Sex Differences in Progesterone Effects on Responses to Stress and Drug Cues
Condition: Cocaine Dependence
MeSH terms: Cocaine-Related Disorders
Study type: Interventional
Phase: Phase 1

Summary: 
      Cocaine dependence is a chronic, relapsing disorder in which stress/negative mood and
      exposure to drug-related stimuli or "cues" are associated with high rates of relapse (McKay
      et al., 1995; O'Brien et al., 1998; R. Sinha, 2001; Shaham et al., 2003). In particular, sex
      differences in relapse precipitants have been noted, with women reporting greater stress
      related relapses while men report higher number of relapses associated with drug
      cue/temptation situations (Lex, 1991; McKay et al., 1996; R. Sinha, 2001; R. Sinha,
      Rounsaville BJ, 2002). Current SCOR studies have shown that stress and cocaine cues increase
      drug craving and stress related arousal, responses that differ in cocaine men and women (R.
      Sinha et al., 2003; H.C. Fox et al., 2005a). Furthermore, stress-induced cocaine craving and
      HPA responses are predictive of cocaine relapse, which is also moderated by gender (R. Sinha
      et al., 2006). However, no previous research has examined the basis of sex differences in
      stress and cue induced craving and arousal, both of which are known to increase relapse
      susceptibility. Greater knowledge of the sex-specific neurobiology of cocaine dependence will
      facilitate development of gender-specific cocaine relapse prevention efforts.

      Growing evidence supports a role for gonadal hormones in explaining the sex differences
      observed in stress responses as well as in the behavioral responses to cocaine (Festa &
      Quinones-Jenab, 2004; K. Carroll, Fenton LR, Ball SA, Nich C, Frankforter TL, Shi J,
      Rounsaville BJ, 2004; Lynch, 2006; Kajanti & Phillips, 2006). Estrogen increases behavioral
      responses to cocaine, while presence of progesterone decreases subjective and behavioral
      effects of cocaine, more so in females than males (Jackson et al., 2006; Sofuogu et al.,
      1999; M. Sofuoglu et al., 2002; Evans & Foltin, 2006). Stress and cocaine each enhance brain
      stress circuits, namely the corticotrophin releasing factor
      (CRF)-hypothalamic-pituitary-adrenal (HPA) axis and central
      noradrenergic/sympatho-adrenomedullary (SAM) pathways and both activate the mesolimbic
      dopaminergic systems involved in the rewarding effects of cocaine (ADD REFS). Exposure to
      Stress, cocaine or cocaine cues will each increase cocaine craving and HPA axis responses.
      Importantly, progesterone which affects behavioral responses to cocaine, also plays a key
      role in stress regulation. However, it is not known whether progesterone alters
      stress-induced and drug cue-induced craving and related stress arousal, markers that predict
      cocaine relapse outcomes. Our preliminary data suggest that women exposed to stress and to
      drug cues in the laboratory during the luteal phase (high progesterone) show lower stress
      induced and drug cue-induced craving, anxiety and cortisol responses compared to those in the
      late follicular phase (high estrogen) (see preliminary Studies section CX). On the basis of
      this previous research, we propose a double-blind placebo controlled study of to examine
      progesterone's effects on stress and cue-related responses in cocaine dependent men and
      women. We hypothesize that high dose of progesterone (200 mg bid) vs. placebo will alter
      stress-induced cocaine craving, negative affect, physiological and HPA responses to stress,
      and these changes will be greater in women than men.
    


Intervention name(s): Progesterone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 200mg BID for 5 days; Placebo
Intervention MeSH terms: Progesterone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)