Abstract

Stress, drug cue exposure and cocaine itself potently stimulate brain stress and reward systems, and each increase drug craving, thereby increasing the susceptibility to relapse. Women show a greater stress and negative affect related susceptibility to relapse. Previous SCOR-related research shows clear sex differences in both the stress responses, behavioral effects of cocaine and in stress-related relapse susceptibility. Cumulating evidence suggest that gonadal hormones, estradiol (E) and progesterone (P), may contribute to these sex differences. While E enhances behavioral responses to cocaine, P attenuates subjective, behavioral and physiological responses to cocaine. Whether gonadal hormones such as progesterone affect stress and drug cue-induced craving, and mediate vulnerability to cocaine relapse, especially in women, remains unknown. Our preliminary findings in cocaine dependent women suggests that high levels of luteal phase P was associated with decreases in stress and drug cue-induced drug seeking, anxiety and blood pressure responses. On the basis of these data, we propose a controlled inpatient laboratory study to assess whether progesterone vs. placebo will decrease stress and drug cue-induced cocaine craving, negative affect and alter physiological and HPA responses to stress, and these effects will be stronger in a sample of treatment-seeking cocaine dependent women compared to men.

Findings from this study will:

1. provide a greater understanding of the effects of progesterone, a key gonadal hormone, important in cocaine reward and stress regulation, stress-related drug seeking and relapse vulnerability; and
2. contribute crucial information needed to develop progesterone as a potential pharmacotherapy to prevent stress-related cocaine relapse in women.
   
   

Relevant Previous Publications (In Print)

Sofuoglu M, Dudish-Poulsen S, Nelson D, Pentel PR, Hatsukami DK. Sex and menstrual cycle differences in the subjective effects from smoked cocaine in humans. Exp Clin Psychopharmacol 1999; 7(3): 274-83.

Sofuoglu M, Babb DA, Hatsukami DK. Progesterone treatment during the early follicular phase of the menstrual cycle: effects on smoking behavior in women. Pharmacol Biochem Behav 2001; 69(1-2): 299-304.

Sofuoglu M, Babb DA, Hatsukami DK. Effects of progesterone treatment on smoked cocaine response in women. Pharmacol Biochem Behav 2002; 72(1-2): 431-5.

Sofuoglu M, Mitchell E, Kosten TR. Effects of progesterone treatment on cocaine responses in male and female cocaine users. Pharmacol Biochem Behav 2004; 78(4): 699-705.

Sinha R, Talih M, Malison, R, Anderson GA, Cooney N, Kreek MJ (2003). Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states. Psychopharmacology, 170, 62-72.

Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ (2006). Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Archives of General Psychiatry, 63, 324-331.

Fox HC, Garcia M, Kemp K, Milivojevic V, Kreek MJ, Sinha R (2006). Gender differences in cardiovascular and corticoadrenal response to stress and drug cues in cocaine dependent individuals. Psychopharmacology (Berl). 2006 Apr;185(3):348-57.

Sinha R, Catapano D, O'Malley SS (1999). Stress-induced craving and stress responses in cocaine dependent individuals. Psychopharmacology, 142, 343-351.

Sinha R, Fuse T, Renee-Aubin L, O’Malley SS (2000). Psychological stress, drug cues and cocaine craving. Psychopharmacology, 152(2), 140-148.

Sinha R (2001). How does stress increase risk of drug abuse and relapse? Psychopharmacology, 158, 343-359.