Adolescent peer-rejection persistently alters pain perception and CB1 receptor expression in female rats

Abstract

Peer-interactions are particularly important during adolescence and teenagers display enhanced sensitivity toward rejection by peers. Social rejection has been shown to induce alterations in pain perception in humans. However, the neurobiological consequences of adolescent social rejection have yet to be extensively characterized, and no appropriate animal model is available. Here, we propose inadequate playful interactions in adolescent rats as a novel animal model for social peer-rejection and examine potential long-term consequences into adulthood. Acute social pairing of female adolescent Wistar rats with an age-matched rat from the less playful Fischer344 strain was found to alter social play and decrease pain reactivity, indicating Fischer rats as inadequate social partners for Wistar animals. Therefore, in a second experiment, adolescent female Wistar rats were either reared with another Wistar rat (adequate social rearing; control) or with a Fischer rat (inadequate social rearing; play-deprived). Beginning on day 50, all Wistar rats were group housed with same-strain partners and tested for behavioral, neurobiological and endocrine differences in adulthood. Playful peer-interactions were decreased during adolescence in play-deprived animals, without affecting social contact behavior. Consequently, adult play-deprived rats showed decreased pain sensitivity and increased startle reactivity compared to controls, but did not differ in activity, anxiety-related behavior or social interaction. Both groups also differed in their endocrine stress-response, and expression levels of the cannabinoid CB1 receptor were increased in the thalamus, whereas FAAH levels were decreased in the amygdala. The present animal model therefore represents a novel approach to assess the long-term consequences of peer-rejection during adolescence.

Introduction

Adolescence, the time during which an individual matures from an infertile child into an adult, comprises one of the most important postnatal periods of neurodevelopment. From an evolutionary perspective, adolescence is crucial for the maturation of social skills that are required for reproduction and are necessary to slowly separate an individual from the protective influence of the family (Spear, 2000). Peer interactions become particularly important during this period. Teenagers spend more time interacting with peers than during any other developmental period, are more susceptible to peer influence, and the rewarding value of peer-relationships is considerably increased (La Greca et al., 2001, Sebastian et al., 2010). Increased peer interactions are not only observed in human teenagers but have been described across species, and may therefore represent important adaptive skills to remove an adolescent from the home territory in order to avoid inbreeding or early reproduction (Gluckman and Hanson, 2006, Spear, 2000).

Given the importance of peer-relationships during adolescence, sensitivity toward social rejection has been reported to be higher during adolescence than in adulthood (Sebastian et al., 2010), with girls being particularly sensitive to the perception of peer-rejection (O'Brien and Bierman, 1988, Sebastian et al., 2010). Social rejection elicits strong feelings of distress, and may interfere with pain perception (MacDonald and Leary, 2005). Indeed, by means of functional imaging studies, comparable activity patterns have been reported in distinct brain regions during “social pain” following exposure to both social exclusion and physical pain (Eisenberger et al., 2003, Masten et al., 2009). Furthermore, social rejection has recently been demonstrated to play a role in the development of neuropsychiatric disorders, such as borderline personality disorder (BPD) (Mier et al., 2012, Staebler et al., 2011).

Consistent with the findings in humans, peer interactions during adolescence are also important in rodents. Rats are highly social animals and adolescent rats spend more time in peer interactions than younger or older animals. These peer-directed activities have a considerable incentive value during adolescence (Douglas et al., 2004) and are crucial for the development of social competence (Vanderschuren et al., 1997).

Most studies investigating the long-term consequences of restricted adolescent peer-experiences in rodents use deprivation models in which animals are completely deprived of social contact for several weeks. These manipulations have been found to induce a broad array of persistent adverse behavioral and neurobiological alterations (Fone and Porkess, 2008). However, these deprivation models also represent an enormous stressor for the animals, as no social contact occurs over an extended period, and are therefore not well-suited to model peer-rejection in humans.

The aim of the present study was to establish an animal model for human peer-rejection during adolescence through more subtle alterations in the social environment: rats of the playful Wistar strain were paired with either a same-strain partner or with a rat from the less playful Fischer344 strain (Siviy and Panksepp, 2011), considered as potentially inadequate social partners for Wistar rats. Pairing with such an inadequate social partner may decrease adequate playful peer-interactions for Wistar rats, without depriving the animals of normal social contact. In addition to acute effects on social play and pain perception, we examined the long-term consequences of inadequate pairing during adolescence on adult behavioral performance, including emotional behavior and pain perception. Effects on corticosterone levels and the endocannabinoid (ECB) system were also determined, as the ECB system is strongly implicated in pain processing and emotional reactivity (Guindon and Hohmann, 2009, Lichtman et al., 2004, Moreira and Lutz, 2008), as well as social development (Schneider and Koch, 2005).