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Cited by 205Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyPrimate Behavior and Ecology

Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications

Open access
Freeman, Sara M., Young, Larry J.·2016·Journal of Neuroendocrinology
DOI 10.1111/jne.12382PMC PMC4886472
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Abstract

In the last several decades, sophisticated experimental techniques have been used to determine the neurobiology of the oxytocin and vasopressin systems in rodents. Using a suite of methodologies, including electrophysiology, site‐specific selective pharmacology, receptor autoradiography, in vivo microdialysis, and genetic and optogenetic manipulations, we have gained unprecedented knowledge about how these neuropeptides engage neural circuits to regulate behaviour, particularly social behaviour. Based on this foundation of information from rodent studies, we have started generating new hypotheses and frameworks about how the oxytocin and vasopressin systems could be acting in humans to influence social cognition. However, despite the recent inundation of publications using intranasal oxytocin in humans, we still know very little about the neurophysiology of the oxytocin system in primates more broadly. Furthermore, the design and analysis of these human studies have remained largely uninformed of the potential neurobiological mechanisms underlying their findings. Although the methods available for studying the oxytocin and vasopressin systems in humans are incredibly limited as a result of practical and ethical considerations, there is great potential to fill the gaps in our knowledge by developing better nonhuman primate models of social functioning. Behavioural pharmacology and receptor autoradiography have been used to study the oxytocin and vasopressin systems in nonhuman primates, and there is now great potential to broaden our understanding of the neurobiology of these systems. In this review, we discuss comparative findings in receptor distributions in rodents and primates, with perspectives on the functionality of conserved regions of expression in these distinct mammalian clades. We also identify specific ways that established technologies can be used to answer basic research questions in primates. Finally, we highlight areas of future research in nonhuman primates that are experimentally poised to yield critical insights into the anatomy, physiology and behavioural effects of the oxytocin system, given its remarkable translational potential.

AI snapshot

Written from the paper’s full text.

TL;DR

This review compares oxytocin/vasopressin receptor distributions in rodents and primates, arguing that rodent OXTR is olfactory-centric while primate OXTR is enriched in visual-attention and cholinergic circuits. It concludes that nonhuman primates, guided by selective receptor mapping and pharmacology, can provide mechanistic translational insights that current human intranasal oxytocin studies cannot.

Key findings

  • Rodent OXTR expression is concentrated in olfactory pathways (olfactory bulb, accessory olfactory nucleus, medial amygdala, central amygdala, bed nucleus of stria terminalis, piriform cortex) plus lateral septum, hippocampus, NAcc, and prefrontal cortex; primate OXTR overlaps visual processing, gaze, and attention regions (superior colliculus, pulvinar, primary visual cortex, oculomotor nucleus, nucleus prepositus) and cholinergic regions including the nucleus basalis of Meynert in all four species investigated and the pedunculopontine tegmental nucleus in rhesus macaques.
  • Species differences are marked: prairie voles have dense NAcc OXTR that is low to absent in meadow and montane voles; marmosets have dense NAcc OXTR; titi monkeys lack NAcc OXTR but have AVPR1a in NAcc and dense OXTR in the dentate gyrus; rhesus macaques show sparse OXTR relative to AVPR1a, with densest OXTR in the NBM and superficial grey layer of the superior colliculus.
  • Translational/clinical links include that IN-OT acutely increases gaze to the eye region in autistic populations, three rhesus studies found IN-OT impacts social visual attention and looking behaviours, IN-OT alters neural responses to emotional faces in macaques, and OXTR SNP rs2254298 has been linked to smaller amygdala volume.
  • Pharmacological findings: 125I-OVTA and 125I-LVA lose binding selectivity in primate tissue; an optimised competitive binding autoradiography method mapped OXTR in rhesus and titi monkeys; selective antagonists include ALS-II-69, SR49059, and L-368,899, but radiolabelled L-368,899 showed minimal brain uptake and appeared to accumulate in ventricles rather than neural tissue on PET.

Methods

  • Design: narrative comparative review of oxytocin and vasopressin receptor research in rodents and primates, with translational implications.
  • Data/sample: literature on rodent species (including mice, rats, hamsters, guinea pigs, California and deer mice, tuco-tucos, singing mice, naked and Cape mole-rats, prairie, pine, montane, and meadow voles) and primates (common marmoset, rhesus macaque, coppery titi monkey, human), drawing on receptor autoradiography, behavioural pharmacology, electrophysiology, microdialysis, and genetic/optogenetic manipulations.
  • Main analysis: qualitative synthesis of receptor distributions and pharmacological findings; no meta-analysis or new primary quantitative dataset is reported.

Limitations

  • The paper states that primate OXTR mapping has lagged because 125I-OVTA and 125I-LVA lose binding selectivity in primate tissue; human OT system methods are “incredibly limited” by practical and ethical considerations; human IN-OT studies are often underpowered with modest effect sizes; and invasive NHP brain manipulations face ethical, cost, and animal welfare constraints.
  • The paper states that species differences in receptor distribution mean NHP central OXTR may or may not predict human OXTR, and that IN-OT effects may be mediated by AVPR1a or peripheral OXTR, complicating interpretation.
  • Evident from the text: as a narrative review, it relies on selected literature and some unpublished or ongoing observations, without a systematic search or quantitative synthesis.

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Integrity signals

Registry

Crossref · 10.1111/jne.12382

Cites

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Statistics

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Claims the paper makes

0 of 130 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The authors independently confirmed the reported oxytocin receptor and vasopressin receptor 1a binding in the forebrain of the common marmoset.

    “We have also independently confirmed the findings reported by Schorscher-Petcu et al. (2009) for OXTR and AVPR1a binding in the forebrain of the common marmoset (Callithrix jacchus) (S. M. Freeman, unpublished observations).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schorscher-Petcu et al. (2009)

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  • Findingcitation

    The authors designed a pharmacologically optimised competitive binding receptor autoradiography method that can selectively and reliably reveal oxytocin receptor and vasopressin receptor 1a distributions in primate tissue.

    “We have recently reported the design of a pharmacologically optimised method for competitive binding receptor autoradiography that can selectively and reliably reveal the distributions of OXTR and AVPR1a in primate tissue (27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Freeman SM Inoue K Smith AL Goodman MM Young LJ The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta) Psychoneuroendocrinology 2014 45 128 141 24845184 PMC4043226 source

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  • Findingnone given

    All primate species investigated to date have oxytocin receptors in the nucleus basalis of Meynert.

    “For example, all of the primate species investigated to date have OXTR in the NBM”
    Quote in the paperSubstantial claim
  • Findingown data

    There is considerable overlap in oxytocin receptor expression among primate species in areas important for visual processing, shifts in gaze direction, and allocation of attention to visual stimuli.

    “In this context, it is not surprising that there is considerable overlap in OXTR expression among primate species in areas that are important for visual processing, shifts in gaze direction and the allocation of attention to visual stimuli (Fig. 1c,d and Table 1).”
    Quote in the paperSubstantial claim
  • Findingcitation

    Oxytocin receptors are expressed in areas involved in saccadic eye movements, including the superficial grey layer of the superior colliculus, deeper layers, the oculomotor nucleus, and the nucleus prepositus.

    “In areas involved in saccadic eye movements in response to visual stimuli, OXTR is expressed in the superficial grey layer of the SC (Fig. 2), as well as deeper layers, and in the oculomotor nucleus (III) and the nucleus prepositus, which are two brainstem motor nuclei that control the muscles of the eye and participate in the horizontal gaze stabilisation system, respectively (41-43).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [41] Büttner-Ennever JA Anatomy of the oculomotor system Dev Ophthalmol 2007 40 1 14 17314476 source

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    • cites [42] McCrea RA Horn AKE Nucleus prepositus Prog Brain Res 2006 151 205 230 16221590 source

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    • cites [43] Gandhi NJ Katnani HA Motor functions of the superior colliculus Annu Rev Neurosci 2011 34 205 231 21456962 PMC3641825 source

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  • May combine two claims. 27
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    Findingown data

    Oxytocin receptor expression across primate species has been found in the nucleus basalis of Meynert in all four species and in the pedunculopontine tegmental nucleus in rhesus macaques.

    “OXTR expression across primate species has also been found in two major cholinergic regions of the brain: in all four species, in the nucleus basalis of Meynert (NBM) (Fig. 2) and, in rhesus macaques, in the pedunculopontine tegmental nucleus (PPT).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In the primary visual path from the retina, oxytocin receptors have been detected in the superior colliculus, pulvinar, and primary visual cortex, and vasopressin receptor 1a binding has also been detected in many of these regions.

    “In the primary visual path from the retina, OXTR has been detected in the superior colliculus (SC), pulvinar (Pv) and primary visual cortex (interestingly, AVPR1a binding has also been detected in many these regions) (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Titi monkeys are socially monogamous but do not exhibit oxytocin receptor binding in the nucleus accumbens.

    “Similar experiments could also be performed in titi monkeys, which are socially monogamous but, unexpectedly, do not exhibit OXTR binding in the NAcc (Fig. 3b).”
    Quote in the paperSubstantial claim

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    Findingcitation

    The rhesus macaque brain exhibits extremely sparse oxytocin receptor expression relative to vasopressin receptor 1a, with the densest oxytocin receptor binding in the nucleus basalis of Meynert and superficial grey layer of the superior colliculus.

    “The rhesus macaque brain in general exhibits extremely sparse OXTR expression relative to AVPR1a (27,31), with the most dense OXTR binding seen in the NBM and superficial grey layer of the SC (Fig. 2c,f).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Freeman SM Inoue K Smith AL Goodman MM Young LJ The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta) Psychoneuroendocrinology 2014 45 128 141 24845184 PMC4043226 source

      Not checked in the free run.

    • cites [31] Young LJ Toloczko D Insel TR Localization of vasopressin (V1a) receptor binding and mRNA in the rhesus monkey brain J Neuroendocrinol 1999 11 291 297 10223283 source

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  • May combine two claims.

    Findingcitation

    Titi monkeys have vasopressin receptor 1a expression in the nucleus accumbens and extremely dense oxytocin receptor binding in the dentate gyrus of the hippocampus.

    “Instead, titi monkeys have AVPR1a expression in the NAcc (Fig. 3c) and extremely dense OXTR binding in the dentate gyrus (Fig. 3d) of the hippocampus (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Freeman SM Walum H Inoue K Smith AL Goodman MM Bales KL Young LJ Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus) Neuroscience 2014 273 12 23 24814726 PMC4083847 source

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  • May combine two claims.

    Premisecitation

    125I-OVTA and 125I-LVA bind selectively in rodents but have relatively high affinities for both oxytocin receptors and vasopressin receptor 1a in primates.

    “Although these compounds bind selectively to their respective receptors in rodents, they have now been shown to exhibit relatively high affinities for both OXTR and AVPR1a in primates (27,28).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Freeman SM Inoue K Smith AL Goodman MM Young LJ The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta) Psychoneuroendocrinology 2014 45 128 141 24845184 PMC4043226 source

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    • cites [28] 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 J Neuroendocrinol 2012 24 609 628 22375852 PMC3490377 source

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    Premisecitation

    The earliest radioligand for oxytocin receptor autoradiography was tritiated oxytocin, but its cross-reactivity with vasopressin receptor 1a and long film exposure times made it unfavourable and inconvenient.

    “The earliest radioligand available for this purpose was a tritiated version of OT (14), although the cross-reactivity of this ligand with the closely-related AVPR1a, combined with long exposure times needed on film before results can be attained, caused it to be an unfavourable and generally inconvenient tool for autoradiographic analysis of the brain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Freund-Mercier MJ Stoeckel ME Palacios JM Pazos A Reichhart JM Porte A Richard P Pharmacological characteristics and anatomical distribution of [3H]oxytocin-binding sites in the Wistar rat brain studied by autoradiography Neuroscience 1987 20 599 614 3647280 source

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    Premisecitation

    There is a significant gap in understanding the neural systems responsive to oxytocin and vasopressin in primates, and intranasal oxytocin use in humans has advanced despite lack of knowledge of the mechanism or targets engaged.

    “Specifically, there has been a significant gap in the understanding of the neural systems responsive to OT and AVP in primates, and the use of intranasal OT (IN-OT) in humans, in particular, has advanced rapidly despite a lack of knowledge of the mechanism or neurological targets engaged by this manipulation (11-13).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Walum H Waldman ID Young LJ Statistical and methodological considerations for the interpretation of intranasal oxytocin studies Biol Psychiatry 2015 79 251 257 26210057 PMC4690817 source

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    • cites [12] Leng G Ludwig M Intranasal oxytocin: myths and delusions Biol Psychiatry 2015 79 243 250 26049207 source

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    • cites [13] Insel TR Translating oxytocin neuroscience to the clinic: a National Institute of Mental Health perspective Biol Psychiatry 2016 79 153 154 26723108 source

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    Premisecitation

    Infants, toddlers, and adolescents with autism spectrum disorder show disrupted eye movement patterns to faces or social scenes, including avoidance of the eye region, atypical fixation on nonsocial aspects, and lack of attentional bias toward faces.

    “It has been shown that infants, toddlers and adolescents with autism spectrum disorder (ASD) all show disrupted patterns of eye movements in response to images/videos of human faces or naturalistic social scenes, including avoidance of the eye region of faces, atypical fixation targets to the nonsocial aspects of social scenes and a lack of attentional bias toward faces, as measured by faster sacc”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [61] Rice K Moriuchi JM Jones W Klin A Parsing heterogeneity in autism spectrum disorders: visual scanning of dynamic social scenes in school-aged children J Am Acad Child Adolesc Psychiatry 2012 51 238 248 22365460 PMC3306820 source

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    • cites [62] Chawarska K Volkmar F Klin A Limited attentional bias for faces in toddlers with autism spectrum disorders Arch Gen Psychiatry 2010 67 178 185 20124117 PMC4871149 source

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    • cites [63] Jones W Carr K Klin A Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old toddlers with autism spectrum disorder Arch Gen Psychiatry 2008 65 946 954 18678799 source

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    • cites [64] Klin A Jones W Schultz R Volkmar F Cohen D Visual fixation patterns during viewing of naturalistic social situations as predictors of social competence in individuals with autism Arch Gen Psychiatry 2002 59 809 816 12215080 source

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    Premisecitation

    The nucleus basalis of Meynert and pedunculopontine tegmental nucleus are major sources of cholinergic input to the rest of the brain and important regulators of selective attention and motivation.

    “These nuclei are major sources of cholinergic input to the rest of the brain (44-46) and are important regulators of selective attention and motivation (47-52).”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [44] Mesulam MM Mufson EJ Levey AI Wainer BH Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey J Comp Neurol 1983 214 170 197 6841683 source

      Not checked in the free run.

    • cites [45] Garcia-Rill E The pedunculopontine nucleus Prog Neurobiol 1991 36 363 389 1887068 source

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    • cites [46] Jones EG Burton H Saper CB Swanson LW Midbrain, diencephalic and cortical relationships of the basal nucleus of Meynert and associated structures in primates J Comp Neurol 1976 167 385 419 818134 source

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    • cites [47] Demeter E Sarter M Leveraging the cortical cholinergic system to enhance attention Neuropharmacology 2013 64 294 304 22796110 PMC3445745 source

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    • cites [48] Sarter M Gehring WJ Kozak R More attention must be paid: the neurobiology of attentional effort Brain Res Rev 2006 51 145 160 16530842 source

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    • cites [49] Balducci C Nurra M Pietropoli A Samanin R Carli M Reversal of visual attention dysfunction after AMPA lesions of the nucleus basalis magnocellularis (NBM) by the cholinesterase inhibitor donepezil and by a 5-HT1A receptor antagonist WAY 100635 Psychopharmacology 2003 167 28 36 12618916 source

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    • cites [50] Sarter M Givens B Bruno JP The cognitive neuroscience of sustained attention: where top-down meets bottom-up Brain Res Brain Res Rev 2001 35 146 160 11336780 source

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    • cites [52] Kobayashi Y Inoue Y Yamamoto M Isa T Aizawa H Contribution of pedunculopontine tegmental nucleus neurons to performance of visually guided saccade tasks in monkeys J Neurophysiol 2002 88 715 731 12163524 source

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    Premisecitation

    Cholinergic input from the pedunculopontine tegmental nucleus strongly innervates the macaque superior colliculus, and its neurones are active during saccade tasks and directly stimulate superior colliculus neurones to facilitate saccadic initiation.

    “Furthermore, cholinergic input from the PPT strongly innervates the macaque SC (53), and neurones in the PPT have also been shown to be active in monkeys during saccade tasks (54) and to directly stimulate SC neurones and facilitate the initiation of saccadic eye movements (55).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [53] Ma TP Graybiel AM Wurtz RH Location of saccade-related neurons in the macaque superior colliculus Exp Brain Res 1991 85 21 35 1715825 source

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    • cites [54] Okada K-I Kobayashi Y Characterization of oculomotor and visual activities in the primate pedunculopontine tegmental nucleus during visually guided saccade tasks Eur J Neurosci 2009 30 2211 2223 20128856 source

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    • cites [55] Kobayashi Y Saito Y Isa T Facilitation of saccade initiation by brain-stem cholinergic system Brain Dev 2001 23 Suppl 1 S24 S27 11738837 source

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    Premisecitation

    The pulvinar has been implicated in the salience of visual stimuli.

    “The Pv has also been implicated in the salience of visual stimuli (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Robinson DL Petersen SE The pulvinar and visual salience Trends Neurosci 1992 15 127 132 1374970 source

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    Premisecitation

    In cortically blind patients with visual cortex damage, right amygdala activity increased in response to direct gaze compared with averted gaze and co-varied with superior colliculus and pulvinar activity.

    “Activity in the right amygdala was increased in these patients in response to presentation of images of faces with direct gaze compared to averted gaze (38,39), and this activity co-varied in a condition-dependent way with activity in the SC and Pv (38).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [38] Morris JS DeGelder B Weiskrantz L Dolan RJ Differential extrageniculostriate and amygdala responses to presentation of emotional faces in a cortically blind field Brain 2001 124 1241 1252 11353739 source

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    • cites [39] Burra N Hervais-Adelman A Kerzel D Tamietto M de Gelder B Pegna AJ Amygdala activation for eye contact despite complete cortical blindness J Neurosci 2013 33 10483 10489 23785160 PMC6618602 source

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  • May combine two claims.

    Premisecitation

    The nucleus basalis of Meynert projects to the amygdala and is the primary source of cholinergic input to the basolateral amygdala.

    “Furthermore, NBM projects to the amygdala and is the primary source of cholinergic input to the basolateral amygdala (44,46,56,57).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [44] Mesulam MM Mufson EJ Levey AI Wainer BH Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey J Comp Neurol 1983 214 170 197 6841683 source

      Not checked in the free run.

    • cites [46] Jones EG Burton H Saper CB Swanson LW Midbrain, diencephalic and cortical relationships of the basal nucleus of Meynert and associated structures in primates J Comp Neurol 1976 167 385 419 818134 source

      Not checked in the free run.

    • cites [56] Woolf NJ Butcher LL Cholinergic projections to the basolateral amygdala: a combined Evans Blue and acetylcholinesterase analysis Brain Res Bull 1982 8 751 763 6182963 source

      Not checked in the free run.

    • cites [57] Nagai T Kimura H Maeda T McGeer PL Peng F McGeer EG Cholinergic projections from the basal forebrain of rat to the amygdala J Neurosci 1982 2 513 520 7069469 PMC6564247 source

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  • May combine two claims.

    Premisenone given

    Titi monkeys form lasting pair bonds and are highly territorial.

    “Titi monkeys, similar to prairie voles, form lasting pair bonds and are highly territorial, which renders this species an excellent primate model for similar questions of nonapeptide function in social and spatial memory.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cholinergic input is required for memory consolidation, possibly promoting memory encoding during sustained attention to visual stimuli.

    “This cholinergic input is required for memory consolidation (58,59), possibly promoting the encoding of memory during sustained attention to visual stimuli.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] Power AE Vazdarjanova A McGaugh JL Muscarinic cholinergic influences in memory consolidation Neurobiol Learn Mem 2003 80 178 193 14521862 source

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    • cites [59] Power AE McGaugh JL Phthalic acid amygdalopetal lesion of the nucleus basalis magnocellularis induces reversible memory deficits in rats Neurobiol Learn Mem 2002 77 372 388 11991764 source

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    Interpretationown data

    These findings provide new insights into the diversity and conservation of oxytocin and vasopressin function in the primate brain and contrast with rodent findings.

    “These findings provide new insights into the diversity and conservation of OT and AVP function in the primate brain and contrast with findings from rodent studies.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Conserved oxytocin receptor expression regions across primates have comparable functional roles relevant to social behaviour.

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    Premisecitation

    L-368,899 is a small-molecule OXTR antagonist employed in NHP research.

    “The Merck compound L-368,899 is another small molecule OXTR antagonist that has been used in NHP studies (93), has excellent bioavailability after oral administration (94) and has been also reported to accumulate in limbic structures of the brains of rhesus macaques after peripheral injection (95).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Smith AS Ågmo A Birnie AK French JA Manipulation of the oxytocin system alters social behavior and attraction in pair-bonding primates, Callithrix penicillata Horm Behav 2010 57 255 262 20025881 PMC2824532 source

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  • May combine two claims.

    Premisecitation

    Current studies in rhesus macaques found that oxytocin delivered directly to the nucleus basalis of Meynert changed social looking behaviour and neural activity in the basolateral amygdala.

    “Current studies in progress in rhesus macaques have found that OT delivered directly to the NBM changed social looking behaviour, as well as neural activity, in the basolateral amygdala (84), which is an area that lacks OXTR mRNA but receives strong cholinergic input from the NBM.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Putnam P Zimmerman P Gothard K Oxytocin injected into the nucleus basalis of Meynert of monkeys enhanced basic social behaviors and modulated neural activity in the basolateral nuclei of the amygdala Gordon Research Conference. New Frontiers in Amygdala Research: From Rodent to Man Easton, MA 2015

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  • May combine two claims.

    Interpretationreasoning

    The mixed selectivity issue in primate oxytocin and vasopressin research suggests that many effects of oxytocin could be mediated by vasopressin receptor 1a, and vice versa.

    “First, the mixed selectivity issue within the study of OT and AVP in primates suggests that many of the effects of OT could be mediated by AVPR1a, and vice versa.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Several previous studies suggested that the effects of oxytocin and vasopressin result from activation of the opposite receptor.

    “This concept is not new; several previous studies suggested that the effects of OT and AVP are a result of the activation of the ‘opposite’ receptor (4,80,86-89).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [4] Takayanagi Y Yoshida M Bielsky IF Ross HE Kawamata M Onaka T Yanagisawa T Kimura T Matzuk MM Young LJ Nishimori K Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice Proc Natl Acad Sci USA 2005 102 16096 16101 16249339 PMC1276060 source

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    • cites [80] Liu N Hadj-Bouziane F Jones KB Turchi JN Averbeck BB Ungerleider LG Oxytocin modulates fMRI responses to facial expression in macaques Proc Natl Acad Sci USA 2015 112 E3123 E3130 26015576 PMC4475931 source

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    • cites [86] Ragnauth AK Goodwillie A Brewer C Muglia LJ Pfaff DW Kow L-M Vasopressin stimulates ventromedial hypothalamic neurons via oxytocin receptors in oxytocin gene knockout male and female mice Neuroendocrinology 2004 80 92 99 15528951 source

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    • cites [87] 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 2008 155 118 126 18552879 PMC2527840 source

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    • cites [88] Schorscher-Petcu A Sotocinal S Ciura S Dupré A Ritchie J Sorge RE Crawley JN Hu S-B Nishimori K Young LJ Tribollet E Quirion R Mogil JS Oxytocin-induced analgesia and scratching are mediated by the vasopressin-1A receptor in the mouse J Neurosci 2010 30 8274 8284 20554879 PMC2902996 source

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    • cites [89] Song EZ McCann KE McNeill JKIV Huhman KL Albers HE Oxytocin Induces Social Communication in Male Syrian Hamsters by Activating V1a and not OT Receptors Society for Neurosceince Annual Meeting San Diego, CA 2013

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  • May combine two claims.

    Premisecitation

    Peripheral Melanotan-II activates OT neurones and increases central OT release after a physiological stimulus.

    “Melanotan-II, an MC4R agonist, given peripherally, activates OT neurones and potentiates central OT release following a physiological stimulus (103).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Modi ME Inoue K Barrett CE Kittelberger KA Smith DG Landgraf R Young LJ Melanocortin receptor agonists facilitate oxytocin-dependent partner preference formation in the prairie vole Neuropsychopharmacology 2015 40 1856 1865 25652247 PMC4839509 source

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

    Premisecitation

    After peripheral injection, L-368,899 has been reported to accumulate in limbic brain regions of rhesus macaques.

    “The Merck compound L-368,899 is another small molecule OXTR antagonist that has been used in NHP studies (93), has excellent bioavailability after oral administration (94) and has been also reported to accumulate in limbic structures of the brains of rhesus macaques after peripheral injection (95).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Boccia ML Goursaud A-PS Bachevalier J Anderson KD Pedersen CA Peripherally administered non-peptide oxytocin antagonist, L368,899, accumulates in limbic brain areas: a new pharmacological tool for the study of social motivation in non-human primates Horm Behav 2007 52 344 351 17583705 PMC2712625 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Recent work is mapping receptor distributions and creating selective agents.

    “New studies are now revealing receptor distributions and developing selective agents.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Human IN-OT studies often lack power because effect sizes are modest, making few-subject studies unreliable.

    “IN-OT studies even in humans are often underpowered given the modest effect sizes, making the interpretation of studies with few subjects unreliable (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Walum H Waldman ID Young LJ Statistical and methodological considerations for the interpretation of intranasal oxytocin studies Biol Psychiatry 2015 79 251 257 26210057 PMC4690817 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    NHP allow more precise study of brain OT function than current human IN-OT studies, aiding understanding of how IN-OT affects behaviour.

    “Second, NHP can be used to more precisely understand OT function in the brain than is currently possible using IN-OT in humans, which is useful for understanding the mechanisms by which IN-OT influences behaviour.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    These advances have implications for basic behavioural neurobiology and social neuroscience in NHP and for developing therapies that may improve social cognition in psychiatric disorders like ASD and schizophrenia.

    “These advancements have remarkable implications not only for basic behavioural neurobiology and social neuroscience in NHP, but also for honing pharmacological therapies that may improve social cognition in psychiatric disorders, such as ASD and schizophrenia.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Targeting the OT system can improve social cognition in psychiatric disorders such as ASD and schizophrenia.

  • May combine two claims.

    Interpretationnone given

    NHP neurohypophyseal receptor distributions show species differences and a conserved core linked to visual processing of social stimuli.

    “Neurohypophyseal receptor distributions in NHP display species differences, as well as a conserved core distribution related to the importance of visual processing of social stimuli.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    IN-OT in NHP models human IN-OT studies better but cannot reveal whether effects are central or peripheral or mediated by OXTR or AVPR1a.

    “Although intranasal delivery of OT in NHP more accurately models current human IN-OT studies, this approach does not provide information on whether the effects are mediated by central or peripheral receptors, or whether they are mediated by OXTR or AVPR1a (12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Leng G Ludwig M Intranasal oxytocin: myths and delusions Biol Psychiatry 2015 79 243 250 26049207 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    NHP research on OT and AVP in social behaviour and cognition is in its infancy and less precise than rodent research.

    “Research on the role of OT and AVP in regulating social behaviour and cognition in NHP is in its infancy, far behind the level of precision found in rodent research.”
    Quote in the paperSubstantial claim
30 of 30

  • The paper relies on this without support.

    Nonhuman primate models of social functioning can yield knowledge that translates to human oxytocin and vasopressin neurobiology.

    “there is great potential to fill the gaps in our knowledge by developing better nonhuman primate models of social functioning.”

  • The paper relies on this without support.

    Conserved oxytocin receptor expression regions across primates have comparable functional roles relevant to social behaviour.

    “with perspectives on the functionality of conserved regions of expression in these distinct mammalian clades.”

  • The paper relies on this without support.

    A tool must not interact with other behaviourally relevant neurochemical systems to isolate OT function.

    “Although MC4R agonists show promise for eliciting OT-mediated behaviours, they also interact with other behaviourally relevant neurochemical systems (23) and thus are not useful tools for isolating OT function.”

  • The paper relies on this without support.

    Targeting the OT system can improve social cognition in psychiatric disorders such as ASD and schizophrenia.

    “These advancements have remarkable implications not only for basic behavioural neurobiology and social neuroscience in NHP, but also for honing pharmacological therapies that may improve social cognition in psychiatric disorders, such as ASD and schizophrenia.”
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?

  • Comparative studies have revealed remarkable species diversity in oxytocin receptor distribution in the brain, likely contributing to species-specific social behaviors.

    “Comparative studies have revealed remarkable species diversity in receptor distribution in the brain (Figure 2), likely contributing to species-specific social behaviors”

    From Oxytocin, Neural Plasticity, and Social Behavior (2021) · cites this paper as Freeman & Young 2016

  • The NBM and SC have been shown to contain OXTR across all nonhuman primates studied to date.

    “the two areas that have been shown to contain OXTR across all nonhuman primates studied to date39: the nucleus basalis of Meynert (NBM) in the basal forebrain and the superior colliculus (SC) of the midbrain.”

    From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [39]

  • OXTR binding in primate brains is limited to a small number of subcortical areas and putatively absent in the cortex.

    “Because OXTR binding in primate brains is limited to a small number of subcortical areas and putatively absent in the cortex35,39”

    From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [39]

  • OXT acting at OXTR in the NBM could modulate the activity of an extensive network of brain areas and influence social behavioral processes like social visual attention, gaze direction, and social decision making.

    “Based on this connectivity of the NBM, we and others have postulated that OXT acting at OXTR in the NBM could modulate the activity of an extensive network of brain areas (which may themselves lack OXTR) and influence social behavioral processes like social visual attention, gaze direction, and social decision making38,39,64,65.”

    From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [39]

  • Although OXTR mRNA can be measured in some portions of the human cortex, autoradiographic studies of OXTR binding have not generated complementary evidence of functional, cell-surface OXTR in these regions of the cortex in humans or in nonhuman primates.

    “Although these studies and others59–61 indicate that OXTR mRNA can be measured in some portions of the human cortex, autoradiographic studies of OXTR binding have not generated complementary evidence of functional, cell-surface OXTR in these regions of the cortex in humans35 or in nonhuman primates39.”

    From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [39]

Cites

Flagged first, then by citations

1 of the 114 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. PutnamP ZimmermanP GothardK.Oxytocin injected into the nucleus basalis of Meynert of monkeys enhanced basic social behaviors and modulated neural activity in the basolateral nuclei of the amygdala. Gordon Research Conference. New Frontiers in Amygdala Research: From Rodent to Man.2015. Easton MA.
  2. Hubel DH, 1995, Eye, Brain, and Vision

Cited by

Sorted by citations

Related

Authors
Freeman, S. M., & Young, L. J.
Affiliations
  • University of California, Davis (US)
  • Emory University (US)
Corresponding author
Freeman, Sara M.
ORCID
Venue
Journal of Neuroendocrinology
Publisher
Wiley
Published
2016-04
Volume
28
Issue
4
ISSN
  • 0953-8194 (ISSN-L)
  • 1365-2826
DOI
10.1111/jne.12382
PMC
PMC4886472
OpenAlex
W2288695197
Cited by
196
References
114
Citations by year
2026: 11 · 2025: 9 · 2024: 15 · 2023: 13 · 2022: 18 · 2021: 17 · 2020: 32 · 2019: 12 · 2018: 30 · 2017: 22 · 2016: 16
FWCI
4.23
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 24 d)
Locations
  • Journal of Neuroendocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (MH090776, 1P50MH100023)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Social Sciences › Psychology › Social Psychology › Primate Behavior and Ecology
Keywords
oxytocin, vasopressin, oxytocin receptor, vasopressin receptor, non-human primates, rodents, social behavior, social cognition, translational research, receptor distribution, intranasal oxytocin, behavioral pharmacology, receptor autoradiography, optogenetics, comparative neurobiology
MeSH terms
Animals, Species Specificity, Receptors, Vasopressin, Receptors, Oxytocin, Translational Research, Biomedical

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.

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