Stress, drug cue exposure and cocaine itself potently stimulate stress and reward systems in the brain andeach increase drug craving, thereby increasing the susceptibility to relapse. Women, in particular, show agreater stress and negative affect related susceptibility to relapse. Previous SCOR-related research showsclear sex differences in stress responses, behavioral effects of cocaine and in negative affect and anxietyassociated with cocaine craving and stress related relapse susceptibility. However, no previous research hasexamined the basis of sex differences in stress and cue induced craving and arousal, both of which are knownto increase relapse susceptibility. Cumulating evidence suggest that gonadal hormones, estradiol (E) andprogesterone (P), may contribute to these sex differences. While E enhances behavioral responses tococaine, P attenuates subjective, behavioral and physiological responses to cocaine. Whether gonadalhormones such as progesterone affect stress and drug cue-induced craving, and mediate vulnerability tococaine relapse, especially in women has been studied thus far. Our preliminary findings in cocainedependent women suggested that high levels of luteal phase P was associated with decreases in stress anddrug cue-induced drug seeking, anxiety and blood pressure responses. On the basis of these data, wehypothesize that progesterone treatment vs. placebo will decrease stress and drug cue-induced cocainecraving, negative affect and alter physiological and HPA responses to stress, and these changes will begreater in women than men. In a sample of 120 treatment-seeking cocaine dependent men and women (60men and 60 women), the following specific aims are proposed: (1) to examine if progesterone alters stressand cue-induced craving, anxiety and negative emotion responses in cocaine dependent men and women,with sex differences in these effects; (2) To assess progesterone's sex-specific effects on HPA axismeasures (ACTH, cortisol and prolactin) during stress and drug cue exposure; (3) To examineprogesterone's sex-specific effects on cardiovascular responses to stress and drug cue exposure and toassess its effects on plasma catecholamines; (4) To explore whether progesterone's effects on craving, HPAaxis and sympathetic responses are associated with neuroactive steroids and whether these are differentiallyaffected in men and women. Findings from this study will (A) provide a greater understanding of the effectsof progesterone, a key gonadal hormone, and it's role in stress regulation, stress-related cocaine seekingand relapse vulnerability, and (B)contribute crucial information needed to develop progesterone as apotential pharmacotherapy to prevent stress-related cocaine relapse in women.
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