Epidemiological studies have demonstrated relationships between socioeconomic status (SES) and substance abuse (e.g. Wohlfarth and Van Den Brink 1998
; Amick et al. 2002
; Goodman and Huang 2002
). Although SES affects emotional and cognitive development to varying degrees, growing up in a family with low SES has been associated with poor health and impaired cognitive development (cf. Hackman et al. 2010
). Data discussed in the next section indicate that social status can prominently influence the abuse-related behavioral effects of cocaine. In translating these findings from monkeys to humans, however, it is clear that equating social rank and SES is overly simplistic; people of all socioeconomic strata can and do experience stress and enrichment to varying degrees and may become addicted to drugs. The dominance hierarchy is conceptualized as a continuum consisting of chronic social stress at the lower end and environmental enrichment at the upper end (Nader and Czoty 2005
). The research question addressed in this section is how individuals of varying social ranks respond to changes in their environment.
In the studies described in this section, social status was determined for each cynomolgus monkey according to the outcomes of agonistic encounters as described previously (Kaplan et al. 1982
; Morgan et al. 2000
; Czoty et al. 2009
). Initially, aggressive, submissive, and affiliative behaviors were recorded for individual monkeys in each pen during 45-min observation sessions. The animal that aggressed towards, and elicited submissive behaviors from, all others was designated the dominant monkey. The subordinate monkey received aggression from all others and rarely aggressed.
In these experiments, cynomolgus monkeys living in groups of four in which stable dominance hierarchies had been established self-administered cocaine under a food-cocaine choice procedure (Czoty and Nader 2012
). Under this procedure, in each session ascending doses of cocaine were made available as an alternative to one food pellet. These reinforcers were delivered as a consequence of responding on one of two photo-optic switches under a fixed-ratio (FR) schedule of reinforcement. Ascending cocaine doses (0.0, 0.003, 0.01, 0.03 and 0.1 mg/kg per injection cocaine) were available in separate, consecutive components throughout the session; components lasted until monkeys made a total of 10 choices or 20 min elapsed. As observed previously (Paronis et al. 2002
; Negus 2003
), there was a dose-related increase in allocation of responding towards the cocaine-associated lever. That is, when the alternative to a food pellet was no injection, monkeys emitted nearly all responses on the food-associated lever, whereas monkeys chose drug injections exclusively when choosing between a high cocaine dose and a food pellet. When responding was deemed stable, a variety of interventions occurred as described below.
We hypothesized that stressful events would shift the cocaine-choice curve to the left (i.e., monkeys would choose more cocaine compared to baseline conditions), whereas enriching manipulations would shift the cocaine-choice curve to the right. A primary question was whether dominant and subordinate monkeys would respond similarly to a given manipulation. In general, a monkey was considered “affected” by a manipulation if the ED50 for cocaine choice was shifted by 0.25 log units or more in either direction. One conclusion that was true across all manipulations was that not every individual was affected by a given manipulation. This result is reminiscent of the clinical situation in which a drug treatment or other intervention is not universally effective. Nonetheless, several conclusions could be drawn with respect to the interaction between chronic living conditions and acute exposure to environmental stimuli.
Some examples of environmental manipulations hypothesized to shift the curve to the left (stressors) and to the right (enrichers) are provided. Initial studies examined brief, unexpected exposure to a rubber snake in the monkeys’ home cage prior to a cocaine self-administration session (Czoty and Nader 2012
). Exposure to a rubber snake has been shown to elicit fear responses in monkeys comparable to those elicited by real snakes (Kalin et al. 2001
; Prather et al. 2001
; Nelson et al. 2003
). All monkeys clearly exhibited a fear-like reaction to the presence of the snake, retreating to the opposite end of the test cage. Despite this similarity, the presence of the snake only altered cocaine self-administration in half of the 12 monkeys. Data from two socially dominant monkeys are shown in . For one monkey (C-7426), exposure to the rubber snake increased cocaine preference at the lower cocaine doses, when choice was primarily for food reinforcement, suggesting exposure to a stressor. For the other monkey (C-6628), cocaine preference decreased from baseline, suggesting exposure to an environmental enricher.
Figure 1 Individual differences in effects of “stressful” environmental stimuli on cocaine self-administration. Data for two dominant monkeys are shown following exposure to a toy snake in the home cage (circles) and presentation of capture gloves (more ...)
In these same two monkeys, another manipulation hypothesized to be stressful was examined. Each monkey was exposed to capture gloves while seated in a primate chair in an unfamiliar room. Capture gloves have been used as an aversive stimulus in laboratory studies (Bowers et al. 1998
; Machado et al. 2009
) and, when monkeys are in the home cage, the appearance of an individual wearing these gloves elicits vocalizations and other fear-related behaviors. In the present experiment, there was some evidence of fear-related behaviors, primarily yawning and vocalization. In monkey C-7426, while the toy snake appeared stressful, exposure to the capture glove did not impact cocaine choice. The same capture glove manipulation in the monkey in which the toy snake decreased cocaine choice (C-6628), also decreased choice, but at a higher cocaine dose.
Given these findings, what is different about C-7426 and C-6628 that could account for such disparate results? Both monkeys are dominant in their social group and there were no differences in their cocaine-food choice baseline behavior. Cortisol concentrations, measured immediately before the self-administration sessions, did not differentiate monkeys either. Monkey C-7426 appears to be particularly sensitive to stimuli in his home cage (the snake), but not to stimuli presented in a novel context (the capture gloves in another room), while C-6628 appears to be affected in an entirely different manner by both manipulations. In this animal stress may have altered choice by making the food more salient. As with people, in monkeys stress may manifest itself in different ways. While some individuals may be more vulnerable to drug abuse, others may seek an increase in caloric intake or palatable food substances.
While the previous set of studies was designed to evaluate “stress-induced” increases in cocaine self-administration, manipulations that decrease the reinforcing effects of cocaine by providing environmental enrichment may more directly inform treatment approaches. In a recent study, two environmental manipulations hypothesized to serve as enrichment was examined in socially housed monkeys (Czoty and Nader 2012
). The manipulations were providing food treats prior to the cocaine-food choice session and allowing individual monkeys to live in a large enclosure for the weekend. Below, we describe data from the large enclosure and a third manipulation involving pair-housing a male monkey with a female.
In one experiment, monkeys were allowed to live in their entire pen in the absence of their cage-mates for three days. Increasing monkeys’ living space has previously been shown to decrease abnormal behaviors (Draper and Bernstein 1963
; Paulk et al. 1977
; Kaufman et al. 2004
), while increasing density of individuals per cage has been shown to have deleterious physiological and behavioral effects in rodents (e.g. Brown and Grunberg 1996
; Gadek-Michalska and Bugajski 2003
; Botelho et al. 2007
). Data from a subordinate male monkey (C-7425) are shown in . When this monkey was allowed to self-administer cocaine in the context of the choice paradigm after spending 3 days living in the large pen without his 3 cage mates, he chose only food throughout the session (, left panel). A few weeks later this monkey was retested with another manipulation hypothesized to be enriching – pair housing him with a female for a 3-day period. In contrast to the hypothesis that this manipulation was enriching, pair-housing this monkey with a female resulted in his cocaine dose-response curve shifting to the left (, right panel); the manipulation appeared to be an environmental stressor. These data reinforce the observation that environmental events cannot be defined as stressful or enriching in the absence of behavior and, more importantly, the same event may have different effects in different individuals.
Figure 2 Individual differences in effects of environmental “enrichers” on cocaine selfadministration. Data are for cocaine vs. food choice from a subordinate monkey following two 3-day manipulations. Left: following a 3-day period in an enlarged (more ...)
Whereas the manipulations described above were expected to function as either stressors or enrichers in all monkeys regardless of social rank, two other interventions were conducted that were hypothesized to have differential effects depending on the social rank of the monkey. In one experiment, competition over food occurred by placing a treat into the cage while monkeys were socially housed. This represented a novel situation for the monkeys because standard operating procedure is to separate monkeys for approximately 90 min each day for feeding to assure that all monkeys in the pen receive adequate food. The presence of a preferred treat would create conflict as a dominant monkey retrieved the treat, aggressing towards lower-ranked monkeys if necessary. In each of the four pens tested, the treat was retrieved by a dominant monkey. In one of these dominant monkeys, the cocaine choice curve was shifted to the right. Other dominant- and intermediate-ranked monkeys were unaffected. In 3 of 4 pens, the most subordinate (#4-ranked) monkey chose significantly more cocaine than under baseline conditions. Thus, this manipulation clearly produced differential effects according to social rank. One possible interpretation of these findings is that whereas most monkeys are unaffected by the manipulation, subordinate monkeys find the experience stressful and consequently self-administer more cocaine when given the opportunity.
In all the studies described in this section, the same environmental stimulus or experience did not affect all monkeys identically with respect to cocaine self-administration. These individual differences in the effects of social/environmental stimuli on sensitivity to cocaine are of clear clinical relevance. In male cocaine-dependent individuals, experiencing a high number of “daily hassles” is associated with greater cocaine use (Waldrop et al. 2007
) and recent studies reporting “real-time” data have demonstrated positive relationships between momentary stress and craving for cocaine (Preston and Epstein 2011
). Such results support the view that, whereas most individuals can manage the many minor inconveniences we all encounter on a daily basis, such experiences appear to be much more stressful in certain people which subsequently makes them more likely to abuse cocaine. Moreover, there are predictive relationships between reactivity to stress, craving, and relapse to cocaine and alcohol use (e.g. Kosten 1992
; Brown et al. 1995
; Back et al. 2010
; Higley et al. 2011
). Understanding the neurobiological mechanisms that underlie this variability may provide insight into the biological basis for differences in individuals’ ability to remain abstinent in the face of social stress and in vulnerability/resilience to becoming addicted in the first place.