Discussion

Studies in both humans and animal models have demonstrated a strong relationship between drug use/abuse and social behavior (Young et al., 2011a). Because of its well known role in the generation of motivated behaviors, the mesolimbic DA system is in a key position to mediate the interaction between drugs of abuse and social behavior. We have recently demonstrated that repeated exposure to AMPH impairs pair-bond formation in male prairie voles and that NAcc DA mediates this effect (Liu et al., 2010). In the present study, we demonstrate that pair-bonding experience impairs AMPH-induced CPP and that this effect is also mediated by NAcc DA. Together, these studies demonstrate a reciprocal interaction between pair bonding and AMPH reward and suggest a role for NAcc DA in regulating such interactions.

In the current study, we used a previously established CPP paradigm (Liu et al., 2010; Young et al., 2011b) to investigate the effects of pair-bonding experience on the rewarding properties of AMPH. We use the ambiguous term “rewarding properties” to describe the impact of AMPH on place conditioning because it allows us to simultaneously address the individual components of reward—including hedonics, associative learning, and incentive motivation (Berridge and Robinson, 2003)—that have been implicated in processes underlying place conditioning (Hnasko et al., 2005; White et al., 2005; Cunningham and Patel, 2007), without distinguishing between them. Our results demonstrate that AMPH conditioning induced a CPP in SN, but not PB, male voles, and as such, offer the first empirical evidence that pair-bonding experience decreases the rewarding properties of AMPH. Although this is the only study to investigate the effects of pair-bonding experience on the rewarding properties of drugs of abuse, previous studies have demonstrated that other social experiences/factors may also influence drug reward. For example, rats reared with multiple social cohorts self-administered less AMPH (Bardo et al., 2001) and cocaine (Schenk et al., 1987) over repeated sessions than rats reared alone. Similarly, rats reared in an enriched environment that contained novel objects and social cohorts self-administered less AMPH, extinguished self-administration behavior sooner, and required higher doses of AMPH to reinstate drug-seeking than did rats housed alone (Schenk et al., 1988; Bardo et al., 1995, 2001; Green et al., 2002; Stairs et al., 2006). Furthermore, female rats trained to lever-press for cocaine showed markedly fewer responses after becoming pregnant and following parturition (Hecht et al., 1999), suggesting that the reproductive process and neurobiological changes involved with maternal experience may decrease the reinforcing properties of cocaine. This notion is further supported by the finding that virgin rats preferred an environment associated with cocaine and readily expressed a cocaine-induced CPP (Seip et al., 2008), whereas lactating dams strongly preferred an environment associated with pups over one associated with cocaine (Mattson et al., 2001). Together, these studies imply that social factors may reduce the rewarding properties of psychostimulants. Our results extend these findings and demonstrate that pair-bonding experience impairs AMPH reward in prairie voles.

The rewarding properties of psychostimulant drugs of abuse, such as AMPH, are dependent on drug-induced increases in NAcc DA release and the subsequent activation of DA receptors (Yokel and Wise, 1975; Di Chiara and Imperato, 1988; Bergman et al., 1990; Kehoe et al., 1996). Therefore, alterations in either of these factors may underlie the effects of pair-bonding experience on AMPH reward. Levels of released DA have been closely correlated with the positive subjective effects of drugs of abuse (Volkow et al., 1999; Drevets et al., 2001; Leyton, 2010) and psychostimulant-induced NAcc DA release has been altered by social experience in some cases [e.g., isolation early in life (Kehoe et al., 1996; Kosten et al., 2005)], but not others [e.g., enriched social housing (Bardo et al., 1995)]. In the present study, AMPH treatment increased the level of extracellular DA in the NAcc, which is consistent with previous reports (Di Chiara and Imperato, 1988; Curtis and Wang, 2007; McKittrick and Abercrombie, 2007). Furthermore, AMPH induced an immediate and prolonged decrease in the level of extracellular DOPAC in both groups. This finding is consistent with those of previous studies and the known role of AMPH in the inhibition of monoamine oxidase—an enzyme involved in the degradation of DA (Green and el Hait, 1978; Jones et al., 1998; Curtis and Wang, 2007). In both cases, the magnitude and temporal pattern of extracellular changes in the NAcc were comparable between SN and PB males, suggesting that it is unlikely that the effects of pair bonding on AMPH reward are related to the release or metabolism of NAcc DA.

Although pair-bonding experience did not influence AMPH-induced DA release or metabolism, it did influence the effects of AMPH on NAcc DA receptor binding (i.e., DA receptor expression and/or affinity). For example, consistent with previous studies, AMPH treatment increased NAcc D1R expression in SN males (Liu et al., 2010) and pair-bonding experience also elevated NAcc D1R binding (Aragona et al., 2006). However, the effect of AMPH on NAcc D1R binding was reversed in PB males compared with SN males, as PB males showed a significant decrease in D1R binding following AMPH treatment. No group differences were found in NAcc D2R binding in either the current or previous studies (Aragona et al., 2006; Liu et al., 2010). Together, these data demonstrate that pair-bonding experience and AMPH exposure each leads to D1R-specific changes within the NAcc of SN males. Further, as AMPH oppositely affected NAcc D1R binding in SN and PB voles, our data indicate that social bonding may be an important mediating factor in the effects of AMPH on the mesolimbic DA system. Correspondingly, cocaine has been found to induce a robust positive blood oxygenation level-dependent (BOLD) signal change throughout the mesolimbic DA system in virgin females, but a largely negative BOLD response in lactating dams, as measured by functional magnetic resonance imaging (Ferris et al., 2005), thus further indicating that social/sexual experience may play an important role in the neurobiological response to drugs of abuse. Alterations in receptor binding, such as those described above, may have profound effects on behavior because they modify the brain’s responsiveness to released neurotransmitters. In SN males, for example, AMPH-induced increases in D1R binding may play an important role during AMPH conditioning as intra-NAcc blockade of D1R, but not D2R, inhibited AMPH-induced CPP—a finding consistent with those in other species (Baker et al., 1998; Pitchers et al., 2010). Consequently, in PB males, decreased NAcc D1R binding may underlie the lack of an AMPH-induced CPP as NAcc D1R activation during AMPH conditioning enabled AMPH-induced CPP in PB males. Collectively, these data indicate that AMPH-induced decreases in NAcc D1R expression/affinity may underlie the effects of pair-bonding experience on AMPH reward.

Two interesting parallels between our findings and those from other studies that have investigated the relationship between drugs of abuse and social behavior are worth mentioning. First, pair bonding and repeated AMPH exposure each independently resulted in similar changes in the mesolimbic DA system of male prairie voles [i.e., enhanced D1R binding (Aragona et al., 2006) and expression (Liu et al., 2010) in the NAcc]. Similarly, sexual experience and repeated exposure to psychostimulants each increased the density of dendritic spines on medium spiny neurons within the NAcc shell in rats (Robinson and Kolb, 1999; Pitchers et al., 2010). Furthermore, pup suckling in lactating dams and cocaine administration in virgin females induced similar patterns of positive BOLD activation in the mesocorticolimbic system (Ferris et al., 2005). Together, these data support the notion that drugs of abuse usurp neural mechanisms and circuits that mediate adaptive behaviors (Panksepp et al., 2002). Second, our data suggest that the differential neurobiological responses to AMPH in SN and PB males may underlie group differences in AMPH-induced behavior. Similarly, lactating rats showed a suppression of activity within the mesocorticolimbic DA system in response to cocaine (as opposed to the increase in activity noted in virgin females) (Ferris et al., 2005) and a reduction in cocaine self-administration (Hecht et al., 1999), further supporting the notion that physiological changes associated with social experience may attenuate the rewarding properties of drugs of abuse.

The presence of strong social bonds in adulthood may decrease the vulnerability to drug abuse (Kosten et al., 1987). However, the neural mechanisms underlying this behavioral phenomenon are relatively unknown, perhaps due to the lack of an appropriate animal model. In the present study, we established the prairie vole as an animal model to investigate the neural mechanisms underlying the protective effects of adult social bonding on the vulnerability to drug abuse. Our findings indicate that pair-bonding experience decreases the rewarding properties of AMPH and that the mesolimbic DA system, particularly DA neurotransmission in the NAcc, mediates this effect. These findings, together with those from our previous study (Liu et al., 2010), establish a foundation for future investigation of the neural mechanisms underlying the reciprocal relationship between drug use/abuse and social bonding, which may ultimately provide important insight into the prevention or treatment of drug abuse.