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.

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

“…These studies were conducted in Syrian hamsters, a species particularly well-suited for the preclinical study of behaviors that underlie psychiatric health and illness [18], and are consistent with recent evidence in humans that women find positive social interactions with same-sex partners to be more rewarding than men do [19]. Further, we test the overarching hypothesis that there is an inverted U-shaped relationship between duration of social interaction and social reward that is mediated by OT in both males and females, and that this dose-response relationship is initiated at lower doses in females than males [8]. Understanding the sex differences in the mechanisms of social reward is particularly important because deficits in social reward are linked with a variety of psychiatric disorders [20,21], many of which are sex-dependent in terms of prevalence and predispositions, e.g., autism spectrum disorder [22].…”

“…We have presented an inverted U-shaped hypothesis as a heuristic tool with which to consider how valence, both positive and negative, is assigned to social stimuli in a sex-dependent manner [8]. This hypothesis proposes that as the dose (i.e., duration or intensity) of social interactions increases, their rewarding nature is initially increased, but ultimately reduced.…”

“…In other words, the duration of social interaction is analogous to the dose or concentration dependent effects seen with drugs of abuse. Recently, we have taken a heuristic approach to better understand social reward by developing the hypothesis that an inverted U describes the relationship between the dose (i.e., duration and/or intensity) of social interaction and the reward value of those interactions [8], similar to the inverted U-shaped dose-response relationship between drug dose and reward value [9]. Initially, as the dose increases, reward value also rises, but only to a point.…”

Oxytocin modulates the intrinsic dynamics between attention-related large scale networks

“…In contrast to an increasing number of task-based OXT administration studies, no sex-differential effects of OXT were observed during the task-free state. Previous studies reported differential effects of OXT on men and women during social evaluation and social interaction (Borland et al, 2018;Feng et al, 2015;Gao et al, 2016) even when stimuli are presented subliminally . The lack of sexdifferential effects during the task-free state suggests that sex-differential effects of OXT evolve in interaction with the social context.…”

Sex matters

“…An additional behavioral measure that has become a key feature in preclinical models for neurodevelopmental disorders, especially for autism studies, is social behavior. Borland et al review the current state of sex differences in the presentation and development of social behaviors in humans and animal models, and discuss the potential therapeutic efficacy of oxytocin in social reward and treatment of social dysfunction [23].…”