Sex Differences in Progesterone Effects on Responses to Stress and Drug Cues
Status:
Completed
Trial end date:
2013-09-01
Target enrollment:
Participant gender:
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.