The role of the vasopressin 1b receptor in aggression and other social behaviours

Abstract

While the importance of vasopressin (Avp) in the neuroendocrine regulation of behaviour is clear, most of Avp's effects on behaviour have been linked to its action via its 1a receptor (Avpr1a) subtype. There is, however, emerging evidence and cross-species consensus that the vasopressin 1b receptor (Avpr1b) is also important in mediating the effects of Avp on behaviour. The Avpr1b is highly expressed in the anterior pituitary where it is thought to play a role in the neuroendocrine response to stress. The Avpr1b is also prominently expressed in the pyramidal cells of the CA2 hippocampal area. Interestingly, in mice, Avpr1b mRNA within the pyramidal neurons of the CA2 field is unaffected by restraint stress or adrenalectomy. Avpr1b knockout mice (−⧸−) have provided strong, consistent evidence that the Avpr1b plays a critical role in the regulation of social behaviour. Avpr1b^−/− mice display reduced levels of social forms of aggression, reduced social motivation and impaired social memory (including the Bruce effect). Avpr1b^−/− mice, however, have normal main olfactory ability, spatial memory and defensive and predatory behaviours. Mice lacking a functional accessory olfactory system display many of these same behavioural deficits, suggesting that Avpr1b^−/− mice may have a deficit in the processing, perception and/or integration of olfactory stimuli detected by the accessory olfactory system. We suggest that the role of the Avpr1b is to couple socially relevant accessory olfactory cues with the appropriate behavioural response. Furthermore, given its prominence in the CA2 field of the hippocampus, we hypothesize that Avpr1b may be important for the formation or recall of memories that have an olfactory-based social component.

Introduction

Originally described in pituitary (Antoni, 1984; Jard et al., 1986; Arsenijevic et al., 1994) and subsequently cloned (Lolait et al., 1995), the vasopressin (Avp) 1b receptor (Avpr1b) is found in several brain areas and peripheral tissues (Arsenijevic et al., 1994; Lolait et al., 1995; Young et al., 2006). Within the anterior pituitary the Avpr1b facilitates the release of adrenocorticotropic hormone (ACTH) from the corticotropes (Jard et al., 1987; Antoni, 1993), thus helping mediate the effects of Avp on the hypothalamic–pituitary–adrenal axis, i.e., the mammalian stress axis (Volpi et al., 2004). In the periphery, Avpr1b mRNA is found in tissues including kidney, thymus, heart, lung, spleen, uterus and breast (Lolait et al., 1995), although its role in these tissues remains unclear. It is only relatively recently that Avpr1b transcripts as well as Avpr1b immunoreactive cell bodies have been found in the rat brain, including in the olfactory bulb, piriform cortical layer II, septum, cerebral cortex, hippocampus, paraventricular nucleus, suprachiasmatic nucleus, cerebellum and red nucleus (Lolait et al., 1995; Saito et al., 1995; Vaccari et al., 1998; Hernando et al., 2001; Stemmelin et al., 2005). It should be noted, however, that Avpr1b distribution has not been mapped by receptor autoradiography due to the lack of a specific radiolabeled ligand. A recent study using in situ hybridization histochemistry with more specific probes on mouse, rat and human tissues found prominent Avpr1b expression in the hippocampal CA2 field pyramidal neurons (Young et al., 2006).

The Avpr1b knockout mouse (Avpr1b^−⧸−) was developed prior to any Avpr1b-specific pharmacology and has provided critical insights into the roles of the Avpr1b in the mouse, and possibly other species. While pharmacologically ‘clean’ compounds have continued to be somewhat elusive, the available pharmacological data are consistent with our observations in Avpr1b^−⧸− mice (Blanchard et al., 2005; Griebel et al., 2005). Originally described by Wersinger et al., 2002, Wersinger et al., 2004, Avpr1b^−/− mice, compared to wildtype controls, have reduced aggression and investigation of social cues as well as mild deficits in social memory. Taken together, these findings suggest that absence of the Avpr1b gene results in impairments that affect social behaviours more than other behaviours. The Avpr1b is also important for normal responses to some acute and chronic stressors (for review see Serradeil-Le Gal et al., 2005). While genetic disruption of the Avpr1b fails to affect measures of anxiety-like behaviour, depression-like behaviour (Wersinger et al., 2002; Caldwell et al., 2006) or the corticosterone response to acute restraint stress (Lolait et al., 2007a); its disruption attenuates the corticosterone response to forced swim, acute insulin treatment, acute immune stress and ethanol intoxication (Tanoue et al., 2004; Lolait et al., 2007a, Lolait et al., 2007b). Avpr1b^−⧸− mice also demonstrate a blunted ACTH response under chronic stress conditions (Lolait et al., 2007a) and pharmacological blockage of Avpr1b receptors reduces ACTH secretion (Serradeil-Le Gal et al., 2002). While the role of the Avpr1b in the mediation of the stress axis and other physiological responses (Oshikawa et al., 2004; Itoh et al., 2006; Fujiwara et al., 2007) are interesting and active areas of research, this chapter will focus on the contributions of the Avpr1b to the regulation of social behaviour.