Sex-dependent regulation of social reward by oxytocin receptors in the ventral tegmental area

Abstract

Social reward is critical for social relationships, and yet we know little about the characteristics of social interactions that are rewarding or the neural mechanisms underlying that reward. Here, we investigate the sex-dependent role of oxytocin receptors within the ventral tegmental area (VTA) in mediating the magnitude and valence of social reward. Operant and classical conditioning tests were used to measure social reward associated with same-sex social interactions. The effects of oxytocin, selective oxytocin receptor agonists, antagonists, and vehicle injected into the VTA on social reward was determined in male and female Syrian hamsters. The colocalization of FOS and oxytocin in sites that project to the VTA following social interaction was also determined. Females find same-sex social interactions more rewarding than males and activation of oxytocin receptors in the VTA is critical for social reward in females, as well as males. These studies provide support for the hypothesis that there is an inverted U relationship between the duration of social interaction and social reward, mediated by oxytocin; and that in females the dose-response relationship is initiated at lower doses compared with males. Same-sex social interaction is more rewarding in females than in males, and an inverted U relationship mediated by oxytocin may have a critical role in assigning positive and negative valence to social stimuli. Understanding these sex differences in social reward processing may be essential for understanding the sex differences in the prevalence of many psychiatric disorders and the development of gender-specific treatments of neuropsychiatric disorders.

Fig. 1

Sex difference in the rewarding properties of same-sex social interaction. a Both males and females made more entries into the chambers containing same-sex stimulus hamsters compared to empty chambers in the operant social preference test. b Both males and females displayed a significant increase in the time spent in the chambers associated with same-sex social interactions during the post-test compared to the pre-test in the conditioned place preference test. c Females had a significantly higher social preference score (number of entries into the social chambers minus number of entries into the empty chambers) in the operant social preference test than males. d Females had a greater social preference score (time spent in the social interaction chambers minus the time spent in the no social interaction chambers) in the conditioned place preference test than males. e Illustration of the inverted U hypothesis of the relationship between the dose/duration/intensity of social interactions and their reward value in males and females. In females the inverted U relationship is shifted to the left relative to males because social reward is initiated at lower doses of social interaction in females than in males. As a result, social interactions that are maximally rewarding in females are only suboptimally rewarding in males. (*indicates significant difference between groups, p < 0.05). Error bars S.E.M

Fig. 2

Effects of inhibiting oxytocin receptor (OTR) activation in the caudal ventral tegmental area (VTA) with a highly selective OTR antagonist (Ant.) on the rewarding properties of social interaction in the conditioned place preference test. Males and females experienced same-sex social interaction in their initially non-preferred chamber and received injections of either saline or a highly selective OTR antagonist (90 μM) into the caudal VTA 5 min prior to social conditioning sessions. a The inverted U hypothesis predicts that antagonism of OTR activation reduces social reward in both males and females. b Male and female controls injected with saline in the VTA but not paired with other hamsters (i.e., No Social Saline) displayed no change in the time spent in the chambers during the post-test. In both males and females injected with saline prior to social interactions (Social Saline) there was an increase in the time spent in the social interaction paired chambers during the post-test. In both males and females, injection of the OTR antagonist into the VTA (Social OTR Antagonist) decreased the time spent in the social interaction paired chambers compared to saline injected controls during the post-test. c Male and female controls (i.e., No Social Saline) displayed no change in the social chamber preference score. In both males and females injected with saline prior to social interactions (Social Saline) there was an increase in the social chamber preference score. In both males and females, injections of the OTR antagonist into the VTA (Social OTR Antagonist) decreased the social chamber preference score compared to saline injected controls. (*indicates significant difference between groups, p < 0.05)

Fig. 3

The effects of oxytocin (OT) injected into the caudal ventral tegmental area (VTA) on social reward. a–c Males and females were injected with either 9 μM OT or saline into the VTA 5 min  prior to each of the three social interaction conditioning sessions in the conditioned place preference test. a The inverted U hypothesis predicts that injection of 9 μM OT will decrease social reward in females but increase social reward in males. b As predicted, OT injected into the VTA decreased the change in the time spent in the social interaction paired chamber compared to saline controls during the post-test in females (Social Oxytocin); but in males, OT increased the change in the time spent in the social interaction paired chamber compared to saline controls. c In females, OT injected into the VTA decreased the change in the social chamber preference score compared to saline controls (Social Oxytocin); but in males, injection of OT increased the change in the social chamber preference score compared to saline controls just missed statistical significance. d–f The effects of oxytocin (OT) (0.9 μM) injected into the VTA on social reward in males and females. d The inverted U hypothesis predicts that injection of 0.9 μM OT into the VTA will decrease social reward a small amount in females and increase social reward a small amount in males, but that the absolute amount of social reward would be similar in males and females. e In both males and females, OT injected into the VTA (Social OT) had no statistically significant effect on the change in the time spent in the social interaction paired chamber during the post-test compared to controls (Social Saline). There was, however, a trend for OT to decrease the time spent in the social interaction paired chamber in the post-test compared to controls in females and for OT to increase the time spent in the social interaction paired chamber compared to controls in males. f In females, there was a trend for OT injected into the VTA to decrease the change in the social chamber preference score compared to controls and in males, the increase in the change in the social chamber preference score compared to controls just missed significance. g–i The effects of oxytocin (OT) injected into the VTA on social reward in females given only a single social interaction conditioning session. g The inverted U hypothesis predicts that reducing the dose of social interaction would place females on the ascending slope of the inverted U-shaped relationship and, as a result, injection of 9 μM OT would increase social reward instead of decreasing it as it did when the dose of social interaction was higher. h OT injected into the VTA increased the change in the time spent in the social interaction paired chamber during the post-test compared to saline injections. i OT increased the change in the social preference score compared to saline injections. (*indicates significant difference between drug groups, *for p < 0.05, **for p < 0.01, ***for p < 0.001; + indicates significant difference between sexes, p < 0.05)

Fig. 4

The effects of injection of a highly selective oxytocin receptor (OTR) agonist into the caudal ventral tegmental area (VTA) supports the hypothesis that social reward is mediated by the activation of OT receptors (OTRs) and not vasopressin receptors in males and females. Males and females were injected with either the OTR agonist (23 μM) or saline into the VTA 5 min prior to each of the three social interaction conditioning sessions in the conditioned place preference test. a Male and female controls injected with saline in the VTA but not paired with other hamsters (No Social Saline) displayed no change in the time spent in the chambers during the post-test. In both males and females injected with saline prior to social interactions (Social Saline) there was an increase in the time spent in the social interaction paired chambers during the post-test. Injections of the OTR agonist (Social OTR agonist) significantly decreased the time spent in the social interaction paired chambers during the post-test compared to saline controls in females, but in males, the OTR agonist increased the time spent in the social interaction paired chamber during the post-test although this difference just missed significance. b Male and female controls (No Social Saline) displayed no change in the social chamber preference score. Both males and females injected with saline (Social Saline) showed an increase in the social chamber preference score. Injections of the OTR agonist (Social OTR agonist) decreased the social chamber preference score compared to saline controls in females, but for males, the OTR agonist had no effect on social chamber preference score

Fig. 5

Social interaction activates oxytocin (OT) immunoreactive (ir) neurons in the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) of the hypothalamus in males and females. a Representative PVN image, b PVN of a male hamster, c PVN of a female hamster. d Both males and females show greater OT FOS colocalization in the PVN following a 10-min social interaction compared to no social interaction controls. e Representative SON image, f SON of a male hamster, g SON of a female hamster. h Both males and females show greater OT FOS colocalization in the SON following a 10-min social interaction compared to no social interaction controls. (*indicates significant difference between groups, p < 0.05)