AVP V_1b selective antagonist SSR149415 blocks aggressive behaviors in hamsters

Abstract

Arginine vasopressin (AVP) has been implicated in a variety of physiological and behavioral responses to stress. Synthesis of receptor-selective AVP agonist and antagonist compounds allows differential analysis of the specific roles of particular receptor subtypes with respect to these responses. Here, effects of the recently synthesized AVP V_1b selective antagonist, SSR149415, were examined for offensive aggression in male Syrian hamsters, using a resident-intruder paradigm. Oral administration of vehicle or 1, 10, or 30 mg/kg of SSR149415 to resident hamsters was followed by evaluation of a range of aggression-related measures of residents confronted by intruders. The 10 and 30 mg/kg doses significantly reduced the duration of offensive sideways and chase behaviors, and the 30 mg/kg dose also reduced chase frequency. The 10 and 30 mg/kg dose also significantly reduced frequency and duration of olfactory investigation and duration of flank marking. These findings suggest a link between activity of the V_1b receptor and the modulation of offensive aggression. These findings agree with previous research on V_1b receptor effects in suggesting that antagonism of this receptor may be useful in modulating a range of emotional responses to highly stressful or threatening conditions.

Introduction

Vasopressin (AVP), a nine-amino acid neurohypophyseal neuropeptide, acts as a neurotransmitter and neurohormone in a wide variety of autonomic and behavioral responses to stress (Aguilera and Rabadan-Diehl, 2000). AVP has been consistently implicated in the aggressive behaviors of a variety of species, including humans (Coccaro et al., 1998). In rodents, AVP infusions into the hypothalamus or amygdala enhance aggression in hamsters and rats (Bamshad and Albers, 1996, Delville et al., 1996a, Delville et al., 1996b, Ferris et al., 1984), while AVP receptor antagonist infusions reduce aggression (Ferris and Potegal, 1988). Similarly, central administration of AVP agonists and antagonists enhances or reduces, respectively, the scent marking (flank marking) that is particularly (Ferris et al., 1986), although not exclusively, associated with dominance in male–male interactions in many rodent species (Albers and Ferris, 1986, Bamshad and Albers, 1996, Ferris et al., 1985, Ferris et al., 1988, Ferris et al., 1993).

The action of AVP involves several receptor subtypes. Of these, AVP V_1a has been more widely used in animal models, in part due to the availability of a range of orally active antagonists for this receptor (Serradeil-Le Gal et al., 2002a). However, a recent study (Wersinger et al., 2002) of vasopressin V_1b receptor knockout mice has reported robust reductions in aggressive behavior for these animals. The V_1b knockout mice also showed a less robust reduction in social investigation, significant only in the context of a stringent test involving familiar versus unfamiliar conspecific females. Wild-type and knockout mice were not different on a range of tests of sensory (olfaction, vision) and motor function, anxiety (open field, elevated plus maze), and spatial memory (Morris water maze), suggesting that AVP V_1b antagonists may be capable of modulating aggressive behavior with minimal impact on other behaviors.

SSR149415 is the first selective, nonpeptide vasopressin V_1b receptor antagonist (Serradeil-Le Gal et al., 2002b). It is orally active and shows competitive nanomolar affinity for animal and human V_1b receptors, with much lower affinity for rat and human V_1a, V₂, and oxytocin receptors. Both in vitro and in vivo SSR149415 potently inhibited AVP-induced activity and reduced emotion-linked behavior in a variety of mouse models after both acute and repeated administration (Griebel et al., 2002). In particular, SSR149415 produced clearcut anxiolytic-like activity in models involving traumatic stress exposure, such as the social defeat paradigm and the mouse defense test battery, and reduced responsivity to stress in the forced swimming test and the chronic mild stress model. Such findings emphasize a potential role for the V_1b receptor in the modulation of emotion-linked responding to stressful stimuli and suggest the value of analysis of the effects of SSR149415 on aggression.