Stress is an important predictor of substance use and misuse. For example, early-life or chronic stress can contribute to the development of disordered patterns of substance use. Similarly, stressful events may precipitate relapse and continued substance use among recovering individuals. However, not everyone reacts to the effects of stress equally. Animal models can help provide insight into the behavioral, physiological, and neural correlates underlying differential responses to environmental events, such as stress. New research by Dr. Michael Nader and colleagues at Wake Forest School of Medicine uses a nonhuman primate model of cocaine use to show that social rank is an important factor related to the behavioral and biological response to social stress. This study is a part of Dr. Nader’s broader research program evaluating the neurobiological and behavioral consequences of social status on measures relevant to cocaine and other substance use disorders. The first experiment in this study began by examining cocaine self-administration in socially housed, male cynomolgus macaques using a food-drug choice procedure. This food-drug choice procedure provides a translationally relevant measure of substance use by modeling the decision to use drugs in the presence of a competing non-drug reinforcer (i.e., food). Subjects were also divided into a dominant or subordinate group based on social behaviors observed in the home cage. Dominant and subordinate monkeys were tested under conditions such that similar rates of self-administration were observed under these “baseline” conditions. Following baseline testing, subjects were exposed to social stress using a resident/intruder procedure. In this procedure, subjects were placed into another social group as an “intruder” for 30 minutes (note that the resident monkeys could not physically contact the intruder). The effects of this social stress on cocaine self-administration were then determined using the same food-drug choice paradigm. A majority of subjects were affected by the social stress manipulation, however the direction of this effect depended on the monkey’s social rank. Specifically, being an intruder in another social group produced increases in sensitivity to the reinforcing effects of cocaine in subordinate monkeys, but produced decreases in sensitivity to the reinforcing effects of cocaine in dominant monkeys. The former effects resemble the consequences of stress, while the latter outcome is what would be hypothesized to occur following an enriching event. Importantly, the same environmental manipulation had different consequences depending on the social rank of the monkey. A second experiment in this study attempted to reveal what neurobiological mechanisms mediated this social rank-stress relationship. To this end, PET imaging was used to study brain glucose metabolism in dominant and subordinate monkeys at baseline and following intruder stress. Clear differences between the dominant and subordinate monkeys were observed under both conditions. At baseline, dominant monkeys showed greater activity in regions associated with visual processing, attentional control, and vigilance, whereas subordinate monkey showed greater activity in regions associated with emotional processing, fear, and anxiety. Social stress increased activity along the HPA-axis in both groups with enhanced activity in the posterior cingulate cortex (a region associated with risk to cocaine relapse) in subordinate monkeys. Dr. Nader and colleagues’ study highlights the importance of preclinical animal models for identifying individual phenotypes conferring resilience or susceptibility to environmental events relevant to substance use. Although food-drug choice behavior was similar between dominant and subordinate monkeys under baseline conditions, acute social stress produced marked differences in responding based on a subject’s social rank. Animal models, such as these, can help detect clinically relevant factors underlying different patterns of behavior observed in the human clinical condition. Such an approach can also reveal behavioral, physiological, and neural markers to promote individualized approaches in treating substance use disorder. Michael Nader has been a member of CPDD since 1988 and served on the Board of Directors from 2006-2010, the Drug Testing and Evaluation Liaison Committee (2000-2003; 2007-2010), being Chair of that committee from 2007-2009, and is a past member of the Nomination Committee (2010). Justin Strickland has been a member of CPDD since 2014 and currently serves on the Animals in Research and Travel Award committees. By Justin C. Strickland, M.S., Animals in Research Committee Member The study was supported by the National Institute on Drug Abuse.
