Community-dwelling cocaine-dependent men and women respond differently to social stressors versus cocaine cues
Introduction
There are important gender differences in the development and course of substance use disorders (Zilberman et al., 2003, Hernandez-Avila et al., 2004). Evidence suggests that despite a lower prevalence of cocaine use and abuse, women may actually have an increased vulnerability to some aspects of cocaine dependence. For example, women meet criteria for drug dependence more quickly and enter treatment programs earlier than men (Anglin et al., 1987, Griffin et al., 1989, Westermeyer and Boedicker, 2000, Brecht et al., 2004, Hernandez-Avila et al., 2004). Cocaine-dependent women also report higher rates of cocaine use and shorter periods of abstinence than cocaine-dependent men (Griffin et al., 1989). These findings suggest gender differences in cocaine use and dependence with important treatment implications.
Stress and substance-related cues have become widely recognized as triggers for relapse to substance use in substance-dependent individuals (Childress et al., 1993, Kreek and Koob, 1998). The HPA axis is a key stress response system and has been examined extensively for its involvement in relapse. Proper functioning of the HPA axis is important for managing a cascade of neuroendocrine responses to stress and other stimuli that must be regulated to maintain homeostasis (Koob and Le Moal, 2001). Chronic cocaine use can lead to dysregulation of the HPA axis which may play a role in relapse through effects on stress and reward circuits (Koob and Kreek, 2007). Of interest, stress responses in the laboratory have been demonstrated to be predictive of relapse to cocaine use in cocaine-dependent individuals (Sinha et al., 2006, Poling et al., 2007). Studies suggest that women report more frequent drug use in response to negative situations, while men are more likely to report drug use in response to positive events (Waldrop et al., 2007b). These gender differences have not been explored in a human laboratory setting.
There are important gender differences in the HPA-axis response to laboratory stress paradigms. In general, laboratory stressors provoke a stronger response in men as compared to women (Kudielka and Kirschbaum, 2005); however, this varies by the type of stress paradigm used. In a study that compared men and women's responses to a laboratory-based social rejection task versus a performance-related task, women reacted more strongly to the socially oriented task and men responded more strongly to the achievement-oriented task (Stroud et al., 2002). An earlier study by the same group found a stronger response among women to the social stressor, as well (Stroud et al., 2000).
Drug-related cues in the environment may also be involved in precipitating relapse through associative learning processes in which cues may prime craving and physiological responses that lead to continued drug use (O’Brien et al., 1990, Childress et al., 1993). Cue exposure paradigms are another branch of active research in the relapse literature. Drug users report that cues for their drugs of choice are likely to be the impetus for renewed use (Waldrop et al., 2007b). In laboratory settings, cocaine cues have been shown to provoke craving, anxiety, and cortisol release in cocaine users (Sinha et al., 2000, Sinha et al., 2003, Coffey et al., 2002); however, studies exploring gender differences in cue reactivity remain few and results are mixed. In at least one study, women reported higher craving to cocaine cues than did men (Robbins et al., 1999) but another study found that men reported statistically nonsignificant but higher craving to cues (Avants et al., 1995).
The focus of the present study was to compare subjective and endocrine responses to a cocaine cue exposure and a social stressor paradigm (TRIER) among men and women with and without cocaine dependence. The primary hypotheses were: (1) men would respond more strongly to the cocaine cues than to the TRIER; (2) women would respond more strongly to the TRIER than to the cocaine cues; and (3) cocaine-dependent participants would evidence significant HPA-axis dysregulation as compared to a matched control group.
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Participants
Male and female cocaine users and healthy controls were recruited for the study (N = 100). Demographic data are presented in Table 1. Participants were recruited primarily through media advertisements and referrals. Exclusion criteria for all groups included (1) medical conditions that might interfere with safe study participation; (2) history of or current psychotic, bipolar, or eating disorders; (3) steroid or glucocorticoid therapy within 1 month of study participation; (4) pregnancy, nursing,
Demographics
In Table 1, demographic and descriptive data by cocaine group and gender are displayed. Study recruitment was designed to equalize groups on gender, age, race, and smoking status. While there were no significant differences in age, race, marital or smoking status, there were significant differences in education and employment, with the cocaine group demonstrating significantly lower educational (p < 0.001) and employment levels (p < 0.001).
Craving
Thirty-one of 54 (57%) cocaine-dependent subjects and none
Discussion
In the present study, subjective and neuroendocrine responses to cocaine cues and a social stress task were compared in cocaine-dependent and control men and women matched on age, race, and smoking status. There were gender differences in the relationships between subjective ratings of craving across the tasks, which are consistent with the observation that social stressors may be more closely associated with relapse for cocaine-dependent women as compared to men. The results of this study also
Role of funding sources
Funding for this study was provided by NIMH Grants P50 DA016511-07 and M01 RR001070-31; the NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. This study was partially funded by NIH-NIDA grant P60 DA05130-21 and New York State OASAS grant C003189.
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgments
We thank the study participants for volunteering their time. Thanks also to Liz Santa Ana, Lisa Jenkins, Amanda Sensenig, and Urmo Jaanimägi for assisting with project coordination and recruitment.
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2014, Advances in PharmacologyCitation Excerpt :As an extension of the same project, additional data were subsequently collected in 27 cocaine-dependent males and 13 cocaine-dependent females in order to better ascertain sex differences in these cocaine-related stress system neuroadaptations (Fox, Morgan, & Sinha, 2013). As mentioned earlier, many prior studies show robust sex variation in the stress- and cue-induced craving state (Brady et al., 2006; Colamussi, Bovbjerg, & Erblich, 2007; Fox, Hong, et al., 2009; Kajantie & Phillips, 2006; Saladin et al., 2012; Waldrop, Back, Verduin, & Brady, 2007; Waldrop et al., 2010) with women generally reporting significantly higher ratings of anxiety, stress, and negative affect (Back et al., 2005; Chaplin et al., 2008; Fox, Hong, Siedlarz, & Sinha, 2008; Fox & Sinha, 2009) alongside unique sympathetic dysregulation patterns compared with those of men (Fox et al., 2006; Fox, Hong, et al., 2009). Preclinical studies have also shown sex diversity, with female rats displaying longer HPA axis activation and greater norepinephrine response to stressors compared to male rats (Heinsbroek et al., 1990; Heinsbroek, Van Haaren, Van de Poll, & Steenbergen, 1991).