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

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Abstract

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.

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References

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Amodio, D. M., & Frith, C. D. (2006). Meeting of minds: the medial frontal cortex and social cognition. Nature Reviews Neuroscience, 7(4), 268–277.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Boccia, M., Petrusz, P., Suzuki, K., Marson, L., & Pedersen, C. (2013). Immunohistochemical localization of oxytocin receptors in human brain. Neuroscience, 253, 155–164.

    Article  CAS  PubMed  Google Scholar 

  • Campbell, A., Ruffman, T., Murray, J., & Glue, P. (2014). Oxytocin improves emotion recognition for older males. Neurobiology of Aging (ahead-of-print), 1–13.

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • De Dreu, C. K. (2012). Oxytocin modulates the link between adult attachment and cooperation through reduced betrayal aversion. Psychoneuroendocrinology, 37(7), 871–880.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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).

  • Domes, G., Heinrichs, M., Michel, A., Berger, C., & Herpertz, S. C. (2007). Oxytocin improves “mind-reading” in humans. Biological Psychiatry, 61(6), 731–733.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Ebstein, R. P., Israel, S., Chew, S. H., Zhong, S., & Knafo, A. (2010). Genetics of human social behavior. Neuron, 65(6), 831–844.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Greve, D. N., & Fischl, B. (2009). Accurate and robust brain image alignment using boundary-based registration. NeuroImage, 48(1), 63–72.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Heinrichs, M., von Dawans, B., & Domes, G. (2009). Oxytocin, vasopressin, and human social behavior. Frontiers in Neuroendocrinology, 30(4), 548–557.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U., & Fehr, E. (2005). Oxytocin increases trust in humans. Nature, 435(7042), 673–676.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

  • 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 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

  • Rilling, J. K., & Sanfey, A. G. (2011). The neuroscience of social decision-making. Annual Review of Psychology, 62, 23–48.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Skuse, D. H., & Gallagher, L. (2009). Dopaminergic-neuropeptide interactions in the social brain. Trends in Cognitive Science, 13(1), 27–35.

    Article  CAS  Google Scholar 

  • Smith, S. M. (2002). Fast robust automated brain extraction. Human Brain Mapping, 17(3), 143–155.

    Article  PubMed  Google Scholar 

  • Sørensen, P., Gjerris, A., & Hammer, M. (1985). Cerebrospinal fluid vasopressin in neurological and psychiatric disorders. Journal of Neurology, Neurosurgery & Psychiatry, 48(1), 50–57.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • Veenema, A. H., Bredewold, R., & De Vries, G. J. (2013). Sex-specific modulation of juvenile social play by vasopressin. Psychoneuroendocrinology, 38(11), 2554–2561.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Anthropology, Emory University, Atlanta, GA, USA

    Chunliang Feng, Patrick D. Hackett, Xu Chen & James K. Rilling

  2. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA

    Xu Chen, Sabrina Stair, Ebrahim Haroon, Beate Ditzen & James K. Rilling

  3. Center for Behavioral Neuroscience, Emory University, Atlanta, GA, USA

    Beate Ditzen & James K. Rilling

  4. Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA

    James K. Rilling

  5. Center for Translational Social Neuroscience, Emory University, Atlanta, GA, USA

    James K. Rilling

  6. Department of Psychology, University of Kansas, Lawrence, KS, USA

    Ashley C. DeMarco

  7. Department of Psychology, University of Zurich, Zurich, Switzerland

    Beate Ditzen

  8. Department of Neural, Biomedical, and Metabolic Sciences, University of Modena and Reggio Emilia, Modena, Italy

    Giuseppe Pagnoni

  9. Department of Anthropology, Department of Psychiatry and Behavioral Sciences, Emory University, 1557 Dickey Drive, Atlanta, GA, 30322, USA

    James K. Rilling

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  1. Chunliang Feng
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Feng, C., Hackett, P.D., DeMarco, A.C. et al. Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans. Brain Imaging and Behavior 9, 754–764 (2015). https://doi.org/10.1007/s11682-014-9333-9

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