Gender differences in cardiovascular and corticoadrenal response to stress and drug cues in cocaine dependent individuals

Rationale Extensive research suggests that gender may affect neuroendocrine and cardiovascular arousal mechanisms underlying biological responses to stress.Objective To examine the impact of gender on response to stress and to drug-cue exposure in treatment-seeking cocaine abusers.Methods Fifty recently abstinent cocaine dependent individuals (25F/25M), who were matched on cocaine use history, were exposed to a brief guided-imagery procedure that involved imagining a recent personal stressful situation, a personal drug-related situation and neutral-relaxing situation, one imagery per session, presented in random order. Subjective craving and anxiety, cardiovascular measures and plasma adrenocorticotrophic hormone (ACTH), cortisol and prolactin were assessed.Results Males showed significantly higher levels of ACTH, cortisol, and SBP, both at baseline and following all three imagery conditions. Females showed significantly higher basal heart rate and prolactin, although no gender differences were observed following imagery. No gender differences were seen in subjective anxiety or cocaine craving.Conclusions Results indicate significant gender differences in baseline sensitivity and subsequent variations in hypothalamus–pituitary–adrenal (HPA) and cardiovascular response to imagery challenge. Such gender-specific responses could have implications for the development of pharmacological treatments that address stress and drug-cue-related relapse in cocaine-abusing individuals.     

Examining the mediating roles of binge eating and emotional eating in the relationships between stress and metabolic abnormalities

To test whether binge eating and emotional eating mediate the relationships between self-reported stress, morning cortisol and the homeostatic model of insulin resistance and waist circumference. We also explored the moderators of gender and age. Data were from 249 adults (mean BMI = 26.9 ± 5.1 kg/m²; mean age = 28.3 ± 8.3 years; 54.2 % male; 69.5 % white) recruited from the community who were enrolled in a cross-sectional study. Participants completed a comprehensive assessment panel of psychological and physiological assessments including a morning blood draw for plasma cortisol. We found negative relationships between stress and morning cortisol (r = ?0.15 to ?0.21; p < 0.05), and cortisol and the homeostatic model of insulin resistance and waist circumference (r = ?0.16, ?0.25, respectively; p < 0.05). There was not statistical support for binge eating or emotional eating as mediators and no support for moderated mediation for either gender or age; however, gender moderated several paths in the model. These include the paths between perceived stress and emotional eating (B = 0.009, p < 0.001), perceived stress and binge eating (B = 0.01, p = 0.003), and binge eating and increased HOMA-IR (B = 0.149, p = 0.018), which were higher among females. Among women, perceived stress may be an important target to decrease binge and emotional eating. It remains to be determined what physiological and psychological mechanisms underlie the relationships between stress and metabolic abnormalities.     

The role of depression symptoms in predicting drug abstinence in outpatient substance abuse treatment

OBJECTIVE: This study examined the role of depressive symptoms in the context of specific demographic and individual treatment characteristics in predicting drug abstinence at discharge from outpatient substance abuse treatment. METHODS: Data from 827 clients entering a large public funded outpatient substance abuse treatment program were analyzed using logistic regression to assess the effects of depressive symptoms on drug abstinence status at discharge. Analyses on the effects of gender, race, age, education level, frequency of drug use, insurance status, referral source, and length of stay in treatment on drug abstinence status at discharge were also conducted. RESULTS: Higher depressive symptom scores significantly predicted a decreased likelihood of clients' abstinence at discharge even after accounting for other significant demographic and treatment variables such as insurance status, race, age, primary drug of choice, frequency of drug use at admission and length of stay in treatment. CONCLUSION: The findings suggest that depression symptoms are an important factor affecting successful substance abuse treatment outcomes. Treatment approaches that address depressive symptoms are likely to enhance substance abuse treatment outcomes in real world clinical settings.     

The Corticotropin Releasing Hormone-1 (CRH1) Receptor Antagonist Pexacerfont in Alcohol Dependence: A Randomized Controlled Experimental Medicine Study

Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress- and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol-dependent patients in early abstinence. Fifty-four anxious alcohol-dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo-controlled study with pexacerfont (300 mg/day for 7 days, followed by 100 mg/day for 23 days). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcohol-related cues, neuroendocrine responses to these stimuli, and functional magnetic resonance imaging (fMRI) responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in cerebrospinal fluid (CSF) that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans.     

Childhood Trauma and Neural Responses to Personalized Stress,Favorite-Food and Neutral-Relaxing Cues in Adolescents

Previous studies have found childhood trauma to be associated with functional and structural abnormalities in corticostriatal-limbic brain regions, which may explain the associations between trauma and negative mental and physical health outcomes. However, functional neuroimaging of maltreatment-related trauma has been limited by largely using generic and predominantly aversive stimuli. Personalized stress, favorite-food, and neutral/relaxing cues during functional magnetic resonance imaging were used to probe the neural correlates of emotional/motivational states in adolescents with varying exposure to maltreatment-related trauma. Sixty-four adolescents were stratified into high- or low-trauma-exposed groups. Cue-related measures of subjective anxiety and craving were collected. Relative to the low-trauma-exposed group, high-trauma-exposed adolescents displayed an increased activation of insula, anterior cingulate, and prefrontal cortex in response to stress cues. Activation in subcortical structures, including the hippocampus, was inversely correlated with subjective anxiety in the high- but not the low-trauma-exposed group. The high-trauma-exposed group displayed hypoactivity of cerebellar regions in response to neutral/relaxing cues. No group differences were observed in response to favorite-food cues. The relationship between trauma exposure and altered cortico-limbic circuitry may in part explain the association between childhood trauma and heightened vulnerability to emotional disturbances and risky behaviour. This may be particularly pertinent during adolescence when such difficulties often emerge. Further work is needed to elucidate the mechanism linking trauma to obesity.     

Interactive Effects of Cumulative Stress and Impulsivity on Alcohol Consumption

Background: Alcohol addiction may reflect adaptations to stress, reward, and regulatory brain systems. While extensive research has identified both stress and impulsivity as independent risk factors for drinking, few studies have assessed the interactive relationship between stress and impulsivity in terms of hazardous drinking within a community sample of regular drinkers. Methods: One hundred and thirty regular drinkers (56M/74F) from the local community were assessed for hazardous and harmful patterns of alcohol consumption using the Alcohol Use Disorders Identification Test (AUDIT). All participants were also administered the Barratt Impulsiveness Scale (BIS‐11) as a measure of trait impulsivity and the Cumulative Stress/Adversity Checklist (CSC) as a comprehensive measure of cumulative adverse life events. Standard multiple regression models were used to ascertain the independent and interactive nature of both overall stress and impulsivity as well as specific types of stress and impulsivity on hazardous and harmful drinking. Results: Recent life stress, cumulative traumatic stress, overall impulsivity, and nonplanning‐related impulsivity as well as cognitive and motor‐related impulsivity were all independently predictive of AUDIT scores. However, the interaction between cumulative stress and total impulsivity scores accounted for a significant amount of the variance, indicating that a high to moderate number of adverse events and a high trait impulsivity rating interacted to affect greater AUDIT scores. The subscale of cumulative life trauma accounted for the most variance in AUDIT scores among the stress and impulsivity subscales. Conclusions: Findings highlight the interactive relationship between stress and impulsivity with regard to hazardous drinking. The specific importance of cumulative traumatic stress as a marker for problem drinking is also discussed.     

The interleukin-17 cytokine family: critical players in host defence and inflammatory diseases

The interleukin-17 (IL-17) cytokines, IL-17A to IL-17F, are emerging as critical players in host defence responses and inflammatory diseases. Substantial data support the role of these proteins in innate and adaptive immunity. Of these family members, IL-17A, IL-17F and IL-17E have been the best studied. Both IL-17A and IL-17F contribute to the host response to extracellular bacteria and fungi, and IL-17E has been shown to play a role in parasitic infections. In addition, numerous pre-clinical and clinical studies link these proteins to the pathogenesis of inflammatory diseases, and a number of therapeutic programmes targeting these family members are in clinical development. This review will highlight the cellular sources, receptors/target cells, and role in inflammation of these and the less-characterized family members, IL-17B, IL-17C and IL-17D.     

Translational and reverse translational research on the role of stress in drug craving and relapse

Rationale and background  

High relapse rates during abstinence are a pervasive problem in drug addiction treatment. Relapse is often associated with stress exposure, which can provoke a subjective state of drug craving that can also be demonstrated under controlled laboratory conditions. Stress-induced relapse and craving in humans can be modeled in mice, rats, and monkeys using a reinstatement model in which drug-taking behaviors are extinguished and then reinstated by acute exposure to certain stressors. Studies using the reinstatement model in rats have identified the role of several neurotransmitters and brain sites in stress-induced reinstatement of drug seeking, but the degree to which these preclinical findings are relevant to the human condition is largely unknown.