Previous research in monkeys has demonstrated that attainment of social dominance is associated with increases in D2 receptor availability in the basal ganglia and a lower sensitivity to the reinforcing effects of cocaine compared to subordinate monkeys (Morgan et al. 2002
). The data further demonstrated an inverse relationship between D2 receptor availability and sensitivity to the reinforcing effects of cocaine, as seen in other studies in laboratory animals and humans (Volkow et al. 1999
; Thanos et al. 2001
; Nader et al. 2006
; Dalley et al. 2007
). After monkeys had self-administered cocaine for several years, D2 receptor availability in the caudate nucleus and putamen no longer differed between dominant and subordinate monkeys, despite continued social housing (Czoty et al. 2004
). In the present study, rank-related differences in D2 receptor availability reemerged while monkeys remained socially housed during abstinence from cocaine self-administration. After approximately 8 months of abstinence from cocaine, the average D2 receptor availability in the caudate nucleus of dominant monkeys was 26% higher than that of subordinates—a statistically significant effect. D2 availability in the putamen was 15% higher in dominant monkeys compared to subordinates, but variability across individuals was large enough to preclude statistical significance. These data provide evidence of neuroplasticity such that, despite several years of exposure to self-administered cocaine 5 days/week, brain D2 receptors remained responsive to environmental factors when cocaine exposure was discontinued. In addition, dominant monkeys were less reactive to novelty than subordinates, and this measure was positively correlated with D2 receptor availability in the caudate nucleus.
Our original study indicated that D2 receptor availability increased in monkeys that became dominant but was unchanged in subordinates (Morgan et al. 2002
). We have conceptualized the dominance hierarchy as a continuum of social experience ranging from the unequivocal stress experienced by subordinate monkeys to environmental enrichment experienced by dominant animals (Nader and Czoty 2005
). Thus, one interpretation of the present results is that the rank-related difference in D2 receptor availability observed after 8 months of abstinence was a result of exposure to environmental enrichment in dominant monkeys. At the outset of these experiments, we intended to assess this hypothesis more directly by determining the percentage change in individual monkeys’ [18
F]FCP DVRs just before (i.e., Czoty et al. 2005b
) and during abstinence. Unfortunately, this comparison was complicated by changes in social rank that occurred during abstinence for some monkeys. It is possible that the present results may be affected by individual differences in rates or extent of recovery from the decreases in D2 receptor availability that resulted from long-term cocaine self-administration, a phenomenon we previously demonstrated in individually housed rhesus monkeys (Nader et al. 2006
). It is worth noting, however, that the average past-year cocaine intake of monkeys in the Nader et al. (2006)
study was almost ten times higher than that of the monkeys in the present study (787.8±128.0 mg/kg versus 84.4±29.7 mg/kg). Although these issues complicate an understanding of the mechanisms through which dominant and subordinate monkeys came to differ in D2 receptor availability, after approximately 8 months of abstinence, dominant monkeys’ DVRs were significantly higher than those of subordinates. The clinical relevance of this finding lies in the demonstration of plasticity of brain DA receptor systems driven by the environment, suggesting that the brain of a cocaine-dependent individual can remain responsive to positive changes in the environment.
An additional aim of these studies was to examine the relationship between social experience, D2 receptor availability, and reaction to novelty—a characteristic that has been associated with increased vulnerability to the reinforcing effects of abused drugs (e.g., Piazza et al. 1989
; Bardo et al. 1996
). In the present study, the average latency of dominant monkeys to touch a novel object placed in the home cage was significantly longer than that of subordinate and individually housed monkeys, suggesting that the experience of being dominant (i.e., environmental enrichment) decreased this measure of reaction to novelty. It is important to note that previous studies examined subjects’ initial experiences with cocaine, whereas monkeys in the present studies had extensive experience self-administering cocaine. Thus, one important implication of these results is that the influence of social dominance on reaction to novelty was not eliminated due to the monkeys’ history of cocaine intake. One alternative explanation is that individual differences may have predated social housing and influenced the establishment of eventual rank. That is, it is possible that monkeys who tend to display higher reactivity to novelty are more likely to become subordinate. Supporting this possibility, female cynomolgus monkeys’ latencies to touch a novel object assessed prior to social housing were predictive of eventual social rank, and the direction of effects was similar to those observed in the present study (Riddick et al. 2009
). In the present study, however, latencies of individually housed male monkeys were low with little between-subject variability to suggest they could predict future social rank. In fact, when these monkeys were eventually placed into social groups, eventual rank was not predicted by latencies to touch the novel object (not shown). It should be noted, however, that in the present study, a direct comparison of monkeys with and without social experience may be confounded by experience self-administering cocaine. Factors underlying the difference between results in male and female monkeys remain to be explored but may be due to the relatively small sample size in the present study.
Considering that dominant monkeys had significantly higher caudate nucleus D2 receptor availability and higher latencies to touch the novel object, it is not surprising that the latter two measures were positively correlated. These data are consistent with PET data in humans that suggest an inverse relationship between novelty seeking and D2 receptor availability (Zald et al. 2008
) and further support the link between D2 dopamine receptors and the temperamental variables reflected in laboratory assessments of various dimensions of impulsivity including novelty seeking. The radiotracer used in the present study, FCP, binds to the D2
, and D4
subtypes of the D2 family of receptors; genetic studies have implicated these subtypes in mediating reaction to novelty and other measures related to impulsivity (e.g., Retz et al. 2003
; Mufano et al. 2008
). Moreover, Dalley and colleagues (2007)
reported relatively lower D2 receptor availability in the nucleus accumbens of rats who were found to be more impulsive and subsequently self-administered greater amounts of cocaine. Although the cognitive processes measured by various laboratory tests of “impulsivity” and the overlap between these aspects of temperament as assessed in humans and animals is unclear (Dellu et al. 1996
; Stoffel and Cunningham 2007
), the predictive capacity of these measures suggests that they represent a reliable behavioral phenotype reflecting enhanced vulnerability to the abuse-related effects of psychostimulants. Moreover, the present and previous studies in socially housed monkeys (Morgan et al. 2002
; Czoty et al. 2004
) demonstrate that these three characteristics can be influenced by environmental variables. Specifically, they support the intriguing hypothesis that social dominance is a form of environmental enrichment that can result in increases in D2 receptor availability, decreases in reaction to novelty (i.e., longer latencies to approach and touch a novel object), and decreases in sensitivity to the abuse-related effects of cocaine. To the clinician, these studies suggest that positive changes in a recovering drug abuser’s environment can be an effective component of substance abuse treatment.