Elsevier

Psychoneuroendocrinology

Volume 39, January 2014, Pages 237-248
Psychoneuroendocrinology

Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction

https://doi.org/10.1016/j.psyneuen.2013.09.022Get rights and content

Summary

Both oxytocin (OT) and vasopressin (AVP) are known to modulate social behavior, and dysfunction in both systems has been postulated as a potential cause of certain psychiatric disorders that involve social behavioral deficits. In particular, there is growing interest in intranasal OT as a potential treatment for certain psychiatric disorders, and preliminary pre-clinical and clinical studies suggest efficacy in alleviating some of the associated symptoms. However, the vast majority of research participants in these studies have been male, and there is evidence for sexually differentiated effects of nonapeptides in both humans and non-human animals. To date, no study has investigated the effect of intranasal OT on brain function in human males and females within the same paradigm. Previously, in a randomized, placebo-controlled, double-blind fMRI study, we reported effects of intranasal OT and AVP on behavior and brain activity of human males as they played an interactive social game known as the Prisoner's Dilemma Game. Here, we present findings from an identical study in human females, and compare these with our findings from males. Overall, we find that both behavioral and neural responses to intranasal OT and AVP are highly sexually differentiated. In women, AVP increased conciliatory behavior, and both OT and AVP caused women to treat computer partners more like humans. In men, AVP increased reciprocation of cooperation from both human and computer partners. However, no specific drug effects on behavior were shared between men and women. During cooperative interactions, both OT and AVP increased brain activity in men within areas rich in OT and AVP receptors and in areas playing a key role in reward, social bonding, arousal and memory (e.g., the striatum, basal forebrain, insula, amygdala and hippocampus), whereas OT and AVP either had no effect or in some cases actually decreased brain activity in these regions in women. OT treatment rendered neural responses of males more similar to responses of females in the placebo group and vice versa, raising the prospect of an inverted u-shaped dose response to central OT levels. These findings emphasize the need to fully characterize the effects of intranasal OT and AVP in both males and females and at multiple doses before widespread clinical application will be warranted.

Introduction

Both oxytocin (OT) and vasopressin (AVP) are known to modulate social behavior, and dysfunction in both systems has been postulated as a potential cause of various psychiatric disorders involving social behavioral deficits (Goodson and Thompson, 2010, Meyer-Lindenberg et al., 2011, Yamasue et al., 2009). There is growing interest in the use of intranasal oxytocin (OT) as a potential treatment for a variety of psychiatric disorders (Heinrichs et al., 2009, Meyer-Lindenberg et al., 2011, Striepens et al., 2011), including autism spectrum disorders (ASD), a group of neurodevelopmental disorders with an estimated prevalence of 1 per 88 children (Wingate et al., 2012). Oxytocin is implicated in a wide range of social functions, including functions specifically compromised in ASD. For example, among healthy male volunteers, intranasal OT administration increased gazing to the eye region of the face (Guastella et al., 2008). In another study of healthy male volunteers, intranasal OT improved accuracy in inferring mental states from the eye region of the face (Domes et al., 2007a, Domes et al., 2007b). Preliminary studies show that intranasal OT can indeed alleviate some social cognitive deficits found in ASD individuals, increasing gaze to the eye region of the face (Andari et al., 2010), improving performance on the Reading the Mind in the Eyes Task (Guastella et al., 2010), and biasing social interactions toward more cooperative social partners (Andari et al., 2010). Although there has been less research on intranasal AVP as a treatment for ASD, specific alleles of AVPR1a gene have been linked with ASD (Kim et al., 2002, Wassink et al., 2004), emphasizing the importance of studying the AVP system and its potential role in ASD as well. In addition to ASD, studies have begun to investigate the effectiveness of intranasal OT as a treatment for schizophrenia, social anxiety disorder and depression (Striepens et al., 2011).

Most research that has investigated the effects of intranasal OT on human social cognition and behavior has been conducted with male subjects. Studies with female subjects are complicated by the fact that estradiol, levels of which vary across the menstrual cycle, is known to induce OT receptors (Champagne et al., 2001, Pedersen et al., 1994) and presumably increase responsivity to OT. Given that ASD is more common in males (Wingate et al., 2012), studies investigating the effect of OT on ASD symptoms are also strongly biased toward males. In fact, across five such recently published studies, 71 of 78 participants were male (Anagnostou et al., 2012, Andari et al., 2010, Guastella et al., 2010, Hollander et al., 2003, Hollander et al., 2007).

Previously, we investigated the effects of intranasal OT and AVP on behavior and brain activity in human males (Rilling et al., 2012). Healthy normal men were randomized to treatment with intranasal OT, AVP or placebo (PL) and their brain activity was measured with fMRI as they played a social interactive task known as the Prisoners Dilemma (PD) game with assumed human and computer partners. The iterated Prisoner's Dilemma Game is a model for relationships based on reciprocal altruism (Axelrod and Hamilton, 1981, Trivers, 1971), that is able to probe psychological processes that are compromised in ASD, including the motivation to participate in mutually cooperative social interactions. OT was found to augment the caudate nucleus response to reciprocated cooperation from assumed human partners, raising the prospect that intranasal OT renders cooperative interactions more rewarding, and that it could potentially increase motivation of ASD subjects to engage with others (Stavropoulos and Carver, 2013). If implemented at an early age, this might facilitate greater attention to the social environment, augment social learning and help normalize the development of social behavior. OT also augmented activation of the left amygdala in response to reciprocated cooperation, another dopamine (DA) rich region. AVP treatment made men more likely to reciprocate cooperation and enhanced the neural response to cooperative intercations in a region spanning known vasopressin circuitry, including the bed nucleus of the stria terminalis (BNST), lateral septum and stria terminalis.

Here, we conduct a study of female subjects using the same paradigm. Among rodents, the social bonds supporting both maternal care and female adult partner preference are heavily dependent on interactions between OT and DA in the ventral striatum (Skuse and Gallagher, 2009, Young et al., 2005). We therefore predicted that OT would augment the ventral striatum response to cooperative social interactions to an even greater extent in females than we previously found for males. On the other hand, given evidence for sex differences in the response to AVP in both humans and rodents (Albers, 2012, Thompson et al., 2006), along with evidence that AVP is more influential in males compared with females (Young et al., 2005), we did not expect AVP to augment activation in BNST, lateral septum and stria terminalis in women as it did in men. Using a sequential-choice version of the PD game (as player 1), we focused on the neural correlates of (1) the realization that one's cooperation had been reciprocated (as player 1), and (2) the choice to cooperate (as player 2). This allowed us to examine both the reaction to (as player 1) and the anticipation of (as player 2) a mutually cooperative outcome. We find pronounced sex differences in the effects of OT and AVP on brain function and behavior, suggesting that pharmacologic manipulation of the OT and AVP systems to treat psychiatric disorders should be investigated in a sex-specific manner.

Section snippets

Subjects

After screening (see supplemental materials), 87 women between the ages of 18 and 22 years (mean = 20.4 years) from the Emory University campus were randomized to receive intranasal OT (n = 29), intranasal AVP (n = 29), or intranasal PL (n = 29). 4 subjects (AVP n = 1, OT n = 2, and PL n = 1) were excluded from the neuroimaging analysis due to excessive motion (>1.5 mm). Also, 10 subjects (AVP n = 0, OT n = 5, and PL n = 5) had only partial neuroimaging data due to excessive motion that occurred in a limited

Player 1 (see supplementary materials for additional information)

Drug treatment effects when playing with putative human partners: There were no effects of drug treatment on any outcome frequencies or any transition probabilities when playing with putative human partners (Fig. 2, supplementary Fig. 1).

Drug treatment effects when playing with computer partners: There were no effects of drug treatment on the frequency of CD or DC outcomes when playing with computer partners. However, subjects in the OT group (mean = 11.8) experienced 2.6 fewer CC outcomes than

Drug effects

There were two important sex differences in drug effects on behavior. First, AVP rendered men but not women more likely to reciprocate cooperation from human partners. In contrast, AVP did not increase cooperation in men following partner defection. This suggests that AVP may have an important role in inter-male cooperation, and that its effects may be context-dependent. These findings are consistent with a recent hypothesis that AVP-related peptides may function to offset male aggression in

Conclusion

Overall, OT and AVP had sexually differentiated effects on both behavior and brain activity. In women, AVP increased conciliatory behavior, and both OT and AVP caused women to treat computer partners more like humans. In men, AVP selectively increased reciprocation of cooperation from both human and computer partners. No common drug effects on behavior were found in both men and women. Although the main effect of reciprocated vs. unreciprocated cooperation (CC-CD) yielded very similar

Role of funding source

Supported by NIMH Grant R01 MH084068-01A1 and PHS Grant UL1 RR025008 from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources. Assay services were provided by the Biomarkers Core Laboratory at the Yerkes National Primate Research Center. This facility is supported by the Yerkes National Primate Research Center Base Grant 2P51RR000165-51.

Conflict of interest statement

None declared.

Acknowledgements

We thank Susan Rogers, Jianguo Xu, Elissar Andari and Elliott Albers for assistance with various aspects of this manuscript.

References (53)

  • G. Domes et al.

    Effects of intranasal oxytocin on emotional face processing in women

    Psychoneuroendocrinology

    (2010)
  • J.L. Goodson

    Deconstructing sociality, social evolution and relevant nonapeptide functions

    Psychoneuroendocrinology

    (2013)
  • J.L. Goodson et al.

    Nonapeptide mechanisms of social cognition, behavior and species-specific social systems

    Curr. Opin. Neurobiol.

    (2010)
  • A.J. Guastella et al.

    Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders.Biol

    Psychiatry

    (2010)
  • A.J. Guastella et al.

    Oxytocin increases gaze to the eye region of human faces

    Biol. Psychiatry

    (2008)
  • M. Heinrichs et al.

    Oxytocin, vasopressin, and human social behavior

    Front. Neuroendocrinol.

    (2009)
  • E. Hollander et al.

    Oxytocin increases retention of social cognition in autism

    Biol. Psychiatry

    (2007)
  • T.R. Insel

    The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior

    Neuron

    (2010)
  • S. Israel et al.

    Oxytocin, but not vasopressin, increases both parochial and universal altruism

    Psychoneuroendocrinology

    (2012)
  • F. Loup et al.

    Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain. An autoradiographic study

    Brain Res.

    (1991)
  • J.P. O’Doherty

    Reward representations and reward-related learning in the human brain: insights from neuroimaging

    Curr. Opin. Neurobiol.

    (2004)
  • J. Rilling et al.

    A neural basis for social cooperation

    Neuron

    (2002)
  • J.K. Rilling et al.

    Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men

    Psychoneuroendocrinology

    (2012)
  • I. Shalev et al.

    Vasopressin needs an audience: neuropeptide elicited stress responses are contingent upon perceived social evaluative threats [Controlled Clinical Trial Research Support, Non-U.S. Gov’t]

    Hormones and Behavior

    (2011)
  • D.H. Skuse et al.

    Dopaminergic–neuropeptide interactions in the social brain

    Trends Cogn. Sci.

    (2009)
  • S.M. Smith et al.

    Advances in functional and structural MR image analysis and implementation as FSL

    Neuroimage

    (2004)
  • Cited by (258)

    View all citing articles on Scopus
    View full text