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Cited by 56Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyFace Recognition and Perception

Oxytocin under opioid antagonism leads to supralinear enhancement of social attention

Open access
Dal Monte, Olga, Piva, Matthew, Anderson, Kevin M., Tringides, Marios, Holmes, Avram J., Chang, Steve W. C.·2017·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1702725114PMC PMC5441805
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Abstract

Significance: In the past decade, there has been an increase in studies using oxytocin (OT) for improving social cognition, but results have been inconsistent. In this study, we took advantage of the physiological relationship between the opioid and OT systems and tested the benefit of administering OT under simultaneously induced opioid antagonism during dyadic gaze interactions. Coadministration of OT and opioid blocker leads to supralinear enhancement of prolonged and selective attention to a live partner and increases interactive gaze after critical social events. Furthermore, we provide neurogenetic evidence in the human brain supporting the interaction between specific opioid receptor genes and the genes for OT processing. Our results suggest a new avenue for amplifying the efficacy of OT in clinical populations.

AI snapshot

Written from the paper’s full text.

TL;DR

Coadministering oxytocin (OT) with the μ-opioid antagonist naloxone (NAL) produced supralinear increases in monkeys’ selective social attention to a live partner, beyond the summed effects of OT and NAL alone. Human transcriptomic data further showed colocalization of μ- and κ-opioid receptor genes with OT genes at OT-releasing sites.

Key findings

  • OTNAL increased fixations to the conspecific’s face compared with saline or OT alone [main effect F(3,76) = 5.14, P = 0.003; OTNAL over SAL P = 0.005; OTNAL over OT P = 0.007; OTNAL over NAL P = 0.073], and this effect was supralinear [t(19) = 2.42, P = 0.026; r² = 0.33, P = 0.008].
  • OTNAL also increased fixations to the eyes [F(3,76) = 5.87, P = 0.004; OTNAL over SAL P = 0.004; OTNAL over OT P = 0.022; OTNAL over NAL P = 0.069], with a supralinear pattern [t(19) = 1.94, P = 0.067; r² = 0.29, P = 0.014]; OT alone marginally increased eye fixations versus SAL [t(19) = 1.63, P = 0.059].
  • After mutual eye contact, only OTNAL strongly increased attention to the conspecific [P < 0.01, permutation test], and the effect was supralinear [t(19) = 2.88, P = 0.010]; after mutual reward, OTNAL again increased gaze to the face [P < 0.001] and was supralinear [t(19) = 2.14, P = 0.046; r² = 0.25, P = 0.023]. No significant effects were found after nonmutual eye contact or no reward (all P > 0.05).
  • In human brain tissue, OXT was most enriched in 10 regions; OPRM1 and OPRK1 showed greater expression than OPRD1 in these regions, and OPRM1 expression correlated with OXT [r(8) = 0.88, P < 0.001], whereas OPRK1 [r(8) = 0.15, P = 0.673] and OPRD1 [r(8) = −0.17, P = 0.632] did not.

Methods

  • Main behavioral task: pairs of rhesus macaques sat facing each other while both animals’ eye positions were recorded continuously at 1,000 Hz. Five animals (three males, two females) across 20 pairs completed all four intranasal nebulized conditions: OT (24 IU), NAL (1 mg), saline, or OTNAL; 640 live-gaze sessions and 320 mutual-reward sessions were collected.
  • Analyses used one-way ANOVA with Tukey–Kramer post hoc tests, paired-sample t tests, permutation tests with 1,000 shuffles, and linear regression; supralinearity was tested by comparing OTNAL effects against the summed effects of OT and NAL alone.
  • Human neurogenetics used averaged microarray expression data from six postmortem donors in the Allen Human Brain Atlas, restricted to 190 regions sampled in at least four donors; OXT-enriched regions were those ≥1 SD above the region-wise mean, followed by within-subject ANOVA with Benjamini–Hochberg correction and Pearson correlations.

Limitations

  • The paper states that the number of males and females was underpowered for fully exploring sex differences, although no significant sex effects were found within the limited sample.
  • The paper states that safety was assessed only qualitatively, with no noticeable side effects observed; it notes that more quantitative measurements such as heart rate and blood pressure should be measured in the future.
  • Evident from the text: the human evidence is correlational gene-expression colocalization from postmortem atlas data, not a direct functional or behavioral test in humans; the causal behavioral evidence comes from the monkey experiments.

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

Integrity signals

Registry

Crossref · 10.1073/pnas.1702725114

Cites

74 of 74 references verified0 citation errors · 0 not checkable

Statistics

34 tests recomputed · 0 with the reported and recomputed p on opposite sides of .05

Claims the paper makes

0 of 66 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Results

    OTNAL increased the number of fixations to the face of a conspecific compared with the saline or oxytocin condition.

    “OTNAL was associated with an increased number of fixations to the face of a conspecific compared with the SAL or OT condition [Fig. 1C; F(3,76) = 5.14, P = 0.003 for main effect, P = 0.005 for OTNAL over SAL, P = 0.073 for OTNAL over NAL, P = 0.007 for OTNAL over OT, one-way ANOVA with Tukey–Kramer post hoc tests].”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Gaze fixation frequency to the face and eyes is a valid measure of social attention.
  • Findingown data
    § Results

    The effect of OTNAL on eye fixations showed a supralinear pattern (t(19) = 1.94, P = 0.067).

    “again with a supralinear pattern [Fig. 1F; t(19) = 1.94, P = 0.067].”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Gaze fixation frequency to the face and eyes is a valid measure of social attention.
  • Findingown data
    § Results

    Oxytocin overall increased fixations to the eyes compared with saline in the real-life dyadic setting, although the effect was marginal (t(19) = 1.63, P = 0.059).

    “OT overall increased fixations to the eyes compared with SAL in this real-life dyadic setting [Fig. 1E; t(19) = 1.63, P = 0.059, paired-sample t test], although the effect was marginal.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Gaze fixation frequency to the face and eyes is a valid measure of social attention.
  • Findingown data
    § Results

    Following mutual reward receipt, gaze frequency to the face of the conspecific was only significant in the OTNAL condition.

    “Gaze frequency to the face of the conspecific was only significant in the OTNAL condition (Fig. 3A; P < 0.001, permutation test).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Gaze fixation frequency to the face and eyes is a valid measure of social attention.
  • Findingown data
    § Results

    Following mutual eye contact, the gaze patterns comparing drug effects were supralinear.

    “Notably, when comparing the effects of drugs following mutual eye contact, the resulting gaze patterns were again supralinear [Fig. 2B; t(19) = 2.88, P = 0.010, paired-sample t test].”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Gaze fixation frequency to the face and eyes is a valid measure of social attention.
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 32

  • May combine two claims.

    Findingown data
    § Results

    Following mutual reward, the effects of OTNAL were supralinear compared with the summed effects of oxytocin and naloxone, with a positive correlation between them.

    “Notably, these effects were again supralinear following mutual reward for OTNAL compared with the summed effects of OT and NAL, with a positive correlation between them [Fig. 3B; t(19) = 2.14, P = 0.046, paired-sample t test; r2 = 0.25, P = 0.023, linear regression].”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Gaze fixation frequency to the face and eyes is a valid measure of social attention.

  • May combine two claims.

    Findingown data
    § Results

    No significant effect of sex was found on fixation frequency to the face or eyes over entire behavioral sessions, or on gaze dynamics following mutual eye contact or mutual reward.

    “when we analyzed fixation frequency to the face (Fig. S6A) and eyes (Fig. S6B) over entire behavioral sessions, as well as gaze dynamics to the conspecific following mutual eye contact (Fig. S6C) and mutual reward (Fig. S6D), we found no significant effect of sex.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Gaze fixation frequency to the face and eyes is a valid measure of social attention.

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

    Findingown data
    § Materials and Methods

    Gaze behavior between drug groups diverged in the 500-3,000 ms window for mutual eye contact and the 1,500-3,500 ms window for mutual reward.

    “Windows of activity were defined in which gaze behavior between the two groups diverged (500–3,000 ms for mutual eye contact and 1,500–3,500 ms for mutual reward).”
    Quote in the paperSubstantial claim

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

    Findingown data
    § Materials and Methods

    After the 5-s and 4-s windows following mutual eye contact and mutual reward, looking behaviors return to a rough baseline with no significant differences between drug groups.

    “These 5-s and 4-s windows were chosen empirically based on the observation that looking behaviors return to a rough baseline, with no significant differences between drug groups observed after these periods (Figs. 2 and 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Materials and Methods

    For gaze to the conspecific following mutual eye contact and mutual reward, there was a significant main effect of drug condition but no significant main effect of sex or an interaction between drug and sex.

    “We noted a significant main effect of drug condition, but no significant main effect of sex or an interaction between these two factors [Fig. S6 C and D; mutual eye contact: main effect of drug F(2,54) = 11.2, P < 0.0001; main effect of sex F(1,54) = 0.82, P = 0.368; interaction between drug and sex F(2,54) = 0.0004, P = 0.989; mutual reward: main effect of drug F(2,54) = 11.9, P < 0.0001; main”
    Quote in the paperNot a substantial claim

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

    Findingown data
    § Materials and Methods

    Monkeys overall preferred to look at conspecific eyes compared with human eyes.

    “When we examined fixations to the eyes, we found that monkeys overall preferred to look at conspecific eyes compared with human eyes [Fig. S2B; F(1,546) = 8.9, P = 0.003 for main effect of images]”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Materials and Methods

    For the number of fixations to the face and eyes, there was a significant main effect of drug condition but no significant main effect of sex or an interaction between drug and sex.

    “We noted a significant main effect of drug condition but no significant main effect of sex or an interaction between these two factors [Fig. S6 A and B; face: main effect of drug F(3,72) = 5.6, P = 0.002; main effect of sex F(1,72) = 0.17, P = 0.679; interaction between drug and sex F(3,72) = 0.91, P = 0.442; eyes: main effect of drug F(3,72) = 5.3, P = 0.002; main effect of sex F(1,72) = 1.03, P”
    Quote in the paperNot a substantial claim

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

    Findingown data
    § Materials and Methods

    Based on qualitative observations by several laboratory staff members, no noticeable side effects of intranasal OTNAL, OT, or NAL were observed in both laboratory and colony settings.

    “Based on qualitative observations by several laboratory staff members, we observed no noticeable side effects of intranasal OTNAL, OT, or NAL in both laboratory and colony settings.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    The effects of naloxone are likely mediated by inhibition of μ-opioid and possibly also κ-opioid receptors, but not δ-opioid receptors.

    “Taken together, these findings suggest that the effects of NAL are likely mediated by inhibition of µ-opioid and possibly also κ-opioid receptors, but not δ-opioid receptors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Colocalization of gene expression in brain regions indicates a functional regulatory relationship between oxytocin and opioid systems.

  • May combine two claims.

    Interpretationown data
    § Discussion

    The supralinear effects of OTNAL were driven by mutually engaged events (mutual eye contact and mutual reward receipt) and resulted in directing selective attention to socially relevant features (eyes and mouth, respectively).

    “The supralinear effects of OTNAL were driven by mutually engaged events (mutual eye contact and mutual reward receipt) and resulted in directing selective attention to socially relevant features (eyes and mouth, respectively).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Gaze fixation frequency to the face and eyes is a valid measure of social attention.

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

    Premisecitation
    § Abstract

    In rhesus macaques, carrying the G allele of the μ-opioid receptor gene OPRM1, compared with homozygous C alleles, is associated with stronger maternal attachment in infants and more effective prevention of infant separation in mothers.

    “In rhesus macaques, carrying the G allele of the μ-opioid receptor gene OPRM1, compared with homozygous C alleles, is associated with stronger maternal attachment in infants (14) and more effective prevention of infant separation in mothers (15).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Barr CS, et al. Variation at the mu-opioid receptor gene (OPRM1) influences attachment behavior in infant primates. Proc Natl Acad Sci USA. 2008;105:5277–5281. doi: 10.1073/pnas.0710225105. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [15] Higham JP, et al. Mu-opioid receptor (OPRM1) variation, oxytocin levels and maternal attachment in free-ranging rhesus macaques Macaca mulatta. Behav Neurosci. 2011;125:131–136. doi: 10.1037/a0022695. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Discussion

    The potential benefit of coadministering oxytocin with naloxone is supported by the mechanistic link between inhibition of opioid processing and increase in oxytocin release from the posterior pituitary, as well as the colocalization of the expressed oxytocin receptor and μ-opioid and κ-opioid receptor genes at the primary oxytocin-releasing sites in the human brain.

    “The potential benefit of coadministering OT with NAL is supported by the mechanistic link between the inhibition of opioid processing and increase in OT release from the posterior pituitary (22), as well as the colocalization of the expressed OT receptor and μ-opioid and κ-opioid receptor genes at the primary OT-releasing sites in the human brain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Bicknell R, Leng G. Endogenous opiates regulate oxytocin but not vasopressin secretion from the neurohypophysis. Nature. 1982;298:161–162. doi: 10.1038/298161a0. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • Rests on an assumption: The Allen Human Brain Atlas microarray expression data from six postmortem donors and 190 regions are representative of the human brain.
    • Rests on an assumption: Colocalization of gene expression in brain regions indicates a functional regulatory relationship between oxytocin and opioid systems.

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

    Study design and conductcitation
    § Materials and Methods

    Probe selection for the human neurogenetics analysis followed Miller et al. to analyze probes that most reliably align to RNA-sequencing values, resulting in 20,736 unique gene probes.

    “Probe selection was conducted according to the analysis of Miller et al. (52) to analyze probes that most reliably align to RNA-sequencing values, resulting in 20,736 unique gene probes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Miller JA, et al. Improving reliability and absolute quantification of human brain microarray data by filtering and scaling probes using RNA-Seq. BMC Genomics. 2014;15:154. doi: 10.1186/1471-2164-15-154. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Abstract

    The chronic administration of morphine influences both the synthesis and secretion of oxytocin.

    “The chronic administration of morphine, a prototypical μ-opioid receptor agonist, also influences both the synthesis and secretion of OT (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] You ZD, Li JH, Song CY, Wang CH, Lu CL. Chronic morphine treatment inhibits oxytocin synthesis in rats. Neuroreport. 2000;11:3113–3116. doi: 10.1097/00001756-200009280-00015. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Study design and conductnone given
    § Materials and Methods

    A within-subjects design was used so that each animal experienced all drug conditions with a randomized order on consecutive days of administration across animals.

    “Finally, we used a within-subjects design so that each animal experienced all drug conditions with a randomized order on consecutive days of administration across animals.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Materials and Methods

    The common dose used for NAL nasal spray in prehospital settings with heroin overdose is 2 mg.

    “Today, the common dose used for NAL nasal spray in prehospital settings with heroin overdose is 2 mg (58, 62).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] Wolfe TR, Bernstone T. Intranasal drug delivery: An alternative to intravenous administration in selected emergency cases. J Emerg Nurs. 2004;30:141–147. doi: 10.1016/j.jen.2004.01.006. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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      Not checked in the free run.

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

    Premisecitation
    § Materials and Methods

    The conventional dose of OT used in both humans and nonhuman primates is 24 IU.

    “For OT (O3251; Sigma), we chose the conventional dose of 24 IU used in both humans and nonhuman primates (34, 64).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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      Not checked in the free run.

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

    Study design and conductcitation
    § Materials and Methods

    All procedures were approved by the Yale Institutional Animal Care and Use Committee and were in compliance with the Public Health Service's Guide for the Care and Use of Laboratory Animals.

    “All procedures were approved by the Yale Institutional Animal Care and Use Committee and were in compliance with the Public Health Service’s Guide for the Care and Use of Laboratory Animals (51).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] National Research Council . Guide for the Care and Use of Laboratory Animals. 8th Ed National Academies Press; Washington, DC: 2011. [Google Scholar]

      Not checked in the free run.

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

    Premisecitation
    § Abstract

    μ-opioid receptors have been studied in relation to reward, emotion, and behavior in the social domain and are strongly expressed in reward-related regions of the primate brain.

    “μ-opioid receptors have been studied in relation to reward, emotion, and behavior in the social domain (12) and are strongly expressed in reward-related regions of the primate brain (13).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Resendez SL, et al. μ-Opioid receptors within subregions of the striatum mediate pair bond formation through parallel yet distinct reward mechanisms. J Neurosci. 2013;33:9140–9149. doi: 10.1523/JNEUROSCI.4123-12.2013. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

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    Premisecitation
    § Materials and Methods

    In rodents, absorption of NAL through the nasal route is equivalent to the i.v. and intraduodenal routes.

    “Similarly, in rodents, the absorption of NAL through the nasal route has been found to be equivalent to the i.v. and intraduodenal routes (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • May combine two claims.

    Premisecitation
    § Discussion

    Observational studies in patients with autism have shown that administration of an opioid antagonist could decrease self-injurious behavior, stereotypies, hyperactivity, and withdrawal, while increasing verbal production, social communication, proximity seeking, and eye contact.

    “Observational studies in patients with autism have shown that administration of an opioid antagonist could decrease self-injurious behavior, stereotypies, hyperactivity, and withdrawal, although increasing verbal production, social communication, proximity seeking, and eye contact (47–50).”
    Quote in the paperSubstantial claim0 of 4 sources checked
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  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    The efficacy of oxytocin in improving social abilities is under debate, largely due to frequently observed weak effect sizes and problems with replicability.

    “The efficacy of oxytocin (OT) in improving social abilities is under debate, largely due to frequently observed weak effect sizes and problems with replicability (1–3).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Bartz J, et al. Oxytocin can hinder trust and cooperation in borderline personality disorder. Soc Cogn Affect Neurosci. 2011;6:556–563. doi: 10.1093/scan/nsq085. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § Materials and Methods

    The same dose of intranasal NAL is as effective as i.v. NAL in reversing effects on the central nervous system caused by opioid overdose in humans.

    “It has been shown that the same dose of intranasal NAL is as effective as i.v. NAL in reversing effects on the central nervous system caused by opioid overdose in humans (59).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation
    § Materials and Methods

    In humans, the pharmacodynamic profile of intranasal NAL has been investigated with doses ranging from 0.5 to 2 mg.

    “In humans, the pharmacodynamic profile of NAL intranasal administration has been investigated with different doses ranging from 0.5 to 2 mg (61).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Middleton LS, Nuzzo PA, Lofwall MR, Moody DE, Walsh SL. The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers. Addiction. 2011;106:1460–1473. doi: 10.1111/j.1360-0443.2011.03424.x. [DOI] [PMC free article] [PubMed] [Google Scholar] source

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    Premisecitation
    § Abstract

    The inhibition of oxytocin secretion from neural tissues by morphine underlies the mechanism by which morphine disrupts milk ejection in lactation.

    “the inhibition of OT secretion from neural tissues by morphine underlies the mechanism by which morphine disrupts milk ejection in lactation (30, 31).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30] Clarke G, Wood P, Merrick L, Lincoln D. Opiate inhibition of peptide release from the neurohumoral terminals of hypothalamic neurons. Nature. 1979;282:746–748. doi: 10.1038/282746a0. [DOI] [PubMed] [Google Scholar] source

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      Not checked in the free run.

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

    Premisecitation
    § Abstract

    Clinical trials of oxytocin in autistic patients are ongoing, yet several studies have produced inconclusive results.

    “Clinical trials of OT in autistic patients are ongoing, yet several studies have produced inconclusive results (4–8)”
    Quote in the paperSubstantial claim0 of 5 sources checked
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    • cites [5] Yatawara CJ, Einfeld SL, Hickie IB, Davenport TA, Guastella AJ. The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: A randomized clinical crossover trial. Mol Psychiatry. 2016;21:1225–1231. doi: 10.1038/mp.2015.162. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [6] Anagnostou E, et al. Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: A randomized controlled trial. Mol Autism. 2012;3:16. doi: 10.1186/2040-2392-3-16. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [7] Preckel K, Kanske P, Singer T, Paulus FM, Krach S. Clinical trial of modulatory effects of oxytocin treatment on higher-order social cognition in autism spectrum disorder: A randomized, placebo-controlled, double-blind and crossover trial. BMC Psychiatry. 2016;16:329. doi: 10.1186/s12888-016-1036-x. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [8] Guastella AJ, et al. The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: A randomized controlled trial. J Child Psychol Psychiatry. 2015;56:444–452. doi: 10.1111/jcpp.12305. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Materials and Methods

    The intranasal delivery method has been suggested as a route to administer NAL quickly in a needle-free system.

    “Recently, the intranasal delivery method has been suggested as a route to administer NAL quickly in a needle-free system (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Wolfe TR, Bernstone T. Intranasal drug delivery: An alternative to intravenous administration in selected emergency cases. J Emerg Nurs. 2004;30:141–147. doi: 10.1016/j.jen.2004.01.006. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    Endogenous opioid inhibition triggers central oxytocin, but not vasopressin, release.

    “endogenous opioid inhibition triggers central OT, but not vasopressin, release (26)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Neumann I, Russell JA, Wolff B, Landgraf R. Naloxone increases the release of oxytocin, but not vasopressin, within limbic brain areas of conscious parturient rats: A push-pull perfusion study. Neuroendocrinology. 1991;54:545–551. doi: 10.1159/000125958. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Study design and conductreasoning
    § Materials and Methods

    Only regions sampled in at least four of the six donors were examined to prevent biased expression values due to sparse sampling.

    “To prevent biased expression values due to sparse sampling across the six donors, only regions that were sampled in at least four donors were examined.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Opioid agonists, such as morphine, decrease physical contact between social partners, whereas naloxone administration increases solicitation for social contact, such as grooming and proximity.

    “opioid agonists, such as morphine, decrease physical contact between social partners, whereas NAL administration increases solicitation for social contact, such as grooming and proximity (16–19).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [16] Kalin NH, Shelton SE, Barksdale CM. Opiate modulation of separation-induced distress in non-human primates. Brain Res. 1988;440:285–292. doi: 10.1016/0006-8993(88)90997-3. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [17] Fabre-Nys C, Meller RE, Keverne EB. Opiate antagonists stimulate affiliative behaviour in monkeys. Pharmacol Biochem Behav. 1982;16:653–659. doi: 10.1016/0091-3057(82)90432-4. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [18] Martel FL, Nevison CM, Simpson MJ, Keverne EB. Effects of opioid receptor blockade on the social behavior of rhesus monkeys living in large family groups. Dev Psychobiol. 1995;28:71–84. doi: 10.1002/dev.420280202. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [19] Keverne EB, Martensz ND, Tuite B. Beta-endorphin concentrations in cerebrospinal fluid of monkeys are influenced by grooming relationships. Psychoneuroendocrinology. 1989;14:155–161. doi: 10.1016/0306-4530(89)90065-6. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Abstract

    Abnormalities in central opioid levels have been observed in some individuals with autism.

    “Abnormalities in central opioid levels have been observed in some individuals with autism”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Enhancing opioidergic tone with morphine severely delays the course of parturition, accompanied by a reduced level of circulating oxytocin, whereas attenuating opioidergic tone with naloxone acutely increases the speed of parturition by greatly elevating oxytocin levels, reversing this delay.

    “Enhancing opioidergic tone with morphine severely delays the course of parturition, accompanied by a reduced level of circulating OT, whereas attenuating opioidergic tone with NAL acutely increases the speed of parturition by greatly elevating OT levels, reversing this delay (27–29).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] Bicknell RJ, et al. Hypothalamic opioid mechanisms controlling oxytocin neurones during parturition. Brain Res Bull. 1988;20:743–749. doi: 10.1016/0361-9230(88)90086-x. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [28] Leng G, et al. Endogenous opioid actions and effects of environmental disturbance on parturition and oxytocin secretion in rats. J Reprod Fertil. 1988;84:345–356. doi: 10.1530/jrf.0.0840345. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [29] Bicknell RJ, Leng G, Lincoln DW, Russell JA. Naloxone excites oxytocin neurones in the supraoptic nucleus of lactating rats after chronic morphine treatment. J Physiol. 1988;396:297–317. doi: 10.1113/jphysiol.1988.sp016963. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Study design and conductnone given
    § Materials and Methods

    Experimental sessions were conducted at the same time of day to control for diurnal fluctuations.

    “In addition, experimental sessions were conducted at the same time of day to control for diurnal fluctuations.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Materials and Methods

    Most studies and clinical applications of NAL have delivered NAL by the i.v., i.m., or s.c. route, with the i.v. route being the recommended route.

    “Most studies and clinical applications of NAL have delivered NAL by the i.v., i.m., or s.c. route, with the i.v. route being the recommended route (57).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Wermeling DP. A response to the opioid overdose epidemic: Naloxone nasal spray. Drug Deliv Transl Res. 2013;3:63–74. doi: 10.1007/s13346-012-0092-0. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Materials and Methods

    Intranasal administration of 24 IU OT affects brain activity in humans.

    “This dose, administered intranasally, has been shown in nonhuman primates to increase OT levels in cerebrospinal fluid significantly (54) and to modulate social behavior (65), as well as to affect brain activity (66) and phasic activity of the parasympathetic nervous system (67) in humans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Gamer M, Zurowski B, Büchel C. Different amygdala subregions mediate valence-related and attentional effects of oxytocin in humans. Proc Natl Acad Sci USA. 2010;107:9400–9405. doi: 10.1073/pnas.1000985107. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Materials and Methods

    Naltrexone has been used successfully to decrease self-injurious behavior, stereotypies, hyperactivity, and withdrawal while increasing verbal production and attentiveness.

    “For example, naltrexone, although less selective to the μ-opioid receptor than NAL, has been used successfully to decrease self-injurious behavior, stereotypies, hyperactivity, and withdrawal while increasing verbal production and attentiveness (69, 70).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [69] Campbell M, et al. Naltrexone in autistic children: A double-blind and placebo-controlled study. Psychopharmacol Bull. 1990;26:130–135. [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [70] Campbell M, et al. Naltrexone in autistic children: An acute open dose range tolerance trial. J Am Acad Child Adolesc Psychiatry. 1989;28:200–206. doi: 10.1097/00004583-198903000-00009. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Materials and Methods

    Naloxone has also been used safely with chronic administration in marketed therapies for opioid dependence.

    “and NAL has also been used safely with chronic administration in marketed therapies for opioid dependence (Suboxone; Reckitt Benckiser)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Suboxone; Reckitt Benckiser

      Not checked in the free run.

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

    Premisecitation
    § Materials and Methods

    Oxytocin has been used safely with chronic administration in recent clinical trials.

    “OT has been used safely with chronic administration in recent clinical trials (5)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Yatawara CJ, Einfeld SL, Hickie IB, Davenport TA, Guastella AJ. The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: A randomized clinical crossover trial. Mol Psychiatry. 2016;21:1225–1231. doi: 10.1038/mp.2015.162. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Materials and Methods

    Intranasal administration of 24 IU OT affects phasic activity of the parasympathetic nervous system in humans.

    “This dose, administered intranasally, has been shown in nonhuman primates to increase OT levels in cerebrospinal fluid significantly (54) and to modulate social behavior (65), as well as to affect brain activity (66) and phasic activity of the parasympathetic nervous system (67) in humans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Gamer M, Büchel C. Oxytocin specifically enhances valence-dependent parasympathetic responses. Psychoneuroendocrinology. 2012;37:87–93. doi: 10.1016/j.psyneuen.2011.05.007. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Materials and Methods

    In a randomized controlled trial of 172 patients suspected of heroin overdose, intranasal and intramuscular naloxone produced similar adverse events, which were generally mild.

    “The adverse events seen were similar between the two groups; they were generally mild in nature and included agitation, nausea, and vomiting.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Kerr D, Dietze P, Kelly AM. Intranasal naloxone for the treatment of suspected heroin overdose. Addiction. 2008;103:379–386. doi: 10.1111/j.1360-0443.2007.02097.x. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Materials and Methods

    Intranasal oxytocin produces no detectable subjective changes in recipients and no reliable side effects, and is not associated with adverse outcomes when delivered in doses of 18-40 IU for short-term use in controlled research settings.

    “These authors reported that intranasal OT produces no detectable subjective changes in recipients and no reliable side effects, and that it is not associated with adverse outcomes when delivered in doses of 18–40 IU for short-term use in controlled research settings.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] MacDonald E, et al. A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology. 2011;36:1114–1126. doi: 10.1016/j.psyneuen.2011.02.015. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Study design and conductnone given
    § Materials and Methods

    The number of macaques used in this study (three males and two females) is underpowered to explore potential sex differences fully.

    “The number of macaques used in this study (three males and two females) is underpowered to explore potential sex differences fully.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Materials and Methods

    Intranasal administration of 24 IU OT modulates social behavior in nonhuman primates.

    “This dose, administered intranasally, has been shown in nonhuman primates to increase OT levels in cerebrospinal fluid significantly (54) and to modulate social behavior (65), as well as to affect brain activity (66) and phasic activity of the parasympathetic nervous system (67) in humans.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Landman R, Sharma J, Sur M, Desimone R. Effect of distracting faces on visual selective attention in the monkey. Proc Natl Acad Sci USA. 2014;111:18037–42. doi: 10.1073/pnas.1420167111. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

43 of 43

  • The paper relies on this without support.

    Gaze fixation frequency to the face and eyes is a valid measure of social attention.

    “OTNAL was associated with an increased number of fixations to the face of a conspecific”

  • The paper relies on this without support.

    The Allen Human Brain Atlas microarray expression data from six postmortem donors and 190 regions are representative of the human brain.

    “using averaged microarray expression data of six postmortem donors from the Allen Human Brain Atlas. Available data included 190 regions containing samples from at least four donors (39).”

  • The paper relies on this without support.

    Colocalization of gene expression in brain regions indicates a functional regulatory relationship between oxytocin and opioid systems.

    “suggesting a regional colocalization of OXT, OXTR, OPMR1, and OPRK1.”

  • The paper relies on this without support.

    Intranasal administration of oxytocin and naloxone reaches the relevant brain regions to produce the observed effects.

    “one of the animals in a given pair received aerosolized drugs intranasally corresponding to one of the four pharmacology conditions”

  • The paper relies on this without support.

    No studies have investigated the effect of NAL on social behaviors in humans or nonhuman primates following intranasal administration.

    “Although increasing evidence points toward nasal spray as a reliable delivery route, no studies have investigated the effect of NAL on social behaviors in humans or nonhuman primates following intranasal administration.”

  • The paper relies on this without support.

    No studies to date have provided a dose–response curve for the impact of intranasal NAL on social attention in either humans or nonhuman primates.

    “Although a recent paper has suggested that the opioid blocker naltrexone alters the processing of social and emotional stimuli in healthy subjects (63), no studies to date have provided a dose–response curve for the impact of intranasal NAL on social attention in either humans or nonhuman primates.”

  • The paper relies on this without support.

    NAL and naltrexone are potent, safe, and long-lasting opioid antagonists with minimal side effects.

    “NAL and naltrexone are potent, safe, and long-lasting opioid antagonists with minimal side effects.”

  • The paper relies on this without support.

    OT and NAL are approved by the US Food and Drug Administration for intranasal delivery at the doses used in the study and are considered to have a low risk of side effects.

    “both OT and NAL are approved by the US Food and Drug Administration for intranasal delivery at our doses and are considered to have a low risk of side effects”
8 of 8

Claims other papers make about this one

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

  • IN-OXT treatment increases gaze following, increases socially oriented gaze, and alters social attention in a wide variety of contexts in macaques.

    “This work provides anatomical support for other findings in macaques, which indicate that IN-OXT treatment increases gaze following67, increases socially oriented gaze68, and alters social attention in a wide variety of contexts69–74.”

    From Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain (2018) · cites this paper as [71]

  • More recent work has examined whole-brain distribution of OXTR genes against a limited set of genes and overexpression in broad functional brain networks, but researchers have yet to explore OXTR's associations with all protein-coding genes or with gene expression patterns associated with specific cognitive states.

    “While more recent work has exclusively examined whole-brain distribution of OXTR genes against a limited set of genes13 and overexpression in broad functional brain networks (e.g., limbic network)14, researchers have yet to explore OXTR’s associations with all protein-coding genes or with gene expression patterns associated with specific cognitive states.”

    From Oxytocin pathway gene networks in the human brain (2019) · cites this paper as [13]

  • OXT mRNA is highly expressed in the human paraventricular nucleus of the hypothalamus, the lateral hypothalamic area, and the supraoptic nucleus, and there is evidence of co-expression with OXTR mRNA and the μ and κ types opioid receptor mRNA.

    “OXT mRNA has been shown to be highly expressed in human paraventricular nucleus of the hypothalamus, the lateral hypothalamic area, and the supraoptic nucleus, and there is evidence of co-expression with OXTR mRNA and the μ and κ types opioid receptor mRNA13”

    From Oxytocin pathway gene networks in the human brain (2019) · cites this paper as [13]

  • Brain regions with high oxytocin pathway gene expression in humans have been identified, but inference of specific cognitive states from the activity of single brain regions is elusive.

    “While brain regions with high oxytocin pathway gene expression in humans have been identified12,13, inference of specific cognitive states from the activity of single brain regions is elusive.”

    From Oxytocin pathway gene networks in the human brain (2019) · cites this paper as [13]

Statistics that don’t add up

Each reported p-value recomputed from its test statistic and degrees of freedom.

  • Inconsistent p-value: F(2,54) = 0.006, p = .942

    Minor

    The paper reports p = .942 here; recomputing from the test statistic and its degrees of freedom gives p = .994. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .942 · recomputed p = .994

  • Inconsistent p-value: F(1,54) = 0.005, p = .816

    Minor

    The paper reports p = .816 here; recomputing from the test statistic and its degrees of freedom gives p = .944. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .816 · recomputed p = .944

  • Inconsistent p-value: F(2,54) = 0.0004, p = .989

    Minor

    The paper reports p = .989 here; recomputing from the test statistic and its degrees of freedom gives p = 1.000. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .989 · recomputed p = 1.000

  • Inconsistent p-value: F(3,76) = 5.87, p = .004

    Minor

    The paper reports p = .004 here; recomputing from the test statistic and its degrees of freedom gives p = .001. The check cannot tell whether the statistic or the p-value is the misprint.

    Reported p = .004 · recomputed p = .001

  • p-value fits an unstated one-tailed test: t(19) = 1.63, p = .059

    Minor

    The paper reports p = .059 here; recomputing from the test statistic and its degrees of freedom gives p = .120 (two-tailed). The reported value is what a one-tailed test gives, but the paper does not say near this result that a one-tailed test was used.

    Reported p = .059 · recomputed p = .120

5 of 5

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Doesn’t add upF(3, 76) = 5.87reported p = .004 · recomputed p = .001

    “F(3,76) = 5.87, p = .004”

  • Doesn’t add upt(19) = 1.63reported p = .059 · recomputed p = .120

    “t(19) = 1.63, p = .059”

  • Doesn’t add upF(2, 54) = 0.0004reported p = .989 · recomputed p = 1.000

    “F(2,54) = 0.0004, p = .989”

  • Doesn’t add upF(1, 54) = 0.005reported p = .816 · recomputed p = .944

    “F(1,54) = 0.005, p = .816”

  • Doesn’t add upF(2, 54) = 0.006reported p = .942 · recomputed p = .994

    “F(2,54) = 0.006, p = .942”

  • ConsistentF(3, 76) = 5.14reported p = .003 · recomputed p = .003

    “F(3,76) = 5.14, p = .003”

  • Consistentt(19) = 2.42reported p = .026 · recomputed p = .026

    “t(19) = 2.42, p = .026”

  • Consistentt(19) = 1.94reported p = .067 · recomputed p = .067

    “t(19) = 1.94, p = .067”

  • Consistentt(19) = 2.88reported p = .01 · recomputed p = .010

    “t(19) = 2.88, p = .010”

  • Consistentt(19) = 2.14reported p = .046 · recomputed p = .046

    “t(19) = 2.14, p = .046”

  • ConsistentF(1, 3) = 54.64reported p = .005 · recomputed p = .005

    “F(1,3) = 54.64, p = .005”

  • ConsistentF(1, 4) = 39.05reported p = .003 · recomputed p = .003

    “F(1,4) = 39.05, p = .003”

  • ConsistentF(1, 4) = 97.15reported p < .001 · recomputed p < .001

    “F(1,4) = 97.15, p < .001”

  • Consistentr(8) = 0.88reported p < .001 · recomputed p < .001

    “r(8) = 0.88, p < .001”

  • Consistentr(8) = 0.15reported p = .673 · recomputed p = .679

    “r(8) = 0.15, p = .673”

  • Consistentr(8) = -0.17reported p = .632 · recomputed p = .639

    “r(8) = −0.17, p = .632”

  • ConsistentF(2, 552) = 19.2reported p < .001 · recomputed p < .001

    “F(2,552) = 19.2, p < .001”

  • ConsistentF(1, 546) = 8.9reported p = .003 · recomputed p = .003

    “F(1,546) = 8.9, p = .003”

  • ConsistentF(2, 546) = 13.6reported p < .001 · recomputed p < .001

    “F(2,546) = 13.6, p < .001”

  • ConsistentF(3, 76) = 1.1reported p = .364 · recomputed p = .354

    “F(3,76) = 1.1, p = .364”

  • ConsistentF(3, 76) = 0.84reported p = .474 · recomputed p = .476

    “F(3,76) = 0.84, p = .474”

  • Consistentt(18) = 0.78reported p = .447 · recomputed p = .446

    “t(18) = 0.78, p = .447”

  • Consistentt(18) = 1.35reported p = .193 · recomputed p = .194

    “t(18) = 1.35, p = .193”

  • ConsistentF(3, 72) = 5.6reported p = .002 · recomputed p = .002

    “F(3,72) = 5.6, p = .002”

  • ConsistentF(1, 72) = 0.17reported p = .679 · recomputed p = .681

    “F(1,72) = 0.17, p = .679”

  • ConsistentF(3, 72) = 0.91reported p = .442 · recomputed p = .441

    “F(3,72) = 0.91, p = .442”

  • ConsistentF(3, 72) = 5.3reported p = .002 · recomputed p = .002

    “F(3,72) = 5.3, p = .002”

  • ConsistentF(1, 72) = 1.03reported p = .314 · recomputed p = .314

    “F(1,72) = 1.03, p = .314”

  • ConsistentF(3, 72) = 0.62reported p = .603 · recomputed p = .604

    “F(3,72) = 0.62, p = .603”

  • Consistentt(18) = 1.19reported p = .249 · recomputed p = .250

    “t(18) = 1.19, p = .249”

  • Consistentt(18) = 0.41reported p = .686 · recomputed p = .687

    “t(18) = 0.41, p = .686”

  • ConsistentF(2, 54) = 11.2reported p < .0001 · recomputed p < .001

    “F(2,54) = 11.2, p < .0001”

  • ConsistentF(1, 54) = 0.82reported p = .368 · recomputed p = .369

    “F(1,54) = 0.82, p = .368”

  • ConsistentF(2, 54) = 11.9reported p < .0001 · recomputed p < .001

    “F(2,54) = 11.9, p < .0001”

34 of 34

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • OPRD1 is assigned two opioid receptor subtypes

    Minor

    The results identify OPRD1 as the δ-opioid receptor gene, but the methods identify the same gene as a σ-opioid receptor subtype.

1 of 1

Cites

Flagged first, then by citations

1 of the 75 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. RJ Bicknell, G Leng, Endogenous opiates regulate oxytocin but not vasopressin secretion from the neurohypophysis. Nature 298, 161–162 (1982). · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Dal Monte, O., Piva, M., Anderson, K. M., Tringides, M., Holmes, A. J., & Chang, S. W. C.
Affiliations
  • Department of Psychology, Yale University, New Haven, CT 06520;
  • Yale University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2017-05
Volume
114
Issue
20
Pages
5247-5252
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1702725114
PMC
PMC5441805
OpenAlex
W2611733573
Cited by
55
References
75
Citations by year
2026: 4 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 10 · 2021: 6 · 2020: 2 · 2019: 7 · 2018: 9 · 2017: 5
FWCI
9.00
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor, 184 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
Funders
  • Simons Foundation (365029)
  • Alfred P. Sloan Foundation (FG-2015-66028)
  • Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (PGSD3-471313-2015)
  • HHS | NIH | National Institute of Mental Health (R01MH110750, K01MH099232)
  • Georgian National Science Foundation (DGE-1122492)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Face Recognition and Perception
Keywords
oxytocin, opioid antagonism, naloxone, mu-opioid receptor, kappa opioid receptor, social attention, social cognition, eye contact, social dysfunction, genetic colocalization, primate social behavior
MeSH terms
Analgesics, Opioid, Animals, Attention, Behavior, Animal, Female, Fixation, Ocular, Macaca mulatta, Male, Naloxone, Narcotic Antagonists, Oxytocin, Social Behavior, Receptors, Opioid, mu, Receptors, Opioid, kappa, Receptors, Oxytocin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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

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

Statistics and arithmetic are recomputed, not judged.

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

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

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