Stress and drug-cue-induced craving in opioid-dependent individuals in naltrexone treatment

BACKGROUND: Naltrexone is a nonaddictive medication that blocks the euphoric effects of opioids. However, naltrexone treatment is associated with high rates of noncompliance and opioid relapse, possibly because it does not reduce stress and protracted withdrawal symptoms during early recovery. Prior clinical and preclinical research has indicated that both stress and drug-cue-related arousal response is associated with craving and vulnerability to relapse in a range of drug-using populations. AIMS: To examine opioid craving and the subjective and cardiovascular response to stress and drug cues in naltrexone-treated opioid abusers. METHOD: Eleven men and three women engaged in naltrexone treatment for opioid dependence. They were exposed to personalized stress, drug-cue, and neutral-relaxing imagery in a single laboratory session. Subjective (craving, emotion) and cardiovascular (heart rate, systolic blood pressure, and diastolic blood pressure) measures were assessed. RESULTS: Stress and drug-cue-related imagery significantly increased opioid craving, anxiety, and negative emotions and significantly decreased positive emotions compared to neutral imagery. Selective emotional responses were greater in the stress condition than in the drug-cue condition. Only stress-related imagery was associated with an increased cardiovascular response. CONCLUSIONS: Naltrexone-treated opioid abusers demonstrate vulnerability to stress and drug-cue-induced craving and arousal responses that may contribute to the high rates of noncompliance and relapse among opioid-dependent individuals undergoing naltrexone treatment. Pharmacological and behavioral interventions that specifically target the negative affectivity that co-occurs with drug-cue and stress-induced craving could be of benefit in improving naltrexone treatment outcomes in opioid dependence.     

Gender differences in the neural correlates of response inhibition during a stop signal task

We used functional magnetic resonance imaging to examine gender differences in the neural correlates of response inhibition during a stop signal task. The task has a frequent "go" signal to set up a pre-potent response tendency and a less frequent "stop" signal for subjects to withhold their response. A contrast in brain activation was made between successful and failed inhibitions for individual subjects. We compared 20 men and 20 women matched in age and years of education and in stop signal performance, with stop success rate, post-error slowing and task-related frustration ratings as covariates. The results showed greater activation in men, compared to women, in a wide array of cortical and subcortical areas, including the globus pallidus and motor thalamus during stop signal inhibition. In contrast, no brain regions demonstrated greater activation in women, even at a lower statistical threshold. Moreover, while men activated the medial superior frontal and anterior cingulate cortices, women activated the caudate tail to mediate response inhibition. These results extended gender differences in regional brain activation to response inhibition during a cognitive motor task. Men activated the motor circuitry while women appeared to involve visual association or habit learning during stop signal performance.     

Neural correlates of impulse control during stop signal inhibition in cocaine-dependent men.

Altered impulse control is associated with substance use disorders, including cocaine dependence. We sought to identify the neural correlates of impulse control in abstinent male patients with cocaine dependence (PCD). Functional magnetic resonance imaging (fMRI) was conducted during a stop signal task that allowed trial-by-trial evaluation of response inhibition. Fifteen male PCD and 15 healthy control (HC) subjects, matched in age and years of education, were compared. Stop signal reaction time (SSRT) was derived on the basis of a horse race model. By comparing PCD and HC co-varied for stop success rate, task-related frustration rating, and post-error slowing, we isolated the neural substrates of response inhibition, independent of attentional monitoring (of the stop signal) and post-response processes including affective responses and error monitoring. Using region of interest analysis, we found no differences between HC and PCD who were matched in stop signal performance in the pre-supplementary motor area (pre-SMA) previously shown to be associated with SSRT. However, compared with HC, PCD demonstrated less activation of the rostral anterior cingulate cortex (rACC), an area thought to be involved in the control of stop signal inhibition. The magnitude of rACC activation also correlated negatively with the total score and the impulse control subscore of the Difficulty in Emotion Regulation Scale in PCD. The current study thus identified the neural correlates of altered impulse control in PCD independent of other cognitive processes that may influence stop signal performance. Relative hypoactivation of the rACC during response inhibition may represent a useful neural marker of difficulties in impulse control in abstinent cocaine-dependent men who are at risk of relapse.     

A gender specific psychometric analysis of the early trauma inventory short form in cocaine dependent adults

This study evaluated the gender specific psychometric properties of the Early Trauma Inventory-Short Form (ETI-SF) in a clinical sample of cocaine dependent men (N=58) and women (N=34). Participants were administered the ETI-SF, the Childhood Trauma Questionnaire Short Form (CTQ-SF), and the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Tests of internal consistency, convergent validity, and predictive validity were conducted separately by gender. Findings indicated that the ETI-SF demonstrated good internal consistency; Cronbach's alpha ranged from 0.73 to 0.80 for men and from 0.70 to 0.77 for women. The measure also demonstrated good convergence with the CTQ-SF in both sexes, indicating that reports of child maltreatment are consistent across interview and self-report measures. Further, predictive validity was demonstrated by the ability of various ETI-SF scales to predict the co-occurrence of psychiatric disorders commonly associated with early trauma. These included lifetime diagnosis of PTSD in men and women, the lifetime diagnosis of major depressive disorder in men, and the lifetime diagnoses of alcohol use disorders in women. The findings support the utility of the ETI-SF as a clinical research tool to obtain data on specific types of early trauma in drug abusing samples.     

Neural activity associated with stress-induced cocaine craving: a functional magnetic resonance imaging study

Objective Stress is known to increase cocaine craving and relapse risk in cocaine dependence. Identifying neural activity associated with stress and stress-induced cocaine craving is important in understanding the neurobiology of cocaine craving and relapse.Method Blood oxygenation level dependent (BOLD) signal changes were assessed in a functional magnetic resonance imaging (fMRI) session with healthy controls and treatment-engaged, abstinent, cocaine-dependent individuals (patients) as they participated in brief guided imagery and recall of three personal stress and three personal neutral situations.Results During stress, patients showed significantly less BOLD activation than controls in specific frontal and para-limbic regions, such as the anterior cingulate (AC) region, left hippocampal/parahippocampal region, right fusiform gyrus, and the right postcentral gyrus. On the other hand, patients had increased activity in the caudate and dorsal striatum region during stress, activation that was significantly associated with stress-induced cocaine craving ratings.Conclusions Patients failed to activate AC and related circuits during stress, regions associated with control, and regulation of emotion and distress states. Instead, they exhibited greater craving-related activation in the dorsal striatum, a region related to reward pathways and part of the obsessive–compulsive circuitry. Such functional alterations in stress processing may underlie the stress-related vulnerability to cocaine relapse often observed in cocaine-dependent individuals in early recovery.     

Engaging young probation-referred marijuana-abusing individuals in treatment: a pilot trial

Young marijuana abusers rarely seek treatment themselves and are difficult to engage in treatment when referred by social agencies. To evaluate treatment engagement strategies in this population, 65 young probation-referred marijuana abusers were randomly assigned to either three-session motivational enhancement therapy (MET alone) or three-session MET plus contingency management (MET/CM), with vouchers for treatment attendance. A significantly higher number of participants in the MET/CM condition completed the three-session intervention as compared with MET alone. Participants in both conditions reported significant reductions in marijuana use and improvement in legal problems. These findings suggest that young marijuana abusers benefit from scientifically validated treatments.     

Substance abuse treatment characteristics of probation-referred young adults in a community-based outpatient program

Although rates of substance abuse continue to rise among young adults ages 18-25, there is little information on the clinical characteristics of young adults referred to treatment, their readiness to change substance use behaviors, and treatment outcomes. These aspects were examined in young (18-25 years old) and older adult (26-45 years old) substance abusers entering treatment at a large, urban, outpatient substance abuse treatment facility. All clients were referred for outpatient treatment by the local Offices of Adult Probation during 1998-1999. The demographic and substance use characteristics, motivation level/readiness to change substance use behaviors, treatment attendance, completion, and "drug-free" status based on patient self-report and urine/breathalyzer data were assessed. Results. Substance-abusing young adult probationers were more likely to be African-American, with a significantly earlier age of onset of primary substance use. They were more likely to have a marijuana use disorder as compared with older adults, who in turn, were more likely to meet criteria for alcohol use disorders. Furthermore, as compared with older adults, young adults had significantly higher scores on precontemplation, and significantly lower scores on contemplation, determination, action, and maintenance subscales of motivation/change readiness. A significantly higher number of young adults did not complete outpatient treatment and were "drug-positive" at discharge, as compared with older adults. Conclusions. Young adult probationers referred to substance abuse treatment show significantly different substance abuse and treatment characteristics as compared with their older adult counterparts. The findings suggest that specialized treatment approaches that focus on enhancing treatment readiness and motivation to change substance use behaviors may be of particular benefit to substance abusing young adults.     

Effects of ethanol on the acoustic startle reflex in humans

The effect of ethanol on human sensorimotor reactivity was assessed by examining the acoustic startle response. Twelve healthy normal subjects participated in a startle reflex experiment in which placebo or ethanol were given on separate days. Three types of startle probes were used. They consisted of pulse-alone bursts of white noise at 108 dB(A) and 99 dB(A) to explore startle reactivity, and of a 108 dB(A) pulse preceded by a 85 dB(A) prepulse stimulus (prepulse + pulse) to assess prepulse inhibition. Startle amplitude was larger to the 108 dB(A), compared to the 99 dB(A) pulse-alone probes. The prepulse stimulus significantly reduced the amplitude of the startle reflex elicited by the subsequent 108 dB(A) stimulus. The amplitude of the startle response was dramatically reduced by acute ethanol. The effects of ethanol on prepulse inhibition could not be assessed because the startle response was too small in the ethanol condition.Supported by grant 1 RO1 AA0803-01A1 to Dr. O'Malley     

Common and gender-specific associations with cocaine use on gray matter volume: Data from the ENIGMA addiction working group

Gray matter volume (GMV) in frontal cortical and limbic regions is susceptible to cocaine-associated reductions in cocaine-dependent individuals (CD) and is negatively associated with duration of cocaine use. Gender differences in CD individuals have been reported clinically and in the context of neural responses to cue-induced craving and stress reactivity. The variability of GMV in select brain areas between men and women (e.g., limbic regions) underscores the importance of exploring interaction effects between gender and cocaine dependence on brain structure. Therefore, voxel-based morphometry data derived from the ENIGMA Addiction Consortium were used to investigate potential gender differences in GMV in CD individuals compared to matched controls (CTL). T1-weighted MRI scans and clinical data were pooled from seven sites yielding 420 gender- and age-matched participants: CD men (CDM, n = 140); CD women (CDW, n = 70); control men (CTLM, n = 140); and control women (CTLW, n = 70). Differences in GMV were assessed using a 2 × 2 ANCOVA, and voxelwise whole-brain linear regressions were conducted to explore relationships between GMV and duration of cocaine use. All analyses were corrected for age, total intracranial volume, and site. Diagnostic differences were predominantly found in frontal regions (CD < CTL). Interestingly, gender × diagnosis interactions in the left anterior insula and left lingual gyrus were also documented, driven by differences in women (CDW < CTLW). Further, lower right hippocampal GMV was associated with greater cocaine duration in CDM. Given the importance of the anterior insula to interoception and the hippocampus to learning contextual associations, results may point to gender-specific mechanisms in cocaine addiction.     

Altered levels of sex and stress steroid hormones assessed daily over a 28-day cycle in early abstinent cocaine-dependent females

Rationale There is growing evidence of alterations in brain stress and reward circuits associated with cocaine dependence. Sex differences are also documented and sex steroid hormones have been linked to cocaine reinforcement. Objectives The current study therefore assessed daily fluctuations in stress and sex hormones in cocaine-dependent females compared with healthy females. Method Daily salivary samples of cortisol, progesterone, and estradiol were collected at waking across 28 days from 12 cocaine-dependent females receiving inpatient treatment and 10 healthy females. Participants also completed mood-rating scales each week corresponding to four phases of the menstrual cycle and cocaine craving was monitored in cocaine patients at each phase. Results Cocaine-dependent females in their first month of abstinence demonstrated significantly higher levels of both cortisol and progesterone across the menstrual cycle and significantly lower estradiol/progesterone (E2/P) ratios compared to healthy controls. They also showed significantly increased negative mood compared with controls, but no variation in cocaine craving across the menstrual cycle. Conclusions Findings indicate altered stress and sex hormones suggestive of an overactive stress system during the first month of cocaine abstinence after chronic cocaine abuse. These increased levels of cortisol and progesterone could impact both abstinence-related symptoms such as negative mood and susceptibility to drug-seeking behavior in cocaine-dependent females.