Research ReportAdolescent social defeat alters neural, endocrine and behavioral responses to amphetamine in adult male rats
Research Highlights
► Adolescent social defeat alters adult behavior and limbic dopamine (DA). ► Defeated rats have increased locomotion to novel environments in adulthood. ► Adolescent defeat causes decreased adult amphetamine-induced locomotion. ► Adult prefrontal cortex DA responses to amphetamine are blunted by adolescent defeat. ► Nucleus accumbens DA responses to amphetamine are elevated by adolescent defeat.
Introduction
Bullying is a severe social stressor experienced by many teenagers that can result in both immediate and long-term negative psychological consequences (Grossman et al., 2003, Kaltiala-Heino et al., 2000, Nansel et al., 2001, Rigby & Slee, 1993). The vulnerability of adolescents to the detrimental effects of such stressful events is thought to result from disruption of the extensive re-organization of limbic monoamine systems occurring at this time (reviewed by Andersen, 2003, Andersen & Teicher, 2009, Spear, 2000). Based on the role of prior stress exposure in potentiating acquisition and maintenance of drug taking (Covington & Miczek, 2001, Covington & Miczek, 2005, Gordon, 2002, Koob & Le Moal, 2008, Kreek & Koob, 1998, Piazza & Le Moal, 1998), stress-induced disruptions of mesocorticoaccumbal dopamine (DA) system development and maturation during this critical phase are likely to result in alterations in behavioral responses to drugs of abuse later in life (Wise, 1996). With social activity at its peak during adolescence (Douglas et al., 2003, Primus & Kellogg, 1989, Varlinskaya & Spear, 2008), there is a high probability that negative social experiences will have similar long-lasting detrimental effects that persist into adulthood. Indeed, numerous clinical studies have shown that repeated adolescent experience of social stress, including bullying, is correlated with greater incidence of stress-related psychiatric and addictive disorders in adulthood (Gladstone et al., 2006, Hoffmann et al., 2000, Newman et al., 2005, Rossow & Lauritzen, 2001, Tharp-Taylor et al., 2009, Wals & Verhulst, 2005).
Bullying is characterized by an imbalance of power in which the victim is less powerful than the aggressor and is unable to defend themselves adequately. This power imbalance becomes even more noticeable over time, with the bullying increasing in severity (Björkqvist, 2001). The closest parallels of such hierarchical relationships in animal models arise from social defeat paradigms utilizing a resident-intruder paradigm (Björkqvist, 2001). In adult rats, repeated social defeat has been shown to cause increased emotive responses and drug-seeking behavior (Covington & Miczek, 2005, Miczek et al., 2004, Rygula et al., 2005) comparable to that reported for adult recipients of human bullying (Björkqvist, 2001). In particular, rats exposed to repeated defeat in adulthood exhibit increased psychostimulant-induced locomotion and more rapid acquisition of psychostimulant self-administration and greater overall intake (Covington & Miczek, 2001, Covington & Miczek, 2005, Haney et al., 1995, Tidey & Miczek, 1997). Repeated social defeat of adult rats is also associated with functional changes in limbic monoaminergic regions that mediate drug-seeking (Buwalda et al., 2005, Lucas et al., 2004, Miczek et al., 2004, Czeh et al., 2007). However, the effects of repeated social defeat experiences in adolescence on subsequent adult behavioral and neural responses to psychostimulants remain to be determined.
Recently, we demonstrated that male rats exposed to repeated social defeat during the peak of adolescent neural re-organization (postnatal days (P) 35–39, Andersen, 2003, Spear, 2000) display long-lasting alterations to adult monoaminergic function (Watt et al., 2009). In particular, previously defeated rats exhibited decreased baseline medial prefrontal cortex (mPFC) DA content as adults in the absence of any behavioral or pharmacological manipulation prior to tissue collection (Watt et al., 2009). Previous work has shown that decreased mPFC DA content is associated with increased self-administration and responsiveness to psychostimulants (Beyer & Steketee, 1999, Piazza et al., 1991b, Schenk et al., 1991, Ventura et al., 2004). This suggests that the changes to mPFC DA following repeated exposure to social defeat in adolescence may similarly alter responses to psychostimulants in adulthood.
In the current study, we investigated whether experience of adolescent social defeat stress would induce long-lasting effects to subsequently alter adult behavioral, corticosterone and neural responses to amphetamine. We chose to examine these variables in early adulthood (P59–62), as the emergence of symptoms characterizing stress-related addictive disorders often occurs at the equivalent stage of human maturation (Andersen, 2003, Park et al., 2006, Kessler et al., 2007). Since decreased mPFC DA content was found in adult rats defeated during adolescence (Watt et al., 2009), we hypothesized that these animals would exhibit a correspondingly diminished amphetamine-induced DA response in the mPFC. Based on reports that decreased mPFC DA activity potentiates phasic and drug-evoked DA release in the NAc following normal development (Del Arco & Mora, 2008, Mitchell & Gratton, 1992, Pascucci et al., 2007), we hypothesized that DA responses to amphetamine would be higher in the NAc of adult rats subjected to social defeat during adolescence. Furthermore, because greater DA release in the NAc is associated with increased locomotion responses (Johnson et al., 1996, Pijnenburg & van Rossum, 1973) and reinforcing properties of psychostimulants (Di Chiara & Imperato, 1988, Kalivas & O'Brien, 2008), we predicted that rats pretreated with social defeat in adolescence would show increased amphetamine-induced behaviors such as locomotion and stereotypy. We also investigated whether adult corticosterone responses to amphetamine were altered by adolescent social defeat, since psychostimulant-induced increases in plasma corticosterone may play a role in psychostimulant-related behaviors (Covington & Miczek, 2005, Goeders, 2002). We therefore predicted that adolescent defeat, in addition to increasing the expression of behaviors induced by amphetamine, would also result in heightened corticosterone responses to amphetamine in adulthood.
Section snippets
Locomotion in a novel environment and amphetamine-induced behavior
Two-way ANOVA across each time point revealed that previously defeated rats that would subsequently receive either amphetamine or saline spent more time engaged in locomotion over the last 15 min of the 30-min testing period (zero time point) compared to all non-defeated rats, F(1,38) = 11.635; p = 0.002 (Fig. 1A). Following amphetamine or saline injection, there was a significant effect of drug at all post-injection time points (p < 0.001), with all amphetamine-receiving subjects exhibiting higher
Discussion
As hypothesized, amphetamine-induced DA increases in the mPFC were markedly attenuated in adult rats socially defeated in adolescence. Furthermore, the NAc core DA response to amphetamine was greater in previously defeated rats than in non-defeated controls. However, antithetical to our original hypothesis, previously defeated rats showed lower amphetamine-induced locomotion than amphetamine-treated controls when pre-existing differences in locomotion were accounted for. The absence of a
Animals
Forty juvenile male Sprague–Dawley rats were obtained from the University of South Dakota Laboratory Animal Services at P21 (day of weaning) and pair-housed according to adolescent stress treatment (social defeat or control) under a reverse light cycle (lights off from 9:00 to 21:00 h). Food and water were available ad libitum. All testing procedures occurred between 10:00 and 15:00 h under red lighting. All procedures were approved by the Institutional Animal Care and Use Committee of the
Acknowledgments
This work was supported by NIDA RO1 DA019921 (GLF), NIH R03 MH068364 (MJW) and NIH NCRR P20 RRO15567-10, which is designated a Center of Biomedical Research Excellence (COBRE). We thank Jamie Scholl for valuable technical assistance with these experiments.
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2018, Seminars in Cell and Developmental BiologyCitation Excerpt :Other studies have reported effects of social defeat exposure (from PD28 to PD41 and from PD37 to PD49) on immobility in the FST only in female rats [61,62]. Adolescent socially defeated rats exhibit greater amphetamine-induced locomotion in adulthood and amphetamine-induced CPP [63,64]. When exposed to social instability stress (1 h of daily isolation, followed by housing with a new partner from PD 30–45) during adolescence, rats develop greater anxiety-like behavior (in EPM) in adulthood [65].