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Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction
Open accessAbstract
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.
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“Sex differences were also found for the effect of OT on brain activation during reciprocated cooperation.”
From Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior (2016) · cites this paper as Rilling et al., 2014
In the citing paper
“This bias can be observed in much of the prior work on oxytocin in humans as well, with some neuroimaging studies indicating potential differences in the oxytocin system between sexes.13, 14, 47, 48, 49”
From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [48]
In the citing paper
“This bias can be observed in much of the prior work on oxytocin in humans as well, with some neuroimaging studies indicating potential differences in the oxytocin system between sexes.13, 14, 47, 48, 49”
From Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women (2017) · cites this paper as [48]
In the citing paper
“These data have, however, found OT and AVP can have differential effects on neural activity (i.e., BOLD fMRI responses) and cognition, at least in some cases although the effects of OT are more robust [84; 86; 87; 88; 89; 90].”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [88]
In the citing paper
“The few studies that have compared the effects of intranasally administered OT and AVP in humans have reported that these peptides do not have opposing roles.”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [88]
In the citing paper
“In humans, intranasal VP had sex-specific effects during social communication and cooperation interactions”
From Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior (2016) · cites this paper as Rilling et al., 2014
In the citing paper
“Intranasal OT increased the caudate/putamen response in males, whereas it decreased this response in females (Rilling et al., 2014).”
From Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior (2016) · cites this paper as Rilling et al., 2014
In the citing paper
“previous research has shown that oxytocin effects can vary as a function of emotion regulation skills (Quirin et al., 2011), social context history of childhood maltreatment (Ebert et al., 2013; Flanagan et al., 2015), and sex (Ditzen et al., 2012; Rilling et al., 2014).”
From Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial (2018) · cites this paper as Rilling et al., 2014
In the citing paper
“In healthy individuals, OT effects seem to follow an inverted u-shape (Rilling et al, 2014), with doses ~24 IU, resulting in more anxiolytic effects than higher doses of OT (Cardoso et al, 2013).”
From Intranasal oxytocin administration dampens amygdala reactivity towards emotional faces in male and female PTSD patients (2016) · cites this paper as Rilling et al, 2014
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Citations
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MethodSelf-citation
Cited by
Sorted by citations
Empathy: Gender effects in brain and behavior
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“Importantly, both OT and AVP increased activity in males during cooperation, while in females, OT and AVP either decreased activity or had no effect in these and other regions (Rilling et al., 2014).”
BackgroundThe Social Salience Hypothesis of Oxytocin
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“Intranasal VP increased activity in areas such as the striatum, basal forebrain, insula, amygdala, and hippocampus in men, but decreased or had no effect in women (Rilling et al., 2012; 2014).”
BackgroundInfluential
Metadata
- Authors
- Rilling, J. K., DeMarco, A. C., Hackett, P. D., Chen, X., Gautam, P., Stair, S., Haroon, E., Thompson, R., Ditzen, B., Patel, R., & Pagnoni, G.
- Affiliations
- Emory University (US)
- University of Kansas (US)
- Bowdoin College (US)
- University of Modena and Reggio Emilia (IT)
- Corresponding author
- Rilling, James K.
- ORCID
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 39
- Pages
- 237-248
- ISSN
- 0306-4530 (ISSN-L)
- PMC
- PMC3842401
- OpenAlex
- W2129575907
- Cited by
- 343
- References
- 54
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 13 · 2023: 16 · 2022: 19 · 2021: 38 · 2020: 35 · 2019: 50 · 2018: 35 · 2017: 35 · 2016: 32 · 2015: 28 · 2014: 17
- FWCI
- 38.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Funders
- National Institute of Mental Health (R01 MH084068-01A1)
- National Center for Research Resources
- Yerkes Regional Primate Research Center (2P51RR000165-51)
- National Institutes of Health
- Presbyterian Historical Society (UL1 RR025008)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- oxytocin, vasopressin, sex differences, intranasal administration, social interaction, prisoner's dilemma game, cooperation, conciliation, social bonding, reward processing, brain activity, nonapeptide, mental illness
- MeSH terms
- Administration, Intranasal, Adolescent, Arginine Vasopressin, Brain, Cooperative Behavior, Double-Blind Method, Female, Game Theory, Humans, Image Processing, Computer-Assisted, Interpersonal Relations, Magnetic Resonance Imaging, Male, Oxytocin, Sex Characteristics, Social Behavior, Young Adult, Functional Neuroimaging
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