Social Sciences

In the nose or on the tongue? Contrasting motivational effects of oral and intranasal oxytocin on arousal and reward during social processing

Written by Mamie M. Arndt
  • 1.

    Kendrick, K. M., Guastella, A. J., & Becker, B. in Behavioral Pharmacology of Neuropeptides: Oxytocin 321–348 (Springer, 2017).

  • 2.

    Young, L. J. & Barrett, C. E. Can oxytocin treat autism? Science 347, 825–826 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 3.

    Meyer-Lindenberg, A., Domes, G., Kirsch, P. & Heinrichs, M. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat. Rev. Neurosci. 12, 524–538 (2011).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 4.

    Leng, G. & Ludwig, M. Intranasal oxytocin: myths and delusions. Biol. Psychiatry 79, 243–250 (2016).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 5.

    Beard, R., Singh, N., Grundschober, C. D., Gee, A. W. & Tate, E. High-yielding 18 F radiosynthesis of a novel oxytocin receptor tracer, a probe for nose-to-brain oxytocin uptake in vivo. Chem. Commun. 54, 8120–8123 (2018).

    CAS 
    Article 

    Google Scholar
     

  • 6.

    Lee, M. R. et al. Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay. Mol. Psychiatry 23, 115–115 (2018).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 7.

    Lee, M. R. et al. Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques. Nat. Commun. 11, 2783 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 8.

    Modi, M. E., Connor-Stroud, F., Landgraf, R., Young, L. J. & Parr, L. A. Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology 45, 49–57 (2014).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 9.

    Neumann, I. D., Maloumby, R., Beiderbeck, D. I., Lukas, M. & Landgraf, R. Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology 38, 1985–1993 (2013).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 10.

    Smith, A. S., Korgan, A. C. & Young, W. S. Oxytocin delivered nasally or intraperitoneally reaches the brain and plasma of normal and oxytocin knockout mice. Pharmacol. Res. 146, 104324 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 11.

    Paloyelis, Y. et al. A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans. Biol. Psychiatry 79, 693–705 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 12.

    Martins, D. A. et al. Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans. Nat. Commun. 11, 1160 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 13.

    Striepens, N. et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci. Rep. 3, 3440 (2013).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 14.

    Quintana, D. S. et al. Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research. Mol. Psychiatry 26, 1–12, https://doi.org/10.1038/s41380-020-00864-7 (2020).

    CAS 
    Article 

    Google Scholar
     

  • 15.

    Yamamoto, Y. RAGE regulates oxytocin transport into the brain. Commun. Biol. 3, 1–4 (2020).

    Article 

    Google Scholar
     

  • 16.

    Yamamoto, Y. et al. Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice. Commun. Biol. 2, https://doi.org/10.1038/s42003-019-0325-6 (2019).

  • 17.

    Carter, C. S. Oxytocin pathways and the evolution of human behavior. Annu. Rev. Psychol. 65, 17–39 (2014).

    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 18.

    Ring, R. H. et al. Anxiolytic-like activity of oxytocin in male mice: Behavioral and autonomic evidence, therapeutic implications. Psychopharmacology 185, 218–225 (2006).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 19.

    Sakamoto, T., Sugimoto, S. & Uekita, T. Effects of intraperitoneal and intracerebroventricular injections of oxytocin on social and emotional behaviors in pubertal male mice. Physiol. Behav. 212 (2019).

  • 20.

    Mens, W. B. J., Witter, A. & Van Wimersma Greidanus, T. B. Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): Half-times of disappearance of these neuropeptides from CSF. Brain. Res. 262, 143–149 (1983).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 21.

    Ermisch, A. et al. On the blood-brain barrier to peptides: accumulation of labelled vasopressin, DesGlyNH2-vasopressin and oxytocin by brain regions. Endocrinol. Exp. 19, 29–37 (1985).

    CAS 
    PubMed 

    Google Scholar
     

  • 22.

    Ferris, C. F. et al. Distinct BOLD Activation Profiles Following Central and Peripheral Oxytocin Administration in Awake Rats. Front. Behav. Neurosci. 9, https://doi.org/10.3389/fnbeh.2015.00245 (2015).

  • 23.

    Dumais, K. M., Kulkarni, P. P., Ferris, C. F. & Veenema, A. H. Sex differences in neural activation following different routes of oxytocin administration in awake adult rats. Psychoneuroendocrinology 81, 52–62 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 24.

    Galbusera, A. et al. Intranasal oxytocin and vasopressin modulate divergent brainwide functional substrates. Neuropsychopharmacology 42, 1420–1434 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 25.

    Hollander, E. et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology 28, 193–198 (2003).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 26.

    Hollander, E. et al. Oxytocin increases retention of social cognition in autism. Biol. Psychiatry 61, 498–503 (2007).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 27.

    Quintana, D. S. et al. Low dose intranasal oxytocin delivered with Breath Powered device dampens amygdala response to emotional stimuli: a peripheral effect-controlled within-subjects randomized dose-response fMRI trial. Psychoneuroendocrinology 69, 180–188 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 28.

    Daughters, K. et al. Salivary oxytocin concentrations in males following intranasal administration of oxytocin: a double-blind, cross-over study. PLoS ONE 10, e0145104 (2015).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 29.

    van IJzendoorn, M. H., Bhandari, R., van der Veen, R., Grewen, K. M. & Bakermans-Kranenburg, M. J. Elevated salivary levels of oxytocin persist more than 7 h after intranasal administration. Front. Neurosci. 6, 174 (2012).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • 30.

    Quintana, D. S. et al. Saliva oxytocin measuresDESP do not reflect peripheral plasma concentrations after intranasal oxytocin administration in men. Horm. Behav. 102, 85–92 (2018).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 31.

    Takeda, S., Kuwabara, Y. & Mizuno, M. Concentrations and origin of oxytocin in breast milk. Endocrinol. Jpn. 33, 821–826 (1986).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 32.

    Petersson, M., Hulting, A. L., Andersson, R. & Uvnäs-Moberg, K. Long-term changes in gastrin, cholecystokinin and insulin in response to oxytocin treatment. Neuroendocrinology 69, 202–208 (1999).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 33.

    Maejima, Y. et al. Oral oxytocin delivery with proton pump inhibitor pretreatment decreases food intake. Peptides 128, 170312 (2020).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 34.

    Groot, A. N. J. A. D. et al. Bioavailability and pharmacokinetics of sublingual oxytocin in male volunteers. J. Pharm. Pharmacol. 47, 571–575 (1995).

    PubMed 
    Article 

    Google Scholar
     

  • 35.

    Kou, J. et al. A randomized trial shows dose-frequency and genotype may determine the therapeutic efficacy of intranasal oxytocin. Psychol. Med. 10, 1–10, https://doi.org/10.3389/fnbeh (2020).

    Article 

    Google Scholar
     

  • 36.

    Kirsch, P. Oxytocin modulates neural circuitry for social cognition and fear in humans. J. Neurosci. 25, 11489–11493 (2005).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 37.

    Koch, S. B. J. et al. Intranasal oxytocin normalizes amygdala functional connectivity in posttraumatic stress disorder. Neuropsychopharmacology 41, 2041–2051 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 38.

    Domes, G. et al. Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol. Psychiatry 62, 1187–1190 (2007).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 39.

    Spengler, F. B. et al. Kinetics and dose dependency of intranasal oxytocin effects on amygdala reactivity. Biol. Psychiatry 82, 885–894 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 40.

    Power, J. D., Barnes, K. A., Snyder, A. Z., Schlaggar, B. L. & Petersen, S. E. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. NeuroImage 59, 2142–2154 (2012).

    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 41.

    Watson, D., Clark, L. A. & Tellegen, A. Development and validation of brief measures of positive and negative affect: the PANAS scales. J. Pers. Soc. Psychol. 54, 1063–1070 (1988).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 42.

    Friston, K. J. et al. Statistical parametric maps in functional imaging: a general linear approach. Hum. Brain Mapp. 2, 189–210 (1994).

    Article 

    Google Scholar
     

  • 43.

    Flandin, G. & Friston, K. J. Analysis of family-wise error rates in statistical parametric mapping using random field theory. Hum. Brain Mapp. 40, 2052–2054 (2019).

    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 44.

    Woo, C. W., Krishnan, A. & Wager, T. D. Cluster-extent based thresholding in fMRI analyses: Pitfalls and recommendations. NeuroImage 91, 412–419 (2014).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 45.

    McCullough, M. E., Churchland, P. S. & Mendez, A. J. Problems with measuring peripheral oxytocin: Can the data on oxytocin and human behavior be trusted? Neurosci. Biobehav. Rev. 37, 1485–1492 (2013).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 46.

    Noguchi, K., Gel, Y. R., Brunner, E. & Konietschke, F. nparLD: an R software package for the nonparametric analysis of longitudinal data in factorial experiments. J. Stat. Softw. 50 (2012).

  • 47.

    Cramer, A. O. J. et al. Hidden multiplicity in exploratory multiway ANOVA: prevalence and remedies. Psychon. Bull. Rev. 23, 640–647 (2016).

    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 48.

    Cooper, H. & Hedges, L. V. The Handbook of Research Synthesis 1560–1562 (Russell Sage Foundation, 1994).

  • 49.

    Coolican, H. Research Methods and Statistics in Psychology (Routledge, 2018).

  • 50.

    Preacher, K. J. & Hayes, A. F. Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav. Res. Methods 40, 879–891 (2008).

    PubMed 
    Article 

    Google Scholar
     

  • 51.

    Fan, L. et al. The human brainnetome atlas: a new brain atlas based on connectional architecture. Cereb. Cortex 26, 3508–3526 (2016).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 52.

    Jurek, B. & Neumann, I. D. The oxytocin receptor: from intracellular signaling to behavior. Physiol. Rev. 98, 1805–1908 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 53.

    Li, K., Nakajima, M., Ibañez-Tallon, I. & Heintz, N. A cortical circuit for sexually dimorphic oxytocin-dependent anxiety behaviors. Cell 167, 60–72 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 54.

    Borland, J. M., Rilling, J. K., Frantz, K. J. & Albers, H. E. Sex-dependent regulation of social reward by oxytocin: an inverted U hypothesis. Neuropsychopharmacology 44, 97–110 (2019).

    PubMed 
    Article 

    Google Scholar
     

  • 55.

    Gao, S. et al. Oxytocin, the peptide that bonds the sexes also divides them. PNAS 113, 7650–7654 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 56.

    Lieberz, J. et al. Kinetics of oxytocin effects on amygdala and striatal reactivity vary between women and men. Neuropsychopharmacology 45, 1134–1140 (2019).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • 57.

    Luo, L. et al. Sex-dependent neural effect of oxytocin during subliminal processing of negative emotion faces. NeuroImage 162, 127–137 (2017).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • About the author

    Mamie M. Arndt