Sex-dependent regulation of social reward by oxytocin: an inverted U hypothesis

Abstract

The rewarding properties of social interactions are essential for the expression of social behavior and the development of adaptive social relationships. Here, we review sex differences in social reward, and more specifically, how oxytocin (OT) acts in the mesolimbic dopamine system (MDS) to mediate the rewarding properties of social interactions in a sex-dependent manner. Evidence from rodents and humans suggests that same-sex social interactions may be more rewarding in females than in males. We propose that there is an inverted U relationship between OT dose, social reward, and neural activity within structures of the MDS in both males and females, and that this dose-response relationship is initiated at lower doses in females than males. As a result, depending on the dose of OT administered, OT could reduce social reward in females, while enhancing it in males. Sex differences in the neural mechanisms regulating social reward may contribute to sex differences in the incidence of a large number of psychiatric and neurodevelopmental disorders. This review addresses the potential significance of a sex-dependent inverted U dose-response function for OT's effects on social reward and in the development of gender-specific therapies for these disorders.

Fig. 1

Activation of oxytocin (OT) immunoreactive (ir) neurons (green) (as indicated by colocalization with cfos-ir (red)) in the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) of the hypothalamus 1 h after 10 min same-sex social interactions in Syrian male and female hamsters. a Representative image of OT-ir neurons in the PVN, b double labeling of OT- and fos-ir in the PVN of a male hamster, c double labeling of OT- and fos-ir in the PVN of a female hamster, d representative image of OT-ir neurons in the SON, e double labeling of OT- and fos-ir in the SON of a male hamster, and f double labeling of OT- and fos-ir in the SON of a female hamster. Neuronal activity in OT-ir neurons is increased in the PVN and SON of both male and female hamsters following the 10 min social interaction, although no sex differences were observed in the number of OT-ir-activated neurons (Borland and Albers, unpublished). White arrows illustrate examples of the colocalization of OT- and fos-ir

Fig. 2

a Injections of Fluorogold in the nucleus accumbens resulted in retrograde labeling of neurons in the ventral tegmental area in male rats. These neurons were colocalized with tyrosine hydroxylase (TH)-immunoreactive neurons. Of these colocalized Fluorogold and TH-labeled neurons, one-third had oxytocin (OT) immunoreactive axons impinging or in close apposition. b Injections of oxy into the caudal VTA resulted in an increase in dopamine efflux in the nucleus accumbens in male rats, and this effect was attenuated when oxytocin was co-injected with an oxytocin receptor antagonist (OT Ant.) Scale bar is 20 μm. Reproduced from ref. [95]

Fig. 3

a Over a range of current intensities, electrical stimulation of the medial forebrain bundle resulted in greater extracellular dopamine in the caudate nucleus of female rats compared to males [102]. b Administration of 40 mg/kg cocaine i.p. resulted in a greater increase in evoked extracellular dopamine in the striatum in female rats compared to males. Reproduced from ref. [104]

Fig. 4

Female Syrian hamsters find same-sex social interactions more rewarding than males. a Female hamsters displayed a greater social preference score (time spent in the social interaction associated chambers minus the time spent in the no social interaction chambers) following social conditioning sessions in a conditioned place preference test compared to males (* indicates significant differences p < 0.05). b Female hamsters also displayed a greater social preference score (the number of entries into chambers containing same-sex stimulus hamsters minus the number of entries into the empty chambers) in the operant social preference task compared to males. c Hypothesis of the inverted U dose–response function of the relationship between social reward value and the dose (e.g., duration) of same-sex social interaction in males and females. Females are predicted to be more sensitive to the rewarding and aversive properties of social interactions than males (Borland and Albers, unpublished)

Fig. 5

Effects of oxytocin (OT), a selective OT receptor (OTR) agonist and a selective OTR antagonist, on the rewarding properties of same-sex social interactions in Syrian hamsters. a Injection of a selective OTR antagonist into the caudal VTA before each of three social conditioning sessions decreased social reward (the time spent in the chambers associated with social interaction during the social preference posttest) in both males and females. b Injection of OT and a selective OTR agonist into the caudal VTA before social conditioning sessions decreased the rewarding properties of social interactions in females but increased social reward in males. c Predicted effects of OT and OTR antagonist on social reward value in males and females based on the inverted U hypothesis of the relationship between social reward value and the dose (e.g., duration) of same-sex social interaction in males and females. Females are predicted to be more sensitive to the rewarding and aversive properties of social interactions than males. OT and OTR antagonists (OT Ant.) can increase or decrease social reward depending on the sex-dependent inverted U function of the relationship between social reward value and the dose (e.g., duration) of social interaction (* indicated significant difference p > 0.05) (Borland and Albers, unpublished)

Fig. 6

Sex differences in the effects of oxytocin (OT) on brain activations in response to reciprocated cooperation from human partners. a Activations revealed by whole brain analysis, voxel-wise threshold of p < 0.001 in conjunction with cluster-wise threshold of p < 0.05 FWE-corrected; b Region of interest plot from a illustrating the caudate/putamen response as a function of sex and drug treatment. OT-augmented neural response to reciprocated cooperation outcomes from human partners among males, whereas the opposite was found for females. Error bars represent one standard error. *p < 0.05, **p < 0.005 (Bonferroni corrected). Reproduced from ref. [10]

Fig. 7

Effects of oxytocin (OT) on the ventral tegmental area (VTA) response to reciprocated cooperation among women in a within-subject design. a OT attenuated the BOLD response to reciprocated cooperation in the VTA of female participants (FWE-corrected cluster p < .05 with voxel p < .001). b Average BOLD signal change in VTA (mean ± s.e.m.) as a function of scan number for each drug administration order. c This OT effect also replicates in cross-sectional data using the same task in a much larger cohort. d The OT group still has significantly less VTA activation relative to the placebo (PBO) after excluding subjects from the cross-sectional sample who were also in the within-subject sample.**p < 0.005 (1-tail); *p < 0.05 (1-tail). Reproduced from ref. [158]