Sex Steroid Hormones, Stress Response, and Drug Craving in Cocaine-Dependent Women: Implications for Relapse Susceptibility

Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA.
Experimental and Clinical Psychopharmacology (Impact Factor: 2.63). 10/2007; 15(5):445-52. DOI: 10.1037/1064-1297.15.5.445
Source: PubMed

ABSTRACT Cocaine dependence is associated with an enhanced sensitivity to stress and drug craving. Increases in stress-induced craving and hypothalamic-pituitary-adrenal reactivity are also predictive of cocaine relapse outcomes. More important, sex differences in these responses have also been reported. To further understand the basis of the sex differences, the authors examined the influence of sex steroid hormones on subjective and physiological stress responses and drug craving in cocaine-dependent women. Women who had low progesterone levels (n=5) were compared with those with high progesterone levels (n=5) and with those with moderate levels of estradiol and progesterone (n=9) in their responses during exposure to stress, cocaine cues, and neutral imagery conditions. The high progesterone group showed significantly lower stress-induced and drug cue-induced cocaine craving ( p<.05) and reduced drug cue-induced anxiety levels ( p<.08) and lower drug cue-induced systolic and diastolic blood pressure levels compared with the low progesterone group. These data suggest that there are significant effects of sex steroid hormones on stress and drug cue-induced cocaine craving, anxiety, and cardiovascular responses. In particular, high progesterone during the midluteal phase of the cycle was associated with decreased stress-induced and drug cue-induced craving and decreased cue-induced anxiety and blood pressure responses. These findings are consistent with previous preclinical and clinical studies of progesterone's effects on the behavioral responses to cocaine and warrant further research to examine the effects of progesterone on stress-induced cocaine craving, stress arousal, and cocaine relapse susceptibility in women.

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    • "Treatment with P reduced cocaine seeking precipitated by yohimbine, cocaine, cocaine+cocaine-paired cues, and yohimbine+cocaine-paired cues. That this investigation found that exogenously administered P did not decrease cocaine seeking in response to cocaine-paired cues in rats was in contrast to clinical reports showing reduced cocaine-paired cue-induced craving during phases of high endogenous P (Sinha et al. 2007); however, under control conditions, responding precipitated by cues was relatively low compared to other work on cue-induced reinstatement collected in the same laboratory (Anker and Carroll 2010, 2011). These results may be explained by the multicomponent reinstatement procedure whereby cues were presented many times over the course of 20 sessions, facilitating extinction to these stimuli. "
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    ABSTRACT: Individually, both treatment with progesterone and concurrent access to an exercise wheel reduce cocaine self-administration under long-access conditions and suppress cocaine-primed reinstatement in female rats. In the present study, wheel running and progesterone (alone and combined) were assessed for their effects on reinstatement of cocaine-seeking primed by yohimbine, cocaine, and cocaine-paired cues. Male and female rats were implanted with an intravenous catheter and allowed to self-administer cocaine (0.4 mg/kg/inf, iv) during 6-h sessions for 10 days. Subsequently, the groups of male and female rats were each divided into two groups that were given concurrent access to either a locked or unlocked running wheel under extinction conditions for 14 days. Next, all four groups were tested in a within-subjects design for reinstatement of cocaine-seeking precipitated by separate administration of cocaine-paired stimuli, yohimbine, or cocaine or the combination of yohimbine + cocaine-paired stimuli or cocaine + cocaine-paired stimuli. These priming conditions were tested in the presence of concurrent wheel access (W), pretreatment with progesterone (P), or both (W + P). In agreement with previous results, females responded more for cocaine than males during maintenance. Additionally, concurrent wheel running attenuated extinction responses and cocaine-primed reinstatement in females but not in males. Across all priming conditions, W + P reduced reinstatement compared to control conditions, and for cocaine-primed reinstatement in male rats, the combined W + P treatment was more effective than W or P alone. Under certain conditions, combined behavioral (exercise) and pharmacological (progesterone) interventions were more successful at reducing cocaine-seeking behavior than either intervention alone.
    Psychopharmacology 03/2014; 231(18). DOI:10.1007/s00213-014-3513-6 · 3.99 Impact Factor
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    • "). Our findings are also limited by our not having collected menstrual-phase data, which might have increased our power to detect sex differences (Sinha et al., 2007; Sofuoglu et al., 2002, 1999). Like most studies of sex differences in humans, this one cannot distinguish the extent to which any of the differences found were mediated by innate biological differences or by cultural differences. "
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    ABSTRACT: BACKGROUND: Studies of sex differences have shown that men and women with drug-use disorders differ in course and outcome and in cue-induced activation of putative brain "control network" areas. We evaluated sex differences in daily functioning and subjective events related to drug use with ecological momentary assessment (EMA). METHODS: EMA data were collected from cocaine- and heroin-using outpatients (72 men; 42 women) in methadone maintenance in 2-5 randomly prompted (RP) entries per day and in participant-initiated entries for heroin or cocaine use or craving, for up to 25 weeks. Urine drug screens were conducted three times weekly. Data were analyzed via repeated-measures logistic regression, using sex as a predictor of responses. RESULTS: In RP reports, women and men reported significantly different patterns of drug-cue exposure, with women significantly more likely to report having seen cocaine or been tempted to use in the past hour. Women also had higher craving after past-hour exposure to drug cues. In reports of drug use, women, compared to men, were more likely to report that they had used more cocaine than they had meant to, tended to feel guilty more often after drug use, and to have used despite trying not to use. CONCLUSIONS: These findings provide real-time behavioral evidence that women respond differently than men to exposure to drug cues and to drug use, consistent with laboratory and brain-imaging findings. This information may be useful for development of sex-specific treatment strategies.
    Drug and alcohol dependence 01/2013; 132(1-2). DOI:10.1016/j.drugalcdep.2012.12.025 · 3.28 Impact Factor
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    • "Much research surrounding progestogens' effects on drug abuse have focused on cocaine. Autonomic, pleasurable effects, stressinduced cravings, and self-administration for cocaine are reduced when hormone levels are high in women during the luteal phase (Sofuoglu et al., 1999; Evans et al., 2002; Evans and Foltin, 2006; Sinha et al., 2007) and in rats during the proestrus phase (Hecht et al., 1999; Feltenstein and See, 2007). Administration of P 4 to women attenuates subjective and HPA axis autonomic effects of cocaine and reduces craving (Sofuoglu et al., 2002, 2004; Evans and Foltin, 2006). "
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    ABSTRACT: Maternal-offspring interactions begin prior to birth. Experiences of the mother during gestation play a powerful role in determining the developmental programming of the central nervous system. In particular, stress during gestation alters developmental programming of the offspring resulting in susceptibility to sex-typical and stress-sensitive neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. However, neither these effects, nor the underlying mechanisms, are well understood. Our hypothesis is that allopregnanolone, during gestation, plays a particularly vital role in mitigating effects of stress on the developing fetus and may mediate, in part, alterations apparent throughout the lifespan. Specifically, altered balance between glucocorticoids and progestogens during critical periods of development (stemming from psychological, immunological, and/or endocrinological stressors during gestation) may permanently influence behavior, brain morphology, and/or neuroendocrine-sensitive processes. 5α-reduced progestogens are integral in the developmental programming of sex-typical, stress-sensitive, and/or disorder-relevant phenotypes. Prenatal stress (PNS) may alter these responses and dysregulate allopregnanolone and its normative effects on stress axis function. As an example of a neurodevelopmental, neuropsychiatric, and/or neurodegenerative process, this review focuses on responsiveness to drugs of abuse, which is sensitive to PNS and progestogen milieu. This review explores the notion that allopregnanolone may effect, or be influenced by, PNS, with consequences for neurodevelopmental-, neuropsychiatric-, and/or neurodegenerative- relevant processes, such as addiction.
    Frontiers in Psychiatry 10/2011; 2:52. DOI:10.3389/fpsyt.2011.00052
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