The neural mechanisms supporting social bonds between adult men remain uncertain. In this double-blind, placebo-controlled study, we investigate the impact of intranasally administered oxytocin (OT) and vasopressin (AVP) on behavior and brain activity among men in the context of an iterated Prisoner’s Dilemma game, which models a real-life social situation. fMRI results show that, relative to both AVP and placebo, OT increases the caudate nucleus response to reciprocated cooperation, which may augment the reward of reciprocated cooperation and/or facilitate learning that another person can be trusted. OT also enhances left amygdala activation in response to reciprocated cooperation. Behaviorally, OT was associated with increased rates of cooperation following unreciprocated cooperation in the previous round compared with AVP. AVP strongly increased cooperation in response to a cooperative gesture by the partner compared with both placebo and OT. In response to reciprocated cooperation, AVP increased activation in a region spanning known vasopressin circuitry implicated in affiliative behaviors in other species. Finally, both OT and AVP increase amygdala functional connectivity with the anterior insula relative to placebo, which may increase the amygdala’s ability to elicit visceral somatic markers that guide decision making. These findings extend our knowledge of the neural and behavioral effects of OT and AVP to the context of genuine social interactions.

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 preclinical 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, placebocontrolled, 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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Arginine vasopressin (AVP) and related peptides affect social behaviors in numerous species, but AVP influences on human social functions have not yet been established. Here, we describe how intranasal AVP administration differentially affects social communication in men and women, and we propose a mechanism through which it may exert those influences. In men, AVP stimulates agonistic facial motor patterns in response to the faces of unfamiliar men and decreases perceptions of the friendliness of those faces. In contrast, in women, AVP stimulates affiliative facial motor patterns in response to the faces of unfamiliar women and increases perceptions of the friendliness of those faces. AVP also affected autonomic responsiveness to threatening faces and increased anxiety, which may underlie both communication patterns by promoting different social strategies in stressful contexts in men and women.affiliation ͉ aggression ͉ anxiety ͉ autism ͉ emotion C entral arginine vasopressin (AVP; mammals) and arginine vasotocin (AVT; nonmammalian homologue) systems modulate social behaviors in numerous species from diverse vertebrate groups (1). It has therefore been proposed that social functions of these peptides were highly conserved during vertebrate evolution and, if retained in humans, that variations in the AVP system may be related to individual differences in sociality in our own species, particularly aggressive (2) and͞or affiliative (3, 4) tendencies. It has even been hypothesized that extreme variations in the AVP system may be related to the social dysfunctions associated with autism (5-7).Among the social processes most consistently influenced by AVP and AVT in animal models are those related to social communication, particularly the generation of, and͞or responses to, stereotypical signals associated with courtship and aggression. In humans, facial expressions are associated with such forms of emotional communication (8), so we predicted that AVP would influence the motor patterns associated with facial responses to social stimuli, particularly in men, because AVP͞ AVT systems are most often associated with the regulation of male-typical patterns of social communication (1). Indeed, in a preliminary study, we showed that electromyographic (EMG) responses of the corrugator supercilii, which are associated with threat (9), are increased in men by intranasal AVP administration (10). However, we do not yet know whether AVP also modulates social communication in women, which is an intriguing possibility because sexual dimorphisms typical of AVP͞AVT systems in other species in which males have more AVP͞AVT-producing cells and͞or fiber projections have not been detected in human brains (11). We also do not yet know whether AVP can influence social cognition as well as facial motor patterns related to social communication, nor anything about the mechanisms through which AVP may affect social communication in humans.To address these fundamental questions and to determine how rapidly social processes are affected by intr...

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