Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men
Introduction
In nature, the paradigmatic social bond is that between mother and offspring. Research with animal models implicates both the oxytocin (OT) and dopamine (DA) systems in the establishment and maintenance of maternal attachment and caregiving. OT enables mothers to overcome avoidance of proximity to offspring and, together with dopamine, may render maternal caregiving rewarding (Swain et al., 2007, Insel, 2010). The OT and DA systems interact in the ventral striatum, implicating the latter in maternal motivation (Skuse and Gallagher, 2009, Strathearn et al., 2009). This mechanism also appears to mediate female attachment to adult male partners in pair-bonding voles (Liu and Wang, 2003, Young et al, 2005) and possibly humans (Bartels and Zeki, 2004, Aron et al., 2005, Fisher et al., 2005), prompting the suggestion that modification of neural systems involved in maternal care is a parsimonious mechanism for the evolution of adult female pair-bonding (Ross and Young, 2009).
Non-reproductive social bonds between unrelated adults have been less thoroughly investigated; however, similar mechanisms may be involved. Reciprocated cooperation from adult strangers activates the caudate nucleus (Rilling et al., 2002, Rilling et al., 2004, Delgado et al., 2005), a region known to receive DA projections from the midbrain, and caudate activation predicts future reciprocity (King-Casas et al., 2005). Intranasal OT is associated with increased trust (Kosfeld et al., 2005, Baumgartner et al., 2008, Andari et al., 2010), and a recent study presented evidence suggesting that OT mediates bonding among men in groups (De Dreu et al., 2010). Thus, OT and DA may interact to support bonds among adult men. Here, we administered OT to men as they played an iterated Prisoner's Dilemma (PD) game to determine if OT would augment activation in the caudate nucleus in response to reciprocated cooperation.
OT appears to reduce the salience of negative social stimuli and increase the salience of positive social stimuli (Heinrichs et al., 2003, Baumgartner et al., 2008, Guastella et al., 2008, Petrovic et al., 2008, Unkelbach et al., 2008, Heinrichs et al., 2009, Theodoridou et al., 2009, Gamer et al., 2010). Recent studies have revealed a potential neural mechanism for these effects. OT decreases the amygdala response to aversive social stimuli in men (Kirsch et al., 2005, Domes et al., 2007, Baumgartner et al., 2008, Petrovic et al., 2008, Gamer et al., 2010). Domes et al. (2007) also showed that OT decreased amygdala activation to all emotional face stimuli (including happy faces) in the right amygdala, and a recent study showed that OT increased amygdala activation to happy faces in the left amygdala (Gamer et al., 2010). Collectively, these studies led us to the prediction that OT would decrease the right amygdala response to unreciprocated cooperation (an aversive social stimulus), and perhaps also reciprocated cooperation, whereas OT would increase the left amygdala response to reciprocated cooperation.
While OT is anxiolytic, AVP is anxiogenic (Heinrichs et al., 2009) and may play a role in inter-male aggressive communication (Thompson et al., 2004, Thompson et al., 2006). Polymorphisms of the V1a vasopressin receptor (AVPR1a) have been linked with differences in amygdala responses to emotional facial expressions (Meyer-Lindenberg et al., 2009). Consequently, we predicted that AVP administration would be associated with increased amygdala activation and decreased rates of cooperation in our sample of male subjects.
Finally, we hypothesized that neuropeptide effects on behavior and brain activity would be specific to interactions with assumed human partners and would not be observed for interactions with known computer partners. Importantly, this is the first study to simultaneously test the effects of both OT and AVP on behavior and brain activation in a social interactive context.
Section snippets
Subjects
91 men from the Emory University community between the ages of 18 and 22 (mean = 20.2) were randomized to receive intranasal OT (n = 27), intranasal AVP (n = 27) or intranasal placebo (n = 36). Five subjects (AVP n = 2, OT n = 1, and placebo n = 2) were excluded from the neuroimaging analysis due to excessive motion (>1.3 mm) (n = 3) or to missing data (n = 2). One subject was excluded from the behavioral analysis due to missing data. All potential subjects completed a full medical history questionnaire. Subjects
Plasma levels of AVP and OT
Plasma AVP levels were higher in the AVP group (4.5 pg/ml, ±0.49 pg/ml) than the placebo group (3.1 pg/ml, ±0.40 pg/ml) by an average of 1.4 pg/ml (t(31) = 2.15, p = 0.04). However plasma AVP levels were not significantly higher in the AVP group compared with the OT group (3.5 pg/ml, ±0.34 pg/ml). Plasma OT levels were not significantly higher in the OT group (134.7 pg/ml, ±10.2 pg/ml) compared with either the placebo (129.4 pg/ml, ±12.2 pg/ml) or the AVP group (120.6 pg/ml, ±7.3 pg/ml).
PANAS
The Positive and
OT effects on brain and behavior
In the iterated PD game, players must learn whether they can trust their partners. The human caudate nucleus tracks a social partner's decision to reciprocate or not reciprocate cooperation in trust or PD games (Rilling et al., 2002, Rilling et al., 2004, Delgado et al., 2005, King-Casas et al., 2005). Specifically, reciprocated cooperation activates the caudate nucleus, and caudate activation is associated with increased future reciprocity (Rilling et al., 2002, King-Casas et al., 2005). Thus,
Role of funding source
Funding for this study was provided by NIMH Grant R01 MH084068-01A1; the NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Conflict of interest
None declared.
Acknowledgements
We thank Paula Kincheloe, Karl Fernstrom, James Ritchie, Susan Rogers, Jianguo Xu and Larry Young for assistance with various aspects of this experiment.
Contributors: James K. Rilling designed the study, supervised data acquisition and analysis, and wrote the paper. Ashley DeMarco and Patrick Hackett collected and analyzed the data. Richmond Thompson, Beate Ditzen and Giuseppe Pagnoni advised with respect to study design and interpretation of results, and assisted with writing the paper. Rajan
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