Brain Imaging and Behavior

, Volume 9, Issue 4, pp 754–764 | Cite as

Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans

  • Chunliang Feng
  • Patrick D. Hackett
  • Ashley C. DeMarco
  • Xu Chen
  • Sabrina Stair
  • Ebrahim Haroon
  • Beate Ditzen
  • Giuseppe Pagnoni
  • James K. Rilling
Original Research


Recent research has examined the effects of oxytocin (OT) and vasopressin (AVP) on human social behavior and brain function. However, most participants have been male, while previous research in our lab demonstrated sexually differentiated effects of OT and AVP on the neural response to reciprocated cooperation. Here we extend our previous work by significantly increasing the number of participants to enable the use of more stringent statistical thresholds that permit more precise localization of OT and AVP effects in the brain. In a double-blind, placebo-controlled study, 153 men and 151 women were randomized to receive 24 IU intranasal OT, 20 IU intranasal AVP or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner’s Dilemma Game with same-sex partners. Sex differences were observed for effects of OT on the neural response to reciprocated cooperation, such that OT increased the caduate/putamen response among males, whereas it decreased this response among females. Thus, 24 IU OT may increase the reward or salience of positive social interactions among men, while decreasing their reward or salience among women. Similar sex differences were also observed for AVP effects within bilateral insula and right supramarginal gyrus when a more liberal statistical threshold was employed. While our findings support previous suggestions that exogenous nonapeptides may be effective treatments for disorders such as depression and autism spectrum disorder, they caution against uniformly extending such treatments to men and women alike.


Oxytocin Vasopressin fMRI Cooperation Sex differences 



We thank Susan Rogers, Jianguo Xu and Larry Young for assistance with various aspects of this study. This study was supported by National Institute of Mental Health [grant number R01 MH084068-01A1] and the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

Chunliang Feng, Patrick D. Hackett, Ashley C. DeMarco, Xu Chen, Sabrina Stair, Ebrahim Haroon, Beate Ditzen, Giuseppe Pagnoni and James K. Rilling declare that they have no conflict of interest.

Informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, and the applicable revisions at the time of the investigation. Informed consent was obtained from all subjects for being included in the study.

Supplementary material

11682_2014_9333_MOESM1_ESM.doc (1.4 mb)
ESM 1 (DOC 1.38 mb)


  1. Albers, H. E. (2012). The regulation of social recognition, social communication and aggression: vasopressin in the social behavior neural network. Hormones and Behavior, 61(3), 283–292.CrossRefPubMedGoogle Scholar
  2. Altemus, M., Jacobson, K. R., Debellis, M., Kling, M., Pigott, T., Murphy, D. L., et al. (1999). Normal CSF oxytocin and NPY levels in OCD. Biological Psychiatry, 45(7), 931–933.CrossRefPubMedGoogle Scholar
  3. Amodio, D. M., & Frith, C. D. (2006). Meeting of minds: the medial frontal cortex and social cognition. Nature Reviews Neuroscience, 7(4), 268–277.CrossRefPubMedGoogle Scholar
  4. Andari, E., Duhamel, J.-R., Zalla, T., Herbrecht, E., Leboyer, M., & Sirigu, A. (2010). Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proceedings of the National Academy of Sciences, 107(9), 4389–4394.CrossRefGoogle Scholar
  5. Avinun, R., Israel, S., Shalev, I., Gritsenko, I., Bornstein, G., Ebstein, R. P., et al. (2011). AVPR1A variant associated with preschoolers’ lower altruistic behavior. PloS One, 6(9), e25274.PubMedCentralCrossRefPubMedGoogle Scholar
  6. Bales, K. L., & Carter, C. S. (2003). Sex differences and developmental effects of oxytocin on aggression and social behavior in prairie voles (< i > Microtus ochrogaster</i>). Hormones and Behavior, 44(3), 178–184.CrossRefPubMedGoogle Scholar
  7. Bartz, J. A., Zaki, J., Bolger, N., & Ochsner, K. N. (2011). Social effects of oxytocin in humans: context and person matter. Trends in Cognitive Sciences, 15(7), 301–309.PubMedGoogle Scholar
  8. Boccia, M., Petrusz, P., Suzuki, K., Marson, L., & Pedersen, C. (2013). Immunohistochemical localization of oxytocin receptors in human brain. Neuroscience, 253, 155–164.CrossRefPubMedGoogle Scholar
  9. Campbell, A., Ruffman, T., Murray, J., & Glue, P. (2014). Oxytocin improves emotion recognition for older males. Neurobiology of Aging (ahead-of-print), 1–13.Google Scholar
  10. Cardoso, C., Ellenbogen, M. A., Orlando, M. A., Bacon, S. L., & Joober, R. (2013). Intranasal oxytocin attenuates the cortisol response to physical stress: a dose–response study. Psychoneuroendocrinology, 38(3), 399–407.CrossRefPubMedGoogle Scholar
  11. Cardoso, C., Orlando, M. A., Brown, C. A., & Ellenbogen, M. A. (2014). Oxytocin and enhancement of the positive valence of social affiliation memories: An autobiographical memory study. Social neuroscience (ahead-of-print), 1–10.Google Scholar
  12. Coccaro, E. F., Kavoussi, R. J., Hauger, R. L., Cooper, T. B., & Ferris, C. F. (1998). Cerebrospinal fluid vasopressin levels: correlates with aggression and serotonin function in personality-disordered subjects. Archives of General Psychiatry, 55(8), 708–714.CrossRefPubMedGoogle Scholar
  13. De Dreu, C. K. (2012). Oxytocin modulates the link between adult attachment and cooperation through reduced betrayal aversion. Psychoneuroendocrinology, 37(7), 871–880.CrossRefPubMedGoogle Scholar
  14. Ditzen, B., Schaer, M., Gabriel, B., Bodenmann, G., Ehlert, U., & Heinrichs, M. (2009). Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict. Biological Psychiatry, 65(9), 728–731.CrossRefPubMedGoogle Scholar
  15. Dodhia, S., Hosanagar, A., Fitzgerald, D. A., Labuschagne, I., Wood, A. G., Nathan, P. J., et al. (2014). Modulation of Resting-State Amygdala-Frontal Functional Connectivity by Oxytocin in Generalized Social Anxiety Disorder. Neuropsychopharmacology (ahead of print).Google Scholar
  16. Domes, G., Heinrichs, M., Michel, A., Berger, C., & Herpertz, S. C. (2007). Oxytocin improves “mind-reading” in humans. Biological Psychiatry, 61(6), 731–733.CrossRefPubMedGoogle Scholar
  17. Dumais, K. M., Bredewold, R., Mayer, T. E., & Veenema, A. H. (2013). Sex differences in oxytocin receptor binding in forebrain regions: correlations with social interest in brain region-and sex-specific ways. Hormones and Behavior, 64(4), 693–701.CrossRefPubMedGoogle Scholar
  18. Ebstein, R. P., Israel, S., Chew, S. H., Zhong, S., & Knafo, A. (2010). Genetics of human social behavior. Neuron, 65(6), 831–844.CrossRefPubMedGoogle Scholar
  19. Fischer-Shofty, M., Levkovitz, Y., & Shamay-Tsoory, S. G. (2013). Oxytocin facilitates accurate perception of competition in men and kinship in women. Social Cognitive and Affective Neuroscience, 8(3), 313–317.PubMedCentralCrossRefPubMedGoogle Scholar
  20. Goodson, J. L., & Thompson, R. R. (2010). Nonapeptide mechanisms of social cognition, behavior and species-specific social systems. Current Opinion in Neurobiology, 20(6), 784–794.CrossRefPubMedGoogle Scholar
  21. Gordon, I., Vander Wyk, B. C., Bennett, R. H., Cordeaux, C., Lucas, M. V., Eilbott, J. A., et al. (2013). Oxytocin enhances brain function in children with autism. Proceedings of the National Academy of Sciences, 110(52), 20953–20958.CrossRefGoogle Scholar
  22. Greve, D. N., & Fischl, B. (2009). Accurate and robust brain image alignment using boundary-based registration. NeuroImage, 48(1), 63–72.PubMedCentralCrossRefPubMedGoogle Scholar
  23. Guastella, A. J., Einfeld, S. L., Gray, K. M., Rinehart, N. J., Tonge, B. J., Lambert, T. J., et al. (2010a). Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biological Psychiatry, 67(7), 692–694.CrossRefPubMedGoogle Scholar
  24. Guastella, A. J., Kenyon, A. R., Alvares, G. A., Carson, D. S., & Hickie, I. B. (2010b). Intranasal arginine vasopressin enhances the encoding of happy and angry faces in humans. Biological Psychiatry, 67(12), 1220–1222.CrossRefPubMedGoogle Scholar
  25. Guastella, A. J., Kenyon, A. R., Unkelbach, C., Alvares, G. A., & Hickie, I. B. (2011). Arginine Vasopressin selectively enhances recognition of sexual cues in male humans. Psychoneuroendocrinology, 36(2), 294–297.CrossRefPubMedGoogle Scholar
  26. Güroğlu, B., van den Bos, W., van Dijk, E., Rombouts, S. A., & Crone, E. A. (2011). Dissociable brain networks involved in development of fairness considerations: understanding intentionality behind unfairness. NeuroImage, 57(2), 634–641.CrossRefPubMedGoogle Scholar
  27. Harlé, K. M., Chang, L. J., van’t Wout, M., & Sanfey, A. G. (2012). The neural mechanisms of affect infusion in social economic decision-making: a mediating role of the anterior insula. NeuroImage, 61(1), 32–40.CrossRefPubMedGoogle Scholar
  28. Heinrichs, M., von Dawans, B., & Domes, G. (2009). Oxytocin, vasopressin, and human social behavior. Frontiers in Neuroendocrinology, 30(4), 548–557.CrossRefPubMedGoogle Scholar
  29. Hoge, E. A., Anderson, E., Lawson, E. A., Bui, E., Fischer, L. E., Khadge, S. D., et al. (2014). Gender moderates the effect of oxytocin on social judgments. Human Psychopharmacology: Clinical and Experimental, 29(3), 299–304.CrossRefGoogle Scholar
  30. Jenkinson, M., Bannister, P., Brady, M., & Smith, S. (2002). Improved optimization for the robust and accurate linear registration and motion correction of brain images. NeuroImage, 17(2), 825–841.CrossRefPubMedGoogle Scholar
  31. King-Casas, B., Tomlin, D., Anen, C., Camerer, C. F., Quartz, S. R., & Montague, P. R. (2005). Getting to know you: reputation and trust in a two-person economic exchange. Science, 308(5718), 78–83.CrossRefPubMedGoogle Scholar
  32. Knafo, A., Israel, S., Darvasi, A., Bachner-Melman, R., Uzefovsky, F., Cohen, L., et al. (2008). Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA. Genes, Brain and Behavior, 7(3), 266–275.CrossRefGoogle Scholar
  33. Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U., & Fehr, E. (2005). Oxytocin increases trust in humans. Nature, 435(7042), 673–676.CrossRefPubMedGoogle Scholar
  34. Krueger, F., Grafman, J., & McCabe, K. (2008). Neural correlates of economic game playing. Philosophical Transactions of the Royal Society, B: Biological Sciences, 363(1511), 3859–3874.PubMedCentralCrossRefGoogle Scholar
  35. Labuschagne, I., Phan, K. L., Wood, A., Angstadt, M., Chua, P., Heinrichs, M., et al. (2010). Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder. Neuropsychopharmacology, 35(12), 2403–2413.PubMedCentralCrossRefPubMedGoogle Scholar
  36. Liu, Y., & Wang, Z. (2003). Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles. Neuroscience, 121(3), 537–544.CrossRefPubMedGoogle Scholar
  37. Loup, F., Tribollet, E., Dubois-Dauphin, M., & Dreifuss, J. (1991). Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain. An autoradiographic study. Brain Research, 555(2), 220–232.CrossRefPubMedGoogle Scholar
  38. Lynn, S. K., Hoge, E. A., Fischer, L. E., Barrett, L. F., & Simon, N. M. (2014). Gender differences in oxytocin-associated disruption of decision bias during emotion perception. Psychiatry Research (ahead of print), 1–22.Google Scholar
  39. Macdonald, K., & Feifel, D. (2013). Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders. Frontiers in Neuroscience, 7(35), 1–21.Google Scholar
  40. Marsh, A. A., Henry, H. Y., Pine, D. S., & Blair, R. (2010). Oxytocin improves specific recognition of positive facial expressions. Psychopharmacology, 209(3), 225–232.CrossRefPubMedGoogle Scholar
  41. Menon, V., & Uddin, L. Q. (2010). Saliency, switching, attention and control: a network model of insula function. Brain Structure and Function, 214(5–6), 655–667.PubMedCentralCrossRefPubMedGoogle Scholar
  42. Meyer-Lindenberg, A., Domes, G., Kirsch, P., & Heinrichs, M. (2011). Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nature Reviews Neuroscience, 12(9), 524–538.CrossRefPubMedGoogle Scholar
  43. Neumann, I. D., Maloumby, R., Beiderbeck, D. I., Lukas, M., & Landgraf, R. (2013). Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology, 38(10), 1985–1993.CrossRefPubMedGoogle Scholar
  44. Preckel, K., Scheele, D., Kendrick, K. M., Maier, W., & Hurlemann, R. (2014). Oxytocin facilitates social approach behavior in women. Frontiers in Behavioral Neuroscience, 8(191), 1–9.Google Scholar
  45. Rilling, J. K., & Sanfey, A. G. (2011). The neuroscience of social decision-making. Annual Review of Psychology, 62, 23–48.CrossRefPubMedGoogle Scholar
  46. Rilling, J. K., Gutman, D. A., Zeh, T. R., Pagnoni, G., Berns, G. S., & Kilts, C. D. (2002). A neural basis for social cooperation. Neuron, 35(2), 395–405.CrossRefPubMedGoogle Scholar
  47. Rilling, J. K., Sanfey, A. G., Aronson, J. A., Nystrom, L. E., & Cohen, J. D. (2004). The neural correlates of theory of mind within interpersonal interactions. NeuroImage, 22(4), 1694–1703.CrossRefPubMedGoogle Scholar
  48. Rilling, J. K., DeMarco, A. C., Hackett, P. D., Thompson, R., Ditzen, B., Patel, R., et al. (2012). Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men. Psychoneuroendocrinology, 37(4), 447–461.PubMedCentralCrossRefPubMedGoogle Scholar
  49. Rilling, J. K., DeMarco, A. C., Hackett, P. D., Chen, X., Gautam, P., Stair, S., et al. (2014). Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology, 39, 237–248.CrossRefPubMedGoogle Scholar
  50. Ross, H. E., & Young, L. J. (2009). Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior. Frontiers in Neuroendocrinology, 30(4), 534–547.PubMedCentralCrossRefPubMedGoogle Scholar
  51. Shahrestani, S., Kemp, A. H., & Guastella, A. J. (2013). The impact of a single administration of intranasal oxytocin on the recognition of basic emotions in humans: a meta-analysis. Neuropsychopharmacology, 38(10), 1929–1936.PubMedCentralCrossRefPubMedGoogle Scholar
  52. Skuse, D. H., & Gallagher, L. (2009). Dopaminergic-neuropeptide interactions in the social brain. Trends in Cognitive Science, 13(1), 27–35.CrossRefGoogle Scholar
  53. Smith, S. M. (2002). Fast robust automated brain extraction. Human Brain Mapping, 17(3), 143–155.CrossRefPubMedGoogle Scholar
  54. Sørensen, P., Gjerris, A., & Hammer, M. (1985). Cerebrospinal fluid vasopressin in neurological and psychiatric disorders. Journal of Neurology, Neurosurgery & Psychiatry, 48(1), 50–57.CrossRefGoogle Scholar
  55. Striepens, N., Kendrick, K. M., Maier, W., & Hurlemann, R. (2011). Prosocial effects of oxytocin and clinical evidence for its therapeutic potential. Frontiers in Neuroendocrinology, 32(4), 426–450.CrossRefPubMedGoogle Scholar
  56. Striepens, N., Kendrick, K. M., Hanking, V., Landgraf, R., Wüllner, U., Maier, W., et al. (2013). Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Scientific Reports, 3(3440), 1–5.Google Scholar
  57. Thompson, R., George, K., Walton, J., Orr, S., & Benson, J. (2006). Sex-specific influences of vasopressin on human social communication. Proceedings of the National Academy of Sciences, 103(20), 7889–7894.CrossRefGoogle Scholar
  58. Veenema, A. H., Bredewold, R., & De Vries, G. J. (2013). Sex-specific modulation of juvenile social play by vasopressin. Psychoneuroendocrinology, 38(11), 2554–2561.CrossRefPubMedGoogle Scholar
  59. Watanabe, T., Abe, O., Kuwabara, H., Yahata, N., Takano, Y., Iwashiro, N., et al. (2014). Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity: a randomized trial. JAMA Psychiatry, 71(2), 166–175.CrossRefPubMedGoogle Scholar
  60. Woo, C.-W., Krishnan, A., & Wager, T. D. (2014). Cluster-extent based thresholding in fMRI analyses: pitfalls and recommendations. NeuroImage, 91, 412–419.PubMedCentralCrossRefPubMedGoogle Scholar
  61. Woolrich, M. W., Ripley, B. D., Brady, M., & Smith, S. M. (2001). Temporal autocorrelation in univariate linear modeling of FMRI data. NeuroImage, 14(6), 1370–1386.CrossRefPubMedGoogle Scholar
  62. Young, L. J., Murphy Young, A. Z., & Hammock, E. A. (2005). Anatomy and neurochemistry of the pair bond. Journal of Comparative Neurology, 493(1), 51–57.CrossRefPubMedGoogle Scholar
  63. Zink, C. F., Pagnoni, G., Martin-Skurski, M. E., Chappelow, J. C., & Berns, G. S. (2004). Human striatal responses to monetary reward depend on saliency. Neuron, 42(3), 509–517.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Chunliang Feng
    • 1
  • Patrick D. Hackett
    • 1
  • Ashley C. DeMarco
    • 6
  • Xu Chen
    • 1
    • 2
  • Sabrina Stair
    • 2
  • Ebrahim Haroon
    • 2
  • Beate Ditzen
    • 2
    • 3
    • 7
  • Giuseppe Pagnoni
    • 8
  • James K. Rilling
    • 1
    • 2
    • 3
    • 4
    • 5
    • 9
  1. 1.Department of AnthropologyEmory UniversityAtlantaUSA
  2. 2.Department of Psychiatry and Behavioral SciencesEmory UniversityAtlantaUSA
  3. 3.Center for Behavioral NeuroscienceEmory UniversityAtlantaUSA
  4. 4.Yerkes National Primate Research CenterEmory UniversityAtlantaUSA
  5. 5.Center for Translational Social NeuroscienceEmory UniversityAtlantaUSA
  6. 6.Department of PsychologyUniversity of KansasLawrenceUSA
  7. 7.Department of PsychologyUniversity of ZurichZurichSwitzerland
  8. 8.Department of Neural, Biomedical, and Metabolic SciencesUniversity of Modena and Reggio EmiliaModenaItaly
  9. 9.Department of Anthropology, Department of Psychiatry and Behavioral SciencesEmory UniversityAtlantaUSA

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