxytocin ying-yang neurohormones? Psychoneuroendocrinology 26 2001 649 655 11500247 source

      Not checked in the free run.

    • cites [5] Stoop R Neuromodulation by oxytocin and vasopressin Neuron 76 2012 142 159 23040812 source

      Not checked in the free run.

    • cites [6] Heinrichs M von Dawans B Domes G Oxytocin, vasopressin, and human social behavior Front Neuroendocrinol 30 2009 548 57 19505497 source

      Not checked in the free run.

    • cites [7] Carter CS Grippo AJ Pournajafi-Nazarloo H Ruscio MG Porges SW Oxytocin, vasopressin and sociality Prog Brain Res 170 2008 331 6 18655893 source

      Not checked in the free run.

  • May combine two claims. 38
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Premisecitation

    In mammals, OT is considered to have a single canonical receptor (OTR), while AVP is thought to have three receptors: V1aR, V1bR, and V2R.

    “In mammals, OT is considered to have only one canonical receptor (i.e., OTR) while AVP is thought to have three: V1aR, V1bR and V2R [16; 17; 18].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Caldwell HK Young WS III Oxytocin and Vasopressin: Genetics and behavioral implications Lim R Neuroactive Proteins and Peptides Springer New York 2006 573 607

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

    • cites [17] Barberis C Tribollet E Vasopressin and oxytocin receptors in the central nervous system Crit Rev Neurobiol 10 1996 119 54 8853957 source

      Not checked in the free run.

    • cites [18] Hasunuma I Toyoda F Okada R Yamamoto K Kadono Y Kikuyama S Roles of arginine vasotocin receptors in the brain and pituitary of submammalian vertebrates Int Rev Cell Mol Biol 304 2013 191 225 23809437 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxytocin and arginine-vasopressin act in the brain to regulate social behaviors and in the periphery to coordinate physiological functions.

    “Oxytocin (OT) and arginine-vasopressin (AVP) act in the brain to regulate social cognition/social behavior and in the periphery to influence a variety of physiological processes.”
    • Also stated in: § 1. Introduction · plain
      “Oxytocin (OT) and arginine-vasopressin (AVP) are important chemical signals that act in the brain to regulate a large number of adaptive social behaviors and in the periphery to coordinate a diverse group of physiological functions [1; 2].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Caldwell HK Oxytocin and Vasopressin: Powerful Regulators of Social Behavior Neuroscientist 2017 1073858417708284 28492104 source

      Not checked in the free run.

    • cites [2] Leng G Ludwig M Intranasal Oxytocin: Myths and Delusions Biol Psychiatry 79 2016 243 50 26049207 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Dumais KM Veenema AH Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior Front Neuroendocrinol 40 2016 1 23 25951955 PMC4633405 source

      Not checked in the free run.

    • cites [21] Veinante P Freund-Mercier MJ Distribution of oxytocin- and vasopressin-binding sites in the rat extended amygdala: a histoautoradiographic study J Comp Neurol 383 1997 305 325 9205043 source

      Not checked in the free run.

    • cites [22] Smith CJ Poehlmann ML Li S Ratnaseelan AM Bredewold R Veenema AH Age and sex differences in oxytocin and vasopressin V1a receptor binding densities in the rat brain: focus on the social decision-making network Brain Struct Funct 222 2017 981 1006 27389643 PMC5334374 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These effects of OT and AVP can be inhibited by selective V1aR antagonists but not by OTR antagonists.

    “These effects of OT and AVP can be inhibited by selective V1aR but not OTR antagonists.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [37] Hicks C Ramos L Reekie T Misagh GH Narlawar R Kassiou M McGregor IS Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non-peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats Br J Pharmacol 171 2014 2868 87 24641248 PMC4243861 source

      Not checked in the free run.

    • cites [38] Loyens E Vermoesen K Schallier A Michotte Y Smolders I Proconvulsive effects of oxytocin in the generalized pentylenetetrazol mouse model are mediated by vasopressin 1a receptors Brain Res 1436 2012 43 50 22208648 source

      Not checked in the free run.

    • cites [39] Gupta J Russell R Wayman C Hurley D Jackson V Oxytocin-induced contractions within rat and rabbit ejaculatory tissues are mediated by vasopressin V1A receptors and not oxytocin receptors Br J Pharmacol 155 2008 118 26 18552879 PMC2527840 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Peripherally administered OT and AVP produce similar effects in reducing heart rate and body temperature, inducing contractions in ejaculatory tissues, and promoting seizure susceptibility in male rats and rabbits.

    “Peripherally administered OT and AVP produce similar effects in reducing heart rate and body temperature, inducing contractions in ejaculatory tissues, and in promoting seizure susceptibility in male rats and rabbits [37; 38; 39].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [37] Hicks C Ramos L Reekie T Misagh GH Narlawar R Kassiou M McGregor IS Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non-peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats Br J Pharmacol 171 2014 2868 87 24641248 PMC4243861 source

      Not checked in the free run.

    • cites [38] Loyens E Vermoesen K Schallier A Michotte Y Smolders I Proconvulsive effects of oxytocin in the generalized pentylenetetrazol mouse model are mediated by vasopressin 1a receptors Brain Res 1436 2012 43 50 22208648 source

      Not checked in the free run.

    • cites [39] Gupta J Russell R Wayman C Hurley D Jackson V Oxytocin-induced contractions within rat and rabbit ejaculatory tissues are mediated by vasopressin V1A receptors and not oxytocin receptors Br J Pharmacol 155 2008 118 26 18552879 PMC2527840 source

      Not checked in the free run.

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

    Premisecitation

    V1bRs appear to have a much more restricted distribution, although they are expressed prominently in the hippocampus and at lower levels in the hypothalamus and amygdala.

    “V1bRs appear to have a much more restricted distribution, although they are expressed prominently in the hippocampus and at lower levels in the hypothalamus and amygdala [23; 24].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Young WS Li J Wersinger SR Palkovits M The vasopressin 1b receptor is prominent in the hippocampal area CA2 where it is unaffected by restraint stress or adrenalectomy Neuroscience 143 2006 1031 1039 17027167 PMC1748954 source

      Not checked in the free run.

    • cites [24] Stevenson EL Caldwell HK The vasopressin 1b receptor and the neural regulation of social behavior Hormones and Behavior 61 2012 277 282 22178035 PMC3310934 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AVP has similar affinity for OTRs, V1aRs, and V1bRs, whereas OT may have a higher affinity for OTRs than for V1aRs or V1bRs.

    “AVP has a similar affinity for OTRs, V1aRs, and V1bRs while OT may have a higher affinity for OTRs than V1aRs or V1bRs [28; 29; 30; 31; 32; 33].”
    • Also stated in: § 4. Receptor cross-talk in response to exogenously administered peptides · plain
      “AVP has similar affinities for OT and AVP receptors while OT has a higher affinity for OT receptors than AVP receptors.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [28] Chini B Mouillac B Ala Y Balestre MN Trumpp-Kallmeyer S Hoflack J Elands J Hibert M Manning M Jard S Tyr115 is the key residue for determining agonist selectivity in the V1a vasopressin receptor EMBO J 14 1995 2176 2182 7774575 PMC398323 source

      Not checked in the free run.

    • cites [29] Hawtin SR Wesley VJ Parslow RA Patel S Wheatley M Critical role of a subdomain of the N-terminus of the V1a vasopressin receptor for binding agonists but not antagonists; functional rescue by the oxytocin receptor N-terminus Biochemistry 39 2000 13524 33 11063589 source

      Not checked in the free run.

    • cites [30] Kimura T Makino Y Saji F Takemura M Inoue T Kikuchi T Kubota Y Azuma C Nobunaga T Tokugawa Y Molecular characterization of a cloned human oxytocin receptor Eur J Endocrinol 131 1994 385 90 7921228 source

      Not checked in the free run.

    • cites [31] Lolait SJ O’Carroll AM Brownstein MJ Molecular biology of vasopressin receptors Ann N Y Acad Sci 771 1995 273 92 8597406 source

      Not checked in the free run.

    • cites [32] Thibonnier M Coles P Thibonnier A Shoham M The basic and clinical pharmacology of nonpeptide vasopressin receptor antagonists Annu Rev Pharmacol Toxicol 41 2001 175 202 11264455 source

      Not checked in the free run.

    • cites [33] Song Z McCann KE McNeill JK Larkin TE Huhman KL Albers HE Oxytocin induces social communication by activating arginine-vasopressin V1a receptors and not oxytocin receptors Psychoneuroendocrinology 50C 2014 14 19 PMC4252597 25173438 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A highly selective OTR agonist failed to induce flank marking, and a highly selective OTR antagonist failed to inhibit the induction of flank marking by OT.

    “A highly selective OTR agonist failed to induce flank marking and a highly selective OTR antagonist failed to inhibit the induction of flank marking by OT.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Song Z McCann KE McNeill JK Larkin TE Huhman KL Albers HE Oxytocin induces social communication by activating arginine-vasopressin V1a receptors and not oxytocin receptors Psychoneuroendocrinology 50C 2014 14 19 PMC4252597 25173438 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A selective OTR antagonist, but not a selective V1aR antagonist, inhibits OT- and AVP-induced increases in social investigation, suggesting that both peptides act through the OTR.

    “Peripheral administration of a selective OTR antagonist, but not a selective V1aR antagonist, inhibits OT- and AVP-induced increases in social investigation suggesting that both peptides are acting through the OTR [49].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Ramos L Hicks C Caminer A Couto K Narlawar R Kassiou M McGregor IS MDMA (‘Ecstasy’), oxytocin and vasopressin modulate social preference in rats: A role for handling and oxytocin receptors Pharmacol Biochem Behav 150–151 2016 115 123 27725273 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In OTR null mice, social exploration and social recognition are reduced, while aggression is increased compared to wild-type mice.

    “In OTR null mice social exploration and social recognition are reduced, while aggression is increased when compared to wild-type mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Sala M Braida D Lentini D Busnelli M Bulgheroni E Capurro V Finardi A Donzelli A Pattini L Rubino T Parolaro D Nishimori K Parenti M Chini B Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism Biol Psychiatry 69 2011 875 882 21306704 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A highly selective OTR but not V1aR antagonist significantly reduced the duration of social recognition, suggesting that OT and AVP regulate social recognition by acting on OTRs.

    “A highly selective OTR but not a highly selective V1aR antagonist significantly reduced the duration of social recognition suggesting that OT and AVP regulate social recognition by acting on OTRs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Song Z Larkin TE Malley MO Albers HE Oxytocin (OT) and arginine-vasopressin (AVP) act on OT receptors and not AVP V1a receptors to enhance social recognition in adult Syrian hamsters (Mesocricetus auratus) Horm Behav 81 2016 20 7 26975586 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Peripheral administration of either OT or AVP increases social huddling in response to threatening stimuli (cat fur), and these effects are inhibited by a selective V1aR antagonist.

    “Peripheral administration of either OT or AVP also increases social huddling in response to threatening stimuli (i.e., cat fur) and these effects are inhibited by a selective V1aR antagonist [45].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Bowen MT McGregor IS Oxytocin and vasopressin modulate the social response to threat: a preclinical study Int J Neuropsychopharmacol 17 2014 1621 1633 24807123 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In female meadow voles housed in winter-like conditions, injection of OT into the lateral septum prevents the formation of partner preferences, an effect blocked by co-administration of OT with a V1aR but not an OTR antagonist.

    “When housed in winter-like conditions female voles form partner preferences for other females. Injection of OT into the lateral septum prevents the formation of these partner preferences, an effect that is blocked by co-administration of OT with a V1aR but not an OTR antagonist.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Anacker AM Christensen JD LaFlamme EM Grunberg DM Beery AK Septal oxytocin administration impairs peer affiliation via V1a receptors in female meadow voles Psychoneuroendocrinology 68 2016 156 62 26974500 PMC4851907 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A selective V1aR antagonist, but not an OTR antagonist, inhibits adjacent lying following peripheral administration of OT or AVP.

    “A selective V1aR, but not an OTR antagonist, inhibits adjacent lying following peripheral administration of OT or AVP.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Ramos L Hicks C Kevin R Caminer A Narlawar R Kassiou M McGregor IS Acute prosocial effects of oxytocin and vasopressin when given alone or in combination with 3,4-methylenedioxymethamphetamine in rats: involvement of the V1A receptor Neuropsychopharmacology 38 2013 2249 59 23676791 PMC3773675 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A selective V1aR agonist induced flank marking, and a selective V1aR antagonist inhibited the ability of OT to induce flank marking.

    “In contrast, not only did a selective V1aR agonist induce flank marking, a selective V1aR antagonist inhibited the ability of OT to induce flank marking.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Song Z McCann KE McNeill JK Larkin TE Huhman KL Albers HE Oxytocin induces social communication by activating arginine-vasopressin V1a receptors and not oxytocin receptors Psychoneuroendocrinology 50C 2014 14 19 PMC4252597 25173438 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both OT and AVP administered peripherally increase social investigation in male rats.

    “Both OT and AVP administered peripherally also increase social investigation in male rats.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Ramos L Hicks C Caminer A Couto K Narlawar R Kassiou M McGregor IS MDMA (‘Ecstasy’), oxytocin and vasopressin modulate social preference in rats: A role for handling and oxytocin receptors Pharmacol Biochem Behav 150–151 2016 115 123 27725273 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both OT and AVP inhibit neuronal signaling in dorsal root ganglia, and these effects can be inhibited by a selective V1aR antagonist but not by an OTR antagonist.

    “Although both OT and AVP inhibit neuronal signaling in dorsal root ganglia, these effects can be inhibited by a selective V1aR antagonist but not by an OTR antagonist.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Qiu F Qiu CY Cai H Liu TT Qu ZW Yang Z Li JD Zhou QY Hu WP Oxytocin inhibits the activity of acid-sensing ion channels through the vasopressin, V1A receptor in primary sensory neurons Br J Pharmacol 171 2014 3065 76 24641084 PMC4055206 source

      Not checked in the free run.

    • cites [42] Kubo A Shinoda M Katagiri A Takeda M Suzuki T Asaka J Yeomans DC Iwata K Oxytocin alleviates orofacial mechanical hypersensitivity associated with infraorbital nerve injury through vasopressin-1A receptors of the rat trigeminal ganglia Pain 158 2017 649 659 28072605 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ICV injection of OT or AVP can restore wild-type levels of these behaviors, and the effects of OT and AVP are inhibited by a selective V1aR antagonist.

    “While intracerebroventricular (ICV) injection of OT or AVP can restore wild-type levels of these behaviors, the effects of OT and AVP are inhibited by a selective V1aR antagonist.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Sala M Braida D Lentini D Busnelli M Bulgheroni E Capurro V Finardi A Donzelli A Pattini L Rubino T Parolaro D Nishimori K Parenti M Chini B Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism Biol Psychiatry 69 2011 875 882 21306704 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both OT and AVP induce flank marking in a dose-dependent manner, although AVP is around 100-fold more potent than OT.

    “Both OT and AVP induce flank marking in a dose-dependent manner, although AVP is around 100-fold more potent than OT in inducing the behavior (Figure 5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Song Z McCann KE McNeill JK Larkin TE Huhman KL Albers HE Oxytocin induces social communication by activating arginine-vasopressin V1a receptors and not oxytocin receptors Psychoneuroendocrinology 50C 2014 14 19 PMC4252597 25173438 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OT can act on V1bRs as well as OTRs, and AVP can act on OTRs as well as V1bRs, to induce glucagon secretion from pancreatic islet cells in male mice.

    “There is also evidence to suggest that OT can act on V1bRs as well as OTRs and that AVP can act on OTRs as well as V1bRs to induce glucagon secretion from pancreatic islet cells in male mice [52].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Fujiwara Y Hiroyama M Sanbe A Yamauchi J Tsujimoto G Tanoue A Mutual regulation of vasopressin- and oxytocin-induced glucagon secretion in V1b vasopressin receptor knockout mice J Endocrinol 192 2007 361 9 17283236 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Exogenously administered OT can act on V1aRs in the periphery, and exogenously administered AVP can act on peripheral OTRs to influence physiological and behavioral endpoints.

    “There is considerable evidence that exogenously administered OT can act on V1aRs in the periphery and several examples that exogenously administered AVP can act on peripheral OTRs to influence both physiological and behavioral endpoints.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In the brain, OT can act on V1aRs and AVP can act on OTRs to influence several different behaviors.

    “In the brain, there is strong support for the hypothesis that OT can act on V1aRs and that AVP can act on OTRs to influence several different behaviors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    OT and AVP can have differential effects on neural activity (BOLD fMRI responses) and cognition, at least in some cases, although the effects of OT are more robust.

    “These data have, however, found OT and AVP can have differential effects on neural activity (i.e., BOLD fMRI responses) and cognition, at least in some cases although the effects of OT are more robust [84; 86; 87; 88; 89; 90].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [84] Rilling JK DeMarco AC Hackett PD Thompson R Ditzen B Patel R Pagnoni G Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men Psychoneuroendocrinology 37 2012 447 461 21840129 PMC3251702 source

      Not checked in the free run.

    • cites [86] Chen X Hackett PD DeMarco AC Feng C Stair S Haroon E Ditzen B Pagnoni G Rilling JK Effects of oxytocin and vasopressin on the neural response to unreciprocated cooperation within brain regions involved in stress and anxiety in men and women Brain Imaging Behav 10 2016 581 93 26040978 PMC4670292 source

      Not checked in the free run.

    • cites [87] Patel N Grillon C Pavletic N Rosen D Pine DS Ernst M Oxytocin and vasopressin modulate risk-taking Physiol Behav 139 2015 254 60 25446228 PMC4274653 source

      Not checked in the free run.

    • cites [88] Rilling JK Demarco AC Hackett PD Chen X Gautam P Stair S Haroon E Thompson R Ditzen B Patel R Pagnoni G Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction Psychoneuroendocrinology 39 2014 237 48 24157401 PMC3842401 source

      Not checked in the free run.

    • cites [89] Feng C Hackett PD DeMarco AC Chen X Stair S Haroon E Ditzen B Pagnoni G Rilling JK Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans Brain Imaging Behav 9 2015 754 64 25416642 source

      Not checked in the free run.

    • cites [90] Li T Chen X Mascaro J Haroon E Rilling JK Intranasal oxytocin, but not vasopressin, augments neural responses to toddlers in human fathers Horm Behav 2017 PMC5565399 28161387 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Commonly used intranasal concentrations of OT and AVP (20 IU to 40 IU) produce high, supraphysiological levels of peptide in the periphery, and these concentrations are likely high enough to also produce biologically active levels in the brain.

    “The commonly used intranasal concentrations of OT and AVP (i.e., 20 IU to 40 IU) produce high, supraphysiological levels of peptide in the periphery, and these concentrations are likely high enough to also produce biologically active levels in the brain [2].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Leng G Ludwig M Intranasal Oxytocin: Myths and Delusions Biol Psychiatry 79 2016 243 50 26049207 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    There can be substantial cross-talk between OT and AVP and OTRs and V1aRs.

    “Because OT and AVP as well as their canonical receptors display strikingly similar chemical structures, it is not surprising that there can be substantial cross-talk between these peptides and OTRs and V1aRs [79].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Ragnauth AK Goodwillie A Brewer C Muglia LJ Pfaff DW Kow LM Vasopressin stimulates ventromedial hypothalamic neurons via oxytocin receptors in oxytocin gene knockout male and female mice Neuroendocrinology 80 2004 92 9 15528951 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    OT and AVP act exclusively on V1aRs to influence some behaviors, such as social communication, and exclusively on OTRs to influence other behaviors, such as social reward.

    “There is also some evidence to suggest that OT and AVP act exclusively on V1aRs to influence some behaviors (e.g., social communication) and that OT and AVP act exclusively on OTRs to influence other behaviors (e.g., social reward).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The potential for receptor cross-talk would likely be reduced by local synaptic release of neuropeptide and the anatomical segregation of OT and AVP receptors.

    “The potential for receptor cross-talk would likely be reduced by local synaptic release of neuropeptide and the anatomical segregation of OT and AVP receptors.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Differences in the effects of OT and AVP could simply be the result of different doses and/or differences in the selectivity of OTRs for OT in humans.

    “Thus, differences in the effects of OT and AVP could simply be the result of different doses and/or differences in the selectivity of OTRs for OT in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    If the presence of both OT and AVP receptors in the same synaptic regions is rare, then the possibility of cross-talk following synaptic release of these neuropeptides would seem unlikely, with the exception of synaptic spillover.

    “If the presence of both OT and AVP receptors in the same synaptic regions is rare then the possibility of cross-talk following synaptic release of these neuropeptides would seem unlikely, with the exception of when these neuropeptides spillover beyond synaptic regions (i.e., synaptic spillover).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A major source of non-synaptically released OT and AVP is the magnocellular neurons in the hypothalamus, although there is also evidence that hypothalamic parvocellular neurons can release neuropeptides from dense core vesicles non-synaptically.

    “A major source of non-synaptically released OT and AVP is the magnocellular neurons in the hypothalamus, although there is also evidence that hypothalamic parvocellular neurons can also release neuropeptides from dense core vesicles non-synaptically [111].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Castel M Morris J Belenky M Non-synaptic and dendritic exocytosis from dense-cored vesicles in the suprachiasmatic nucleus Neuroreport 7 1996 543 7 8730825 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Non-synaptic neuropeptide release is stimulated by Ca2+ coming from intracellular stores, as opposed to synaptic release that is mediated by the influx of extracellular Ca2+ through voltage-gated channels.

    “Non-synaptic neuropeptide release is stimulated by Ca2+ coming from intracellular stores (e.g., endoplasmic reticulum) as opposed to synaptic release that is mediated by the influx of extracellular Ca2+ through voltage-gated channels [105].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Buijs RM Van Heerikhuize JJ Vasopressin and oxytocin release in the brain--a synaptic event Brain Res 252 1982 71 6 7172022 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    OT and AVP can activate each other's receptors, particularly when present at high levels, resulting in the potential for substantial cross-talk between the OT and AVP systems.

    “Rather, OT and AVP can activate each other’s receptors, particularly when present at high levels, resulting in the potential for substantial cross-talk between the OT and AVP systems.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ICV or hypothalamic injection of α-MSH induces flank marking behavior in hamsters, and α-MSH-induced flank marking is blocked by central administration of a selective V1a antagonist.

    “Studies in hamsters have found that ICV or hypothalamic injection of α-MSH induces flank marking behavior and that α-MSH-induced flank marking is blocked by central administration of a selective V1a antagonist [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Song Z McCann KE McNeill JK Larkin TE Huhman KL Albers HE Oxytocin induces social communication by activating arginine-vasopressin V1a receptors and not oxytocin receptors Psychoneuroendocrinology 50C 2014 14 19 PMC4252597 25173438 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Intranasal administration of OT or AVP may produce a global activation of both OT and AVP receptors.

    “As such, it is important to consider the possibility that intranasal administration of OT or AVP produces a global activation of both OT and AVP receptors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In hamsters, the lateral septum contains large numbers of V1aRs, but few, if any, AVP-containing fibers or cell bodies have been identified with immunohistochemistry.

    “For example, in hamsters the lateral septum contains large numbers of V1aRs but few, if any, AVP containing fibers or cell bodies have been identified with immunohistochemistry [112; 113; 114; 115].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [112] Johnson AE Barberis C Albers HE Castration reduces vasopressin receptor binding in the hamster hypothalamus Brain Res 674 1995 153 8 7773686 source

      Not checked in the free run.

    • cites [113] Albers HE Rowland CM Ferris CF Arginine-vasopressin immunoreactivity is not altered by photoperiod or gonadal hormones in the Syrian hamster (Mesocricetus auratus) Brain Res 539 1991 137 142 2015498 source

      Not checked in the free run.

    • cites [114] Dubois-Dauphin M Pevet P Tribollet E Dreifuss JJ Vasopressin in the brain of the golden hamster: The distribution of vasopressin binding sites and of immunoreactivity to the vasopressin-related glycopeptide Journal of Comparative Neurology 300 1990 535 548 2148751 source

      Not checked in the free run.

    • cites [115] Young LJ Wang Z Cooper TT Albers HE Vasopressin (V1a) receptor binding, mRNA expression and transcriptional regulation by androgen in the Syrian hamster brain J Neuroendocrinol 12 2000 1179 85 11106975 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Certain classes of social behavior are mediated by OTRs while other classes of social behavior are mediated by V1aRs.

    “Although much more work needs to be done, these data suggest that certain classes of social behavior are mediated by OTRs while other classes of social behavior are mediated by V1aRs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Several different social behaviors can be influenced by both OT and AVP, but this influence appears to be mediated by only one of their receptors.

    “Several different social behaviors can be influenced by both OT and AVP, but this influence appears to be mediated by only one of their receptors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    High levels of intranasal oxytocin and vasopressin can cause substantial receptor cross-talk in both the periphery and the brain, leading to activation of many oxytocin and vasopressin receptors.

    “These high levels of peptide have the potential to result in significant amounts of receptor cross-talk in the periphery as well as in the brain resulting in the activation of large numbers of OT and AVP receptors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Intranasal administration of oxytocin and vasopressin produces supraphysiological concentrations of these peptides in peripheral tissues.

  • May combine two claims.

    Interpretationown data

    Although OT and AVP increase social communication, social recognition, and social reward, the effects on social communication are mediated by V1aRs and their effects on social recognition and social reward are mediated by OTRs.

    “For example, although OT and AVP increase social communication, social recognition, and social reward, the effects of these neuropeptides on social communication are mediated by V1aRs and their effects on social recognition and social reward are mediated by OTRs.”
    Quote in the paperSubstantial claim
39 of 39

  • The paper relies on this without support.

    Intranasal administration of oxytocin and vasopressin produces supraphysiological concentrations of these peptides in peripheral tissues.

    “Intranasal OT and AVP administration, which is currently in use in clinical trials, produces supraphysiological levels of these peptides in peripheral tissues.”
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?

  • Social cognition and reward processing can be mediated by OXT and OXTR, while social communication relies more on AVP and V1aR.

    “For example, social cognition and reward processing can be mediated by OXT and OXTR, while social communication relies more on arginine-vasopressin (AVP) and its receptor (V1aR; Song and Albers, 2018).”

    From Music's context-dependent influence on oxytocin, social bonding, and emotion regulation: a systematic review (2026) · cites this paper as Song and Albers, 2018

    The Conclusions (section 6; page not available) say that social recognition and social reward are mediated by OTRs, while social communication is mediated by V1aRs. Section 3.1 reports that AVP was more potent than OT at inducing a form of social communication in hamsters. The claim broadens social recognition and social reward to cognition and reward processing generally; the paper also says both peptides can influence all three behaviors, so the peptide distinction is less clear-cut than the receptor distinction. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • OXT and AVP share structural similarities and can activate each other's receptors, and this 'cross-talk' is likely to participate in shaping social behaviors in musical contexts.

    “Since OXT and AVP share structural similarities and can activate each other's receptors, this phenomenon, “cross-talk” (Song and Albers, 2018), is likely to participate in shaping social behaviors in musical contexts.”

    From Music's context-dependent influence on oxytocin, social bonding, and emotion regulation: a systematic review (2026) · cites this paper as Song and Albers, 2018

  • The OXTR radioligand 125I-OVTA and the AVPR1a radioligand 125I-LVA bind to both receptor types when used in primate brain.

    “These radioligands are now known to bind to both receptor types when they are used in primate brain37.”

    From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [48]

Cites

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Related

Authors
Song, Z., & Albers, H. E.
Affiliations
Georgia State University (US)
Corresponding author
Albers, H. Elliott
ORCID
Venue
Frontiers in Neuroendocrinology
Publisher
Elsevier BV
Published
2018-10
Volume
51
Pages
14-24
ISSN
0091-3022 (ISSN-L)
DOI
10.1016/j.yfrne.2017.10.004
PMC
PMC5906207
OpenAlex
W2767130940
Semantic Scholar
4dbbf2abe3c48e55106808bf85319d02973b36d1
Cited by
244
References
142
Citations by year
2026: 22 · 2025: 32 · 2024: 30 · 2023: 30 · 2022: 25 · 2021: 29 · 2020: 36 · 2019: 18 · 2018: 21 · 2017: 1
FWCI
3.27
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Frontiers in Neuroendocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NSF (IOS-0923301)
  • NIH (MH110212, MH109302)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
oxytocin, vasopressin, receptor cross-talk, oxytocin receptor, vasopressin receptor, social cognition, social behavior, psychiatric drug development
MeSH terms
Animals, Arginine Vasopressin, Mental Disorders, Female, Humans, Male, Oxytocin, Social Behavior, Receptors, Vasopressin, 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.

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