Background Cocaine dependence is a chronic relapsing disorder characterized by periods of abstinence and high rates of return to drug using behavior. Elevated levels of stress have been associated with relapse to cocaine; however, the nature of this association is not well understood. Methods The relationship between reactivity to three human laboratory provocations and relapse to cocaine was investigated. Participants were 53 cocaine-dependent individuals who were admitted for a 2-day inpatient stay during which a psychosocial provocation (i.e., the Trier Social Stress Task), a pharmacological provocation (i.e., administration of 1ųg/kg corticotrophin releasing hormone; CRH), and a drug cue exposure paradigm were completed. Adrenocorticotrophic hormone (ACTH), cortisol, heart rate, and subjective cocaine craving and stress were assessed at baseline and at multiple time points post-task. Participants’ cocaine use was monitored for approximately one month following testing. Results The majority (72.3%) of participants relapsed to cocaine during the follow-up period. In response to the CRH and drug cue exposure, elevated subjective craving and stress were significant predictors of cocaine use during follow-up. In response to the Trier, attenuated neuroendocrine responses were significant predictors of cocaine use. Conclusions The findings provide further evidence of the ability of laboratory paradigms to predict relapse. The observed associations between stress reactivity and subsequent cocaine use highlight the clinical importance of the findings. Predictors of relapse may vary based on the type of provocation utilized. Interventions aimed at normalizing stress response, as measured using laboratory paradigms, may prove useful in relapse prevention.

Although research suggests that ovariectomy (ovx) is detrimental to spatial cognition in young rats, little work has evaluated the cognitive effects of ovx in aged rats. The authors investigated the effects of ovx in aged rats using the water radial-arm maze. In Study 1, young rats and aged rats receiving ovx 1.5 months before testing outperformed aged rats receiving sham surgery or ovx 21 days before testing. In Study 2, young rats and aged rats receiving ovx 2.0 or 6.0 months before testing outperformed aged sham rats. Aged rats exhibited estradiol and elevated progesterone levels comparable to those of young rats. The findings suggest that 1.5-6.0 months, but not 21 days, of ovx improves spatial memory in aged rats. The hypothesis that long-term ovarian hormone loss is detrimental to spatial memory in aged rats was not supported. The authors hypothesize that removal of elevated progesterone levels is related to the ovx-induced cognitive enhancement.

Summary There are likely to be gender differences in determinants of relapse to drug use following abstinence in cocaine-dependent individuals. Cocaine-dependent women are more likely to attribute relapse to negative emotional states and interpersonal conflict. Cocaine dependence has also been linked to dysregulation of stress response and the hypothalamic pituitary adrenal (HPA) axis which may differ between genders. Subjective and HPA axis responses to a social evaluative stressor, the Trier Social Stress Test (TRIER), and in vivo cocaine-related cues were examined in the present study. Results There were no gender differences in magnitude of craving responses to the TRIER or the CUE. Both genders had a greater craving response to the CUE than to the TRIER, but the magnitude of the difference was greater for men than women (p=0.04). Cocaine-dependent subjects, compared to the control group, had significantly higher response throughout the TRIER (p<0.0001) and CUE (p<0.0001) testing sessions. There were no gender differences and no gender by cocaine interaction for ACTH responses to the TRIER, although women had lower baseline ACTH (p=0.049). On the CUE task, in contrast, female cocaine-dependent subjects had a more blunted ACTH response than did the other three groups (p=0.02). Female cocaine-dependent subjects also had a lower odds of a positive cortisol response to the TRIER as compared to the other three groups (OR=0.84, 95% CI=[0.02, 1.01]). During the CUE task, cocaine-dependent subjects had overall higher mean cortisol levels (p=0.0001), and higher odds of demonstrating a positive cortisol response to the CUE (OR=2.61, 95% CI=[1.11, 6.11]). No gender differences were found in ACTH responses to the CUE. The results are reviewed in the context of the existing literature on gender differences in cocaine dependence and potential implications for treatment are discussed.

Rationale Cue-elicited craving and stress responses have been identified as predictors of relapse in drug dependence, but little research exists on the contribution of these factors to marijuana use specifically. Objectives The aims of the present study were to evaluate (1) responses to a psychological stressor, (2) responses to marijuana-related cues, and (3) if an exposure to a psychological stressor augmented craving subsequently elicited by marijuana-related cue exposure in marijuana-dependent individuals. Methods Subjective (craving, stress), neuroendocrine (ACTH, cortisol), and physiologic responses to the presentation of neutral and marijuana cues were assessed after randomization to a stress (Trier Social Stress Task; TSST) or no-stress control condition in marijuana-dependent individuals. Outcome measures were assessed at baseline, post-stressor/pre-neutral cue, post-neutral cue, and post marijuana cue. Results 87 participants completed procedures (stress group, n=45; non-stress group, n=42). The stress group had a significant increase over the non-stressed group in stress rating (p<0.001), craving (p=0.028), cortisol (p<0.001), and ACTH (p<0.001) after completion of the TSST. An increased craving response for all participants was seen following presentation of the marijuana cues (p=0.005). Following the TSST or no-stress condition, the non-stressed group had an increase in craving to marijuana cues as compared to neutral cues (p=0.002); an increase in craving was not observed in the stress group (p=0.404). Conclusions Marijuana cue exposure and a social stressor increased craving in marijuana-dependent individuals. Completion of the TSST did not increase craving response to subsequent marijuana-cue exposure.

Background-D-cycloserine (DCS), a partial glutamate NMDA receptor agonist, enhances extinction of conditioned fear responding in rodents and facilitates exposure-based learning in humans with anxiety disorders.

Rationale D-cycloserine (DCS), a partial glutamate NMDA receptor agonist, enhances extinction of conditioned fear responding; preliminary data suggests that it may facilitate extinction of drug cue reactivity. Objective This study investigates DCS effects on cocaine cue craving and drug use in cocaine-dependent subjects. Methods Thirty-two subjects were randomly assigned to receive 1) DCS only, 2) DCS before sessions 1 and 3, PBO before session 2 or 3) PBO only 15-min before each of 3 1-hour cocaine cue exposure sessions conducted 1 day apart. Craving ratings were obtained before, during and after sessions. Drug use and cue-induced craving were assessed 1 week after the last cue session. Results Repeated presentation of cocaine cues resulted in decreased craving both within and between sessions. DCS did not facilitate extinction learning and may have enhanced craving. The group that received 3 doses of DCS had significantly higher craving than the PBO group at the baseline ratings taken before sessions 2 and 3, as well as significantly higher cue-induced craving at follow-up. The group that received 2 doses of DCS did not differ from the PBO group. There were no group differences in post-extinction cocaine use. Conclusions The reduction of cocaine cue reactivity in the PBO group suggests that the study procedures were sufficient to produce extinction. Under these conditions, DCS did not facilitate extinction and may have enhanced craving. Further studies of glutamatergic agents and extinction in cocaine dependence should include consideration of procedural variables that could have a major impact on study outcomes.

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