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: 2.71). 10/2007; 15(5):445-52. DOI: 10.1037/1064-1297.15.5.445
Source: PubMed


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 · 3.88 Impact Factor
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    • "Individual differences in progesterone (P) levels in women appear to be one factor mediating this relationship. For instance, high P levels have been associated with lower stress and cue-induced craving, anxiety, and cardiovascular reactions (37). This effect may occur because P is a potent positive enhancer of GABA receptors, and GABA is an inhibitory neurotransmitter which diminishes dopamine, reducing stress responses, drug reward, and drug cravings (37). "
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    ABSTRACT: Binge eating disorder (BED) and seasonal affective disorder (SAD) were first described as clinically-relevant conditions in very close temporal proximity a few decades ago. Both disorders have a higher prevalence rate in woman than in men, are characterized by a high proneness-to-stress and manifest heightened responsiveness to high-calorie, hyper-palatable foods. In recent years, a compelling body of evidence suggests that foods high in sugar and fat have the potential to alter brain reward circuitry in a manner similar to that seen when addictive drugs like alcohol and heroin are consumed in excess. These findings have led to suggestions that some cases of compulsive overeating may be understood as an addiction to sweet, fatty, and salty foods. In this paper, it is proposed that high seasonality is a risk factor for binge eating, especially in those characterized by anxious and impulsive personality traits – associations that could only occur in an environment with a superfluity of, and easy access to, rich and tasty foods. Given the well-established links between binge eating and addiction disorders (22-24 for reviews), it is also suggested that seasonality, together with the same high-risk psychological profile, exacerbates the likelihood of engaging in a broad range of addictive behaviors. Data from a community sample (n=412) of adults tested these models using linear regression procedures. Results confirmed that symptoms of binge eating and other addictive behaviors were significantly inter-correlated, and that seasonality, gender, and addictive personality traits were strong statistical predictors of the variance in binge-eating scores. Seasonality and addictive personality traits also accounted for a significant proportion of the variance in the measure of addictive behaviors. Conclusions are discussed in the context of brain reward mechanisms, motivational alternations in response to chronic over-consumption, and their relevance for the treatment of excess
    Frontiers in Psychiatry 12/2013; 4:183. DOI:10.3389/fpsyt.2013.00183
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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 · 3.42 Impact Factor
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