Review
Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior

https://doi.org/10.1016/j.yfrne.2015.04.003Get rights and content

Highlights

  • VP and V1aR in the brain are typically higher in males than in females across species.

  • Across species, fewer sex differences have been reported for OT and OTR than VP and V1aR.

  • If sex differences are reported, OT is higher in females while OTR is higher in males.

  • VP and OT systems very often modulate social behaviors in sex-specific ways.

  • V1aR and OTR show distinct and largely non-overlapping expression in the rodent brain.

Abstract

The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species-specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans.

Introduction

The neuropeptides vasopressin (VP) and oxytocin (OT) are involved in the regulation of diverse social behaviors such as social recognition, pair-bonding, and social cognition in mammals, including humans (Veenema and Neumann, 2008, Ross and Young, 2009, Meyer-Lindenberg et al., 2011, Albers, 2014). VP and OT are evolutionarily conserved, differing from each other by only two amino acids. Importantly, VP and OT often regulate social behavior in sex-specific ways. This may be due to sex differences in the brain VP and OT systems, which will be the overarching topic of this review. Importantly, VP and OT have been implicated in the etiology of psychiatric disorders, such as schizophrenia (Jobst et al., 2014), autism (Yang et al., 2010, Xu et al., 2013, LoParo and Waldman, 2014), depression (Yueng et al., 2014), and borderline personality disorder (Bertsch et al., 2013), disorders which show sex biases in prevalence, symptom severity, and treatment responses. Knowledge of sex differences in these systems, as well as how OT and VP may mediate sex-specific social behavior, may therefore provide useful insight into sex-specific treatment strategies for men and women diagnosed with psychiatric disorders characterized by social dysfunction.

We will start with a discussion on sex differences in VP and OT in the brains of rodents and humans (Section 2). We briefly summarize the well-known sex differences in VP synthesis and fiber distribution in the brain of rodents and other species (for a more extensive review, see De Vries and Panzica, 2006). Interestingly, compared to VP, there is much less research regarding sex differences in OT synthesis in the brain. We generally find that, while there are robust sex differences in VP synthesis in conserved brain regions across species, there are fewer sex differences in OT synthesis in the brain and such sex differences are specific to particular brain regions and species.

Compared to sex differences in VP and OT peptide synthesis, even less is known about sex differences in OT and VP receptors in the brain. We therefore discuss the current knowledge of sex differences in these receptor systems in rodent and human brains (Section 3), as well as show new data of sex differences in the VP V1a receptor (V1aR) in the rat brain (Section 3, Fig. 1, Fig. 2). Interestingly, of the relatively few studies across various species, males seem to have higher V1aR and OT receptor (OTR) expression compared to females.

Despite the reported sex differences in VP and OT systems, surprisingly few comparative studies have investigated the behavioral functions of OT and VP systems in males and females using the same design. Importantly, those studies that do investigate the role of VP and OT in social behavior in both sexes often demonstrate a robust sex-specific modulation of social behavior by VP and OT systems in a variety of rodent species and humans (Section 4). Finally, we provide a short general discussion on the main findings and propose future directions (Section 5). Interestingly, the expression of VP and OT receptors in the rodent brain are non-overlapping (Section 5, Fig 3), suggesting possible implications for either complementary or distinct behavioral functions of VP and OT, a rather unexplored but important area for future research.

Section snippets

Vasopressin

VP acts as a hormone in the periphery and as a neuromodulator in the brain. VP-producing magnocellular neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus project to the posterior pituitary, where VP is released into the general circulation as a hormone (Brownstein et al., 1980, Young and Gainer, 2003). As a hormone, it is involved in the regulation of blood pressure and water retention in the body (Silva et al., 1969, Ishikawa, 1993). VP is also

VP receptors

VP receptors are G protein coupled receptors consisting of two major subtypes, the V1 receptor (V1R) and the V2 receptor (V2R; Jard, 1983). The V1R is further divided into V1aR and V1bR receptor subtypes. V1aR and V1bR are both expressed in the brain and are the most well-known mediators of the effects of VP in the brain on social behavior. For example, V1aR has been implicated in pair bonding, maternal care, aggression, social recognition, and social play (Bielsky et al., 2004, Egashira et

VP system

Although sex differences in VP have been known for several decades and have since been found in various rodent species, there is a surprising lack of comparative studies investigating sex-specific function of VP in the regulation of social behavior. Here we discuss the rodent studies that found sex-specific roles of the VP system in the regulation of partner preference in voles, social recognition in rats, social play in rats, and aggression in hamsters. We also discuss the studies that

General discussion

We discussed above that various rodent species show consistent sex differences in VP-immunoreactive neurons and fiber density in the brain (rats: De Vries et al., 1983, Van Leeuwen et al., 1985, Miller et al., 1989; Wang and De Vries; mice: De Vries et al., 2002, Bakker et al., 2006, Gatewood et al., 2006, Rood et al., 2013; voles: Wang, 1995, Wang et al., 1996; Lonstein and De Vries, 1999; gerbils: Crenshaw et al., 1992; and European hamsters: Buijs et al., 1986). Sex differences in VP neurons

Acknowledgments

We would like to thank Remco Bredewold, Marisa Immormino, and Sterling Karakula for technical assistance with the receptor binding. We would like to thank the Veenema lab for critically reading the manuscript. We would also like to acknowledge Jim Goodson, a dear friend and colleague who recently passed away, for his support, insights, and inspiration given over the years. This work was supported by NIMH F31MH100891 to KMD, and NSF IOS 1253386, NIMH R15MH102807, and NIMH R01MH102456 to AHV.

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