Megan M. Moran-Santa Maria

Gender differences in the effect of early life trauma on hypothalamic–pituitary–adrenal axis functioning†

Background: The objective of this study was to examine the modifying effect of gender on the association between early life trauma and the hypothalamic–pituitary–adrenal (HPA) axis response to a pharmacologic challenge and a social stress task in men and women. Participants (16 men, 23 women) were the control sample of a larger study examining HPA axis function. Individuals with major depressive disorder, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded. Methods: In two test sessions, subjects received 1 µg/kg of corticotropin‐releasing hormone (CRH) intravenously and participated in the Trier Social Stress Test (TSST). Primary outcomes included plasma cortisol and corticotropin levels measured at baseline and more than five time points following the challenges. Predictors included gender and early life trauma, as measured by the Early Trauma Index. Using factor analysis, the domains general trauma, severe trauma, and the effects of trauma were established. Using regression, these constructs were used to predict differential HPA reactivity in men and women following the challenges. Results: The three factors accounted for the majority of the variance in the ETI. Following the CRH challenge, women had higher overall corticotropin response as dictated by the area under the curve analysis. There were no significant associations between trauma and neuroendocrine response to the TSST. Conclusions: CRH challenge results indicate that gender differences in the impact of early trauma may help explain the differential gender susceptibility to psychopathology following adverse childhood events. This may help explain gender differences in some stress‐sensitive psychiatric disorders. Depression and Anxiety, 2011.

D-cycloserine and Cocaine Cue Reactivity: Preliminary Findings

Background: D-cycloserine (DCS), a partial glutamate N-methyl-D-aspartic acid (NMDA) receptor agonist, enhances extinction of conditioned fear responding in rodents and facilitates exposure-based learning in humans with anxiety disorders. Objectives: This preliminary study investigates DCS pretreatment on response to cocaine cues in cocaine-dependent subjects. Methods: Ten cocaine-dependent subjects were randomly assigned to receive either 50 mg DCS or matching placebo two hours before each of two 1-hour cocaine cue exposure sessions one day apart. HR and craving ratings were obtained before and during cue exposure sessions. Results: There was a trend towards increased craving to cocaine cues in cocaine-dependent individuals after administration of DCS. Conclusions: The administration of DCS prior to cue exposure sessions may facilitate response activation. Scientific Significance: While facilitation of extinction-based learning by DCS may have therapeutic potential for cocaine dependence, this drug may exhibit a different profile in cocaine-dependent individuals as compared to those with anxiety disorders.

Right anterior insula connectivity is important for cue‐induced craving in nicotine‐dependent smokers

The insula has been implicated in cue‐induced craving and relapse in nicotine‐dependent tobacco cigarette smokers. The aims of the present study were to identify brain regions that exhibit greater functional connectivity with the right anterior insula in response to smoking cues than to neutral cues and the role of functional connectivity between these regions in mediating cue‐induced craving in healthy (free of axis I psychiatric disorders) nicotine‐dependent tobacco cigarette smokers. Functional magnetic resonance imaging data were collected from 63 healthy nicotine‐dependent smokers viewing blocks of smoking and neutral cues. Craving ratings were obtained after each block. A psychophysiologic interaction approach was used to identify regions that exhibited significantly greater functional connectivity with the right anterior insula (seed) during the smoking cues than during the neutral (corrected cluster thresholding, Z > 2.3, P = 0.05). Parameter estimates of the interaction effects from each region were regressed against the mean cue‐induced craving scores. Significant task by seed interactions were observed in two clusters centered in the bilateral precuneus and left angular gyrus. The strength of connectivity between the right anterior insula and the precuneus, which is involved interoceptive processing and self‐awareness, was positively correlated with the magnitude of the craving response to the smoking cues (r2 = 0.15; P < 0.01). These data suggest that among smokers, cue‐induced craving may be a function of connectivity between two regions involved in interoception and self‐awareness. Moreover, treatment strategies that incorporate mindful attention may be effective in attenuating cue‐induced craving and relapse in nicotine‐dependent smokers.

A Comparison of Trauma Profiles among Individuals with Prescription Opioid, Nicotine, or Cocaine Dependence

BACKGROUND AND OBJECTIVES Exposure to traumatic events is common among individuals with substance use disorders. Little is known, however, about the trauma histories among individuals with various types of addiction. METHODS The present study compared the trauma histories (general, sexual, physical and emotional) of non-treatment seeking outpatients dependent on prescription opioids (n = 41), nicotine (n = 87) or cocaine (n = 73). The Life Stressor Checklist-Revised (LSC-R) was completed by participants to assess childhood and adult trauma. RESULTS The findings revealed that all three groups endorsed high levels of trauma exposure, with 96.5% of the entire sample experiencing at least one traumatic event in their lifetime. The prescription opiate group experienced a greater number of general and total traumas than the nicotine group. However, no group differences in the number of emotional, physical, or sexual traumas were revealed. The prescription opiate group reported a younger age of first traumatic event than the cocaine group, and was significantly more likely to report childhood traumatic events than both the cocaine and nicotine groups. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE The findings provide clinically relevant information that may help improve screening, interventions, and preventative efforts.

Response to Corticotropin-Releasing Hormone Infusion in Cocaine-Dependent Individuals

CONTEXT Corticotropin-releasing hormone (CRH), through the hypothalamic pituitary adrenal axis and other brain stress systems, is involved in the emotional dysregulation associated with cocaine dependence. Little is known about the response of cocaine-dependent individuals to CRH administration. OBJECTIVE The primary objective was to examine the hypothalamic-pituitary-adrenal axis and the subjective and physiologic response to CRH in cocaine-dependent individuals and controls. DESIGN A case-control study. SETTING Subjects were admitted to a General Clinical Research Center for testing and abstinence was verified with a urine drug screening. PARTICIPANTS Participants were male controls (n = 23), female controls (n = 24), cocaine-dependent men (n = 28), and cocaine-dependent women (n = 25). Individuals with dependence on other substances (except caffeine or nicotine) or with major depression, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded. INTERVENTION Subjects received 1 microg/kg of CRH intravenously. MAIN OUTCOME MEASURES Primary outcomes included plasma corticotropin levels, cortisol levels, and heart rate and subjective measurements. RESULTS Cocaine-dependent individuals exhibited higher stress (P < .001) and craving for CRH compared with controls. A positive correlation (r(s) = 0.51; P < .001) between stress and craving was found in cocaine-dependent subjects. Intravenous CRH elevated heart rates in all groups; however, cocaine-dependent women demonstrated a significantly higher heart rate at all time points (P = .05). Women had higher cortisol responses to CRH (P = .03). No effect of cocaine status was observed. The corticotropin response to CRH was independent of sex and cocaine dependence. Cortisol and corticotropin were positively correlated in the controls and cocaine-dependent men, but not in cocaine-dependent women (r(s) = 0.199; P = .4). CONCLUSIONS There is an increased subjective and heart rate response to CRH and a relationship between stress and craving in cocaine-dependent individuals. The lack of difference in hypothalamic pituitary adrenal axis response between the cocaine-dependent and control groups suggests that the heart rate and subjective responses in the cocaine group may be mediated by sensitization of nonhypothalamic stress-responsive CRH systems.

Association of elevated cytokines with childhood adversity in a sample of healthy adults.

OBJECTIVE Childhood trauma has been associated adult stress-related disorders. However, little is known about physiologic alterations in adults with a history of early life trauma that do not have current psychiatric or medical diagnoses. In this study, the relationships between childhood adversity and cytokine and C-reactive protein (CRP) levels in healthy adults were examined. METHOD Participants included men (n = 18) and women (n = 20) who did not meet DSM-IV criteria for Axis I psychiatric disorders or any major medical illness. Cytokine and CRP levels were obtained from baseline blood samples. Subjects completed the Early Trauma Inventory Self Report (ETI-SR). The primary outcomes included serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL1-β), and CRP levels. In addition, the mean numbers of traumatic experiences (sexual, physical, emotional, general, and the summed total) were measured. RESULTS Significant positive associations were found between the total ETI score and IL-6 (p = 0.05), IL1-β (p < 0.05), and TNF-α (p = 0.01). Significant positive correlations were found between the number of general traumas and IL1-β (p < 0.05), TNF-α (p < 0.05), and IL-6 (p < 0.01). Neither the total number of traumas nor any of the trauma subscales were significantly associated with CRP levels. CONCLUSIONS The positive association between childhood trauma and basal cytokine levels supports the extant literature demonstrating the long-term impact of childhood trauma and stress on homeostatic systems. Importantly, this association was found in healthy adults, suggesting that these alterations may precede the development of significant stress-related psychiatric disorder or disease.

Ovarian Hormones and Drug Abuse

There are significant gender differences in course, symptomology, and treatment of substance use disorders. In general data from clinical and preclinical studies of substance use disorders suggest that women are more vulnerable than men to the deleterious consequences of drug use at every phase of the addiction process. In addition data from epidemiologic studies suggest that the gender gap in the prevalence of substance use is narrowing particularly among adolescence. Therefore, understanding the role of estrogen and progesterone in mediating responses to drugs of abuse is of critical importance to women’s health. In this review we will discuss findings from clinical and preclinical studies of 1) reproductive cycle phase; 2) endogenous ovarian hormones; and 3) hormone replacement on responses to stimulants, nicotine, alcohol, opioids, and marijuana. In addition, we discuss data from recent studies that have advanced our understanding of the neurobiologic mechanisms that interact with estrogen and progesterone to mediate drug-seeking behavior.

Relationship between child abuse and adult smoking.

Objective: A strong association between a history of child abuse and subsequent psychiatric disorders including substance use has been demonstrated. However, few studies have examined the relationship between child abuse and cigarette smoking in individuals without co-occurring psychiatric disorders. In this study, the relationship between severe childhood abuse and smoking were examined in a group of adults without significant psychopathology. Methods: Participants (N = 57) represent the control group of a larger study of substance dependence. Participants were without major DSM-IV psychopathology, including substance use disorders, major depression, or posttraumatic stress disorder. The Early Trauma Inventory [20] assessed history of exposure to traumatic events prior to age 18. Results: The majority of individuals with, as compared to without, a history of severe child abuse (79% vs. 47%, p = .02) were current cigarette smokers. The odds of smoking was four times as high in participants with versus without a severe childhood abuse history (OR = 4.0, p = 0.04). Conclusions: Although preliminary, the findings demonstrate a strong link between early childhood trauma and later adult cigarette smoking among individuals without significant substance use or other psychopathology.

Pain and motives for use among non‐treatment seeking individuals with prescription opioid dependence

BACKGROUND AND OBJECTIVES Patients with prescription opioid use disorders and co-occurring pain present a formidable challenge for healthcare providers, and little is known about patients with this dual diagnosis. This study examined the prevalence of pain and motives for use among individuals with prescription opioid dependence. METHODS Participants (N = 127) included 86 non-treatment seeking individuals with current prescription opioid dependence and 41 healthy controls. They were administered a battery of assessments to evaluate pain and substance use. RESULTS Participants with prescription opioid dependence were significantly more likely than controls to report current pain (62.2 vs. 12.2%), as well as higher levels of pain interference and severity. The most common source of prescription opioids was a physician (91.3%) and the most common motive for using prescription opioids, initially and currently, was to relieve pain (70.3% and 81.0%, respectively). Motivation for subsequent non-medical use of prescription opioids included to get high (73.8%), to increase energy (71.0%), to decrease anxiety (51.2%), and to improve sleep (35.7%). CONCLUSION Pain is a significant comorbidity and motivator for the non-medical use of prescription opioids. Provider and patient education regarding the safe use of prescription opioids, as well as interventions targeting prescription opioid dependence, are needed.

Yohimbine administration and cue-reactivity in cocaine-dependent individuals.

RationalePreclinical studies suggest that stress potentiates cue-induced cocaine seeking and that this effect is more pronounced in females. These findings have not been characterized in clinical populations.ObjectivesThe objectives of this study were to examine the impact a pharmacological stressor, alpha-2 adrenergic receptor antagonist yohimbine, on the subjective, endocrine, and physiologic responses to drug-paired cues cocaine-dependent men and women.MethodsIn a double-blind placebo-controlled cross-over study, cocaine-dependent men (n = 32), cocaine-dependent women (n = 30), control men (n = 32), and control women (n = 25) received either yohimbine or placebo prior to two cocaine cue exposure sessions.ResultsYohimbine increased ratings of anxiety both before (p < 0.001) and after (p = 0.035) cues, and the post-cue increase in anxiety was more pronounced in women (p = 0.001). Yohimbine also significantly increased craving, compared with placebo (p < 0.05), following the cue presentation, and this effect was greater in women than men (gender by treatment interaction; p = 0.006). Yohimbine also increased salivary cortisol (p < 0.001) and dehydroepiandrosterone (p = 0.003) levels, regardless of diagnostic group. Women had a significantly greater heart rate response following yohimbine as compared with men (p < 0.001).ConclusionsStress may increase the salience of cocaine cues for cocaine-dependent women as compared with men. This suggests gender differences in vulnerability to craving and relapse under stressful conditions.