Hypothalamic-pituitary-adrenal and autonomic response to psychological stress in abstinent alcohol use disorder individuals with and without depressive symptomatology.

BACKGROUND: Stress and depression have each been associated with relapse risk. In clinical practice, chronic alcohol use is often accompanied by poor emotional and self-regulatory processes. Tonic and phasic changes in stress responsivity impact an individual's relapse risk to alcohol. A further complicating factor is the pervasive coexistence of depressive symptoms in those with Alcohol Use Disorder (AUD), where the contribution of depressive symptomatology to these processes is not well understood. Individuals with AUD (AD) (21 with and 12 without sub-clinical depressive symptoms) and 37 social drinking controls (16 with and 21 without sub-clinical depressive symptoms) as part of a more extensive study (Fox et al., 2019). All participants were exposed to two 5-min personalized guided imagery conditions (stress and neutral) in a randomized and counterbalanced order across consecutive days. Alcohol craving, negative mood, Stroop performance, and plasma measures (cortisol, adrenocorticotrophic hormone, and salivary alpha-amylase) were collected before and after imagery exposure. RESULTS: Elevations in autonomic response (heart rate) to imagery (stress and neutral) were observed as a function of drinking (in both depressed and non-depressed individuals with alcohol use disorder compared with depressed and non-depressed social drinkers). Conversely, suppressed cortisol following stress was observed as a function of depressive symptomatology across both drinking groups. Individuals with comorbid AD and depressive symptoms demonstrated attenuated Adrenocorticotropic Hormone and poor Stroop performance compared with the other groups, indicating an interactive effect between drinking and depression on pituitary and inhibitory systems. CONCLUSION: Sub-clinical depressive pathophysiology may be distinct from drinking severity and may alter relapse-related stress adaptations during protracted abstinence from alcohol.

Therapeutics for Substance-Using Women: The Need to Elucidate Sex-Specific Targets for Better-Tailored Treatments.

In the last decade, alcohol consumption in the US has risen by 84% in women compared with 35% in men. Furthermore, research has shown that sex- and gender-related differences may disadvantage women in terms of developing a range of psychological, cognitive, and medical problems considerably earlier in their drinking history than men, and despite consuming a similar quantity of substances. While this "telescoping" process has been acknowledged in the literature, a concomitant understanding of the underlying biobehavioral mechanisms, and an increase in the development of specific treatments tailored to women, has not occurred. In the current chapter we focus on understanding why the need for personalized, sex-specific medications is imperative, and highlight some of the potential sex-specific gonadal and stress-related adaptations underpinning the accelerated progress from controlled to compulsive drug and alcohol seeking in women. We additionally discuss the efficacy of these mechanisms as novel targets for medications development, using exogenous progesterone and guanfacine as examples. Finally, we assess some of the challenges faced and progress made in terms of developing innovative medications in women. We suggest that agents such as exogenous progesterone and adrenergic medications, such as guanfacine, may provide some efficacy in terms of attenuating stress-induced craving for several substances, as well as improving the ability to emotionally regulate in the face of stress, preferentially in women. However, to fully leverage the potential of these therapeutics in substance-using women, greater focus needs to the placed on reducing barriers to treatment and research by encouraging women into clinical trials.

Effects of Prazosin on Provoked Alcohol Craving and Autonomic and Neuroendocrine Response to Stress in Alcohol Use Disorder.

BACKGROUND: Chronic alcohol use results in changes to stress biology and autonomic arousal contributing to acute alcohol withdrawal symptoms, neuroendocrine tolerance of the hypothalamic-pituitary-adrenal axis responses, high stress-induced craving, and risk of alcohol relapse. Thus, stress coping and recovery from alcohol during early abstinence may be jeopardized by such stress system dysfunction. Significant preclinical evidence suggests that noradrenergic disruption may contribute to these alcohol-related stress arousal changes and that alpha-1 adrenergic antagonists, such as prazosin, may normalize these stress system adaptations and reduce alcohol intake. Thus, we hypothesized that prazosin would reduce stress-induced craving and improve neuroendocrine and autonomic response to stress and alcohol cue exposure during early abstinence. We secondarily also assessed the role of lifetime anxiety disorders on these prazosin effects. METHODS: Forty inpatient treatment-seeking alcohol-dependent individuals were randomly assigned to receive placebo (n = 18) or 16 mg/d, T.I.D., prazosin (n = 22) in a double-blind manner, titrated over 2 weeks. In weeks 3 to 4 after achieving full dose, patients were exposed to 3 5-minute personalized guided imagery conditions (stress cue, alcohol cue, neutral/relaxing cue), on 3 consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, heart rate, cortisol, and adrenocorticotropic hormone (ACTH) levels were assessed at baseline, following imagery and at repeated recovery timepoints. RESULTS: Prazosin reduced stress cue-induced alcohol craving (p < 0.05) and stress- and alcohol cue-induced anxiety (p < 0.05) and increased heart rate responses in all imagery conditions (p < 0.05). Prazosin lowered basal cortisol and ACTH (p's < 0.05) and attenuated stress cue-induced rises in cortisol (p < 0.05) versus placebo. Finally, in those without lifetime anxiety disorder, the placebo group showed stress- and alcohol cue-induced increases in cortisol (p's < 0.05), while the prazosin group did not. CONCLUSIONS: Prazosin may attenuate stress cue-induced alcohol craving and anxiety during early abstinence while improving adrenergic and stress system function, effects which are independent of a history of lifetime anxiety disorders.

Stress-related suppression of peripheral cytokines predicts future relapse in alcohol-dependent individuals with and without subclinical depression.

Chronic alcohol abuse and depressive symptoms are both associated with peripheral cytokine changes. Despite this, cytokine adaptations have not been assessed in co-morbid populations or prospectively as predictors of relapse. We examine cytokine responses to stress in alcohol-dependent individuals and social drinkers, both with and without subclinical depression. We also examine the potential link between cytokine adaptations in response to stress and prospective alcohol relapse risk. Thirty-three, alcohol-dependent individuals (21 with and 12 without high depressive symptoms) and 37 controls (16 with and 21 without high depressive symptoms) were exposed to two 5-minute personalized guided imagery conditions (stress and neutral) across consecutive days in a randomized and counterbalanced order. Alcohol craving and serum measures of tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1ra) were collected prior to and following imagery exposure. Following treatment discharge, follow-up interviews were conducted over 90 days to assess relapse. Dampened IL-1ra and IL-6 in response to stress was observed as a function of alcohol dependence and not moderated by depressive symptoms. Lower levels of IL-6 following stress also predicted greater drinking days following treatment. Conversely, high depressive symptomatology was associated solely with pro-inflammatory adaptations. Stress-related suppression of TNFα predicted drinking severity only in alcohol-dependent individuals with subclinical depression, and suppressed TNFR1 following stress was only seen in individuals with subclinical depression. Stress-induced suppression of pro-inflammatory TNF markers may indicate a risk factor for alcohol-dependent individuals with co-occurring depressive symptoms.

Neuroactive steroid levels and cocaine use chronicity in men and women with cocaine use disorder receiving progesterone or placebo.

BACKGROUND AND OBJECTIVES: Neuroactive steroids (NAS) may play a role in addiction, with observed increases in response to acute stress and drug use, but decreases with chronic substance use, suggesting that NAS neuroadaptations may occur with chronic substance use. However, levels of NAS in addicted individuals have not been systematically examined. Here, we evaluated a panel of NAS in men and women with cocaine use disorder (CUD) who participated in a clinical laboratory study of progesterone. METHODS: Forty six CUD individuals were enrolled in a randomized placebo-controlled laboratory study to evaluate progesterone effects on levels of various NAS. On day 5 of a 7-day inpatient treatment regimen of 400 mg/day progesterone (15M/8F) or placebo (14M/9F), plasma levels of NAS known to be downstream of progesterone (allopregnanolone, pregnanolone), and NAS not in the progesterone synthesis pathway (androstanediol, testosterone, dehydroepiandrosterone [DHEA] and the NAS precursor, pregnenolone) were analyzed using highly sensitive gas chromatography/mass spectrometry (GC/MS). The relationship between each of the NAS and chronicity of cocaine use was also assessed. RESULTS: Progesterone versus placebo significantly increased the GABAergic NAS allopregnanolone and pregnanolone in both CUD men and women. Levels of pregnenolone, testosterone, its GABAergic metabolite androstanediol, and the non-GABAergic DHEA were unaffected by progesterone treatment, and testosterone and androstanediol levels were significantly higher in men than women. Importantly, lower pregnenolone and androstanediol levels were associated with greater years of cocaine use. SCIENTIFIC SIGNIFICANCE: GABAergic NAS that are upstream from the progesterone synthesis pathway appear susceptible to chronic effects of cocaine use. (Am J Addict 2019;28:16-21).

Peripheral Immune System Adaptations and Motivation for Alcohol in Non-Dependent Problem Drinkers.

BACKGROUND: Increasing evidence suggests that levels of pro-inflammatory and anti-inflammatory cytokines are dysfunctional in alcohol dependence. Moreover, some initial findings demonstrate that these adaptations in peripheral inflammation may contribute to motivation for alcohol and problem drinking via possible direct effects or the indirect effects of stress responsivity. Importantly, the role of pro-inflammatory and anti-inflammatory cytokines in the progression from healthy to problem drinking is not well understood. The aim of this study was to assess whether alcohol-related peripheral immune system changes affect stress and alcohol cue-induced craving and anxiety and behavioral alcohol motivation and intake in the laboratory among problem drinkers compared with socially drinking controls. METHODS: Twenty-six problem drinkers and 38 moderate, social drinkers participated in a laboratory challenge procedure during which they were exposed to 3 personalized 5-minute imagery conditions (stress [S], relaxing [R], and alcohol cue [C]), followed by the "alcohol taste test" (ATT) as a measure of implicit alcohol motivation and intake, presented across 3 consecutive days, 1 per day in a randomized and counterbalanced order. Measures of tumor necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), alcohol craving, and anxiety were assessed at baseline, immediately following imagery exposure and at discreet beer cue presentation in the ATT. RESULTS: Compared with moderate drinkers, problem drinkers demonstrated tonic attenuation of IL-6 and IL-1ra. In problem drinkers, these changes also accompanied elevated levels of stress- and cue-induced alcohol craving and anxiety and were predictive of provoked alcohol craving, behavioral alcohol motivation and intake, and severity of problem drinking. CONCLUSIONS: Current findings indicate that selective immunosuppression in problem drinkers may play a key role in motivation for alcohol intake.

Alcohol Effects on Stress Pathways: Impact on Craving and Relapse Risk.

A significant amount of neurobiological research regarding the development of alcohol use disorders (AUDs) has focused on alcohol-related activation and long-term alterations in the mesocortical dopaminergic reward pathways. However, alcohol does not only interact with brain reward systems. Many of its acute and chronic effects may be related to allostatic adaptations in hypothalamic and extrahypothalamic stress regulation pathways. For example, acute binge intoxication is associated with hypothalamically driven increases in blood cortisol, norepinephrine, and sex steroid metabolite levels. This may contribute to the development of mesocortical sensitization to alcohol. Furthermore, chronic alcohol exposure is associated with systemic dysregulation of the hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, and sex steroid systems. This dysregulation appears to manifest as neuroendocrine tolerance. In this review, we first summarize the literature suggesting that alcohol-induced alterations in these hypothalamic systems influence craving and contribute to the development of AUDs. We note that for women, the effects of alcohol on these neuroendocrine stress regulation systems may be influenced by the rhythmic variations of hormones and steroids across the menstrual cycle. Second, we discuss how changes in these systems may indicate progression of AUDs and increased risk of relapse in both sexes. Specifically, neuroendocrine tolerance may contribute to mesocortical sensitization, which in turn may lead to decreased prefrontal inhibitory control of the dopaminergic reward and hypothalamic stress systems. Thus, pharmacological strategies that counteract alcohol-associated changes in hypothalamic and extrahypothalamic stress regulation pathways may slow the development and progression of AUDs.

Effects of endogenous and exogenous progesterone on emotional intelligence in cocaine-dependent men and women who also abuse alcohol.

OBJECTIVE: As sex differences in substance dependence may impinge upon the perception and regulation of emotion, we assess emotional intelligence (EI) as a function of gender, menstrual cycle (MC) phase and hormonal changes in early abstinent cocaine-dependent individuals who abuse alcohol (CDA). METHODS: Study 1: The Mayer, Salovey, and Caruso Emotional Intelligence Test (MSCEIT) was administered to 98 CDA (55 M/43 F) and 56 healthy (28 M/28 F) individuals. Performance in women was also assessed by MC phase. Study 2: The MSCEIT was administered to 28 CDA (19 M/9 F) who received exogenous progesterone (400 mg/day) versus placebo for 7 days (study 2). RESULTS: Study 1: Healthy females were better than healthy males at facilitating thought and managing emotions. This gender discrepancy was not observed in the CDA group. Additionally, all women in the high compared with the low progesterone phase of their MC were better at managing their emotions. Study 2: Exogenous progesterone improved ability to facilitate thought in both males and females. CONCLUSIONS: CDA women may be vulnerable to difficulties managing and regulating emotions. Gonadal hormones may contribute to this gender effect, as increases in both endogenous and exogenous progesterone improved selective aspects of EI.

Alcohol exposure during late adolescence increases drinking in adult Wistar rats, an effect that is not reduced by finasteride.

AIMS: We tested whether an exposure to alcohol in late adolescence, an age of rapid increase in neuroactive steroid precursors, would increase voluntary alcohol consumption in adult rats and whether this effect would be modulated by finasteride, an inhibitor of neuroactive steroid synthesis. METHODS: In Experiment 1, we exposed male Wistar rats to 8% alcohol during the dark cycle for 1 week during late adolescence [postnatal days (PNDs) 51-58], and then measured voluntary alcohol consumption 1 month later in adulthood (PNDs 91-104). In Experiment 2, finasteride was administered during the forced alcohol exposure in late adolescence and, in Experiment 3, during voluntary alcohol consumption in adulthood. Plasma was collected at the end of each finasteride treatment to confirm the reduction of plasma neuroactive steroid levels. RESULTS: We found that a daily 12-h exposure to alcohol for 7 days in late adolescence significantly increased voluntary alcohol consumption (4-fold) a month later during adulthood. Finasteride administration in late adolescence increased group alcohol intake in late adolescence but did not block the effect of adolescent alcohol exposure on increasing alcohol preference in adulthood. There was no effect of finasteride treatment in adulthood on alcohol preference. CONCLUSIONS: A daily 12-h exposure to alcohol for 7 days in late adolescence was sufficient to induce chronically increased alcohol preference in adulthood, indicating that this age may be sensitive to the effects of alcohol.

Laboratory and Real-World Experimental Approaches to Understanding Alcohol Relapse.

Alcohol use disorder is highly prevalent and high risk of relapse remains a significant treatment challenge. Therefore, the utility of human laboratory models of relapse to further the understanding of psychobiological mechanisms that precipitate relapse risk and allow testing of novel interventions could be of benefit in expediting the development of effective treatments to target high relapse risk. Stress is a risk factor for the development of AUD and for relapse, and furthermore, chronic alcohol use leads to adaptations in central and peripheral stress biology. Here, we review our efforts to assess the integrity of these stress pathways in individuals with alcohol use disorder and whether adaptations in these systems play a role in relapse risk. Using validated human laboratory procedures to model two of the most common situations that contribute to relapse risk, namely stress and alcohol cues, we review how such models in the laboratory can predict subsequent relapse, and how we can measure specific identified biobehavioral markers of relapse effectively and ecologically in the real world. Finally, we discuss the significant implications of these findings for the development of novel and effective interventions that target stress dysregulation and craving as risk factors to treatment.

Sex differences in neural responses to stress and drug cues predicts future drug use in individuals with substance use disorder.

BACKGROUND: Substance use disorders (SUDs) are chronically recurring illnesses, where stress and drug cues significantly increase drug craving and risk of drug use recurrence. This study examined sex differences in functional magnetic resonance imaging (fMRI) brain responses to stress and drug cue exposure and assessed their prospective association with future drug use post-treatment. METHODS: Inpatient, treatment engaged men (N = 46) and women (N = 26) with SUDs, including alcohol, cocaine and/or cannabis use disorders, participated in an fMRI scan that assessed subjective (anxiety, drug craving), heart rate and neural responses to brief individualized script-driven imagery of stress, drug, and neutral-relaxing trials. Prospective follow-up interviews post-treatment assessed future drug use recurrence over 90 days. RESULTS: During fMRI, stress and drug versus neutral cue exposure led to increased anxiety, heart rate and craving responses (p's < 0.004) in both men and women, but greater drug cue-induced anxiety (p < .017) and higher drug use days during follow-up (p < .006) in women relative to men. In whole brain analyses of stress and drug cues (p < .05 FWE corrected), and in whole brain correlation (p < .05, FWE corrected) with drug use days, significant sex differences revealed drug cue-related striatal hyperactivation (caudate, putamen) in men, but drug cue-related cortico-limbic (insula and dorsolateral prefrontal cortex) hypoactivation and stress-related hypoactivation in the ventromedial prefrontal cortex (VmPFC) in women; and these were significantly associated with higher future drug use days. CONCLUSIONS: Findings indicate sex-specific pathophysiology of SUD recurrence and support the need for differential treatment development for men and women with SUD to improve drug use outcomes.

Pregnenolone effects on provoked alcohol craving, anxiety, HPA axis, and autonomic arousal in individuals with alcohol use disorder.

RATIONALE: Chronic alcohol intake down-regulates GABAergic transmission and reduces levels of neuroactive steroids. These changes are associated with greater stress dysregulation and high alcohol craving which in turn increases relapse risk. OBJECTIVES: This study tested whether potentiation of the neurosteroid system with pregnenolone (PREG), a precursor to neuroactive steroids and known to increase GABAergic transmission, will normalize chronic alcohol-related stress adaptations in the hypothalamic-pituitary-adrenal (HPA) axis and autonomic responses and reduce alcohol craving to significantly impact relapse risk. METHODS: Forty-three treatment-seeking individuals with alcohol use disorder (AUD) were randomized to placebo (PBO) or supraphysiologic pregnenolone doses of 300 mg or 500 mg treatment using a parallel-between subject design as part of a larger 8-week pilot clinical trial. In week 2, they participated in a 3-day laboratory experiment where on each day they self-administered the assigned study drug in the laboratory and were then exposed to 5-min personalized guided imagery provocation of stress, alcohol, or neutral/relaxing cues, one condition per day on separate days, in a random, counterbalanced order. Repeated assessments of alcohol craving, anxiety, HPA axis, heart rate (HR), systolic (SBP), and diastolic blood pressure (DBP) and serum pregnenolone levels were made on each day. RESULTS: Pregnenolone levels were significantly increased in the PREG groups versus PBO. PREG treatment decreased stress- and alcohol cue- induced craving and dose-specifically reduced stress-induced anxiety in the 300 mg/day group. Both PREG doses compared to PBO also normalized CORT/ACTH and increased stress-induced HR, stress- and cue-induced SBP, and in the 300 mg PREG group cue-induced DBP responses relative to neutral condition. CONCLUSIONS: Findings indicate that pregnenolone decreases stress- and alcohol cue-provoked craving and normalizes HPA axis and autonomic arousal in individuals with AUD, thereby supporting the need for further assessment of pregnenolone in the treatment of AUD.

Enforced Pax6 expression rescues alcohol-induced defects of neuronal differentiation in cultures of human cortical progenitor cells.

BACKGROUND: Alcohol is the most widely consumed substance of abuse, and its use during pregnancy can lead to serious disorders of brain development. The precise molecular action of alcohol on human brain development, however, is still unknown. We previously enriched multipotent progenitor cells, radial glia (RG) cells, from human fetal forebrain and demonstrated that they express transcription factor Pax6 that is necessary for their neurogenic fate. METHODS: Enriched human fetal RG cells were maintained in vitro as either control or Pax6-expressing retrovirus infected cells. Cultures were treated with increasing doses of alcohol to evaluate Pax6 expression, proliferation, and differentiation of RG cells by immunocytochemistry, Western blot, and RT-PCR methods. RESULTS: In vitro treatment with alcohol reduced the expression of transcription factor Pax6 and proliferation of RG cells, which decreased neurogenesis. Consistent with this finding, the overexpression of Pax6 in RG cells under alcohol treatment rescued cell proliferation and restored the generation of neurons. In contrast to this effect on neurogenesis, the overexpression of Pax6 inhibits the generation of astroglia regardless of alcohol treatment, implying lineage-specific effects. CONCLUSIONS: These findings suggest that the effect of alcohol on human neurogenesis is partially due to the reduced expression of transcription factor Pax6 in RG cells.

Pregnenolone Reduces Stress-Induced Craving, Anxiety, and Autonomic Arousal in Individuals with Cocaine Use Disorder.

Chronic cocaine use leads to adaptations in stress biology and in neuroactive steroid system. These adaptations are associated with high cocaine craving and increased relapse risk. This study tested whether potentiation of the neuroactive steroid system with the precursor pregnenolone (PREG) affects stress- and cue-induced cocaine craving, anxiety and autonomic response in individuals with cocaine use disorder (CUD). Thirty treatment-seeking individuals (21 Male, 9 Female) with CUD were randomized to placebo (PBO) or supraphysiologic PREG doses of 300 mg or 500 mg per day for 8 weeks. After 2 weeks of treatment, participants were exposed to 5-min personalized guided imagery provocation of stress, cocaine, or neutral/relaxing cues in a 3-day experiment, one condition per day on separate days, in a random, counterbalanced order. Repeated assessment of cocaine craving, anxiety, heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) were assessed on each day. PREG significantly increased pregnenolone levels compared to PBO. Both PREG doses decreased stress- and cocaine cue-induced craving and reduced both stress- and cue-induced anxiety only in the 500 mg/day group. The 500 mg/day PREG group also displayed decreased stress-induced HR, SBP and DBP. Findings indicate that pregnenolone decreases stress- and cocaine cue-provoked craving and anxiety and reduces stress-induced autonomic arousal in individuals with CUD.

Variation in genes encoding the neuroactive steroid synthetic enzymes 5α-reductase type 1 and 3α-reductase type 2 is associated with alcohol dependence.

BACKGROUND: Studies of alcohol effects in rodents and in vitro implicate endogenous neuroactive steroids as key mediators of alcohol effects at GABA(A) receptors. We used a case-control sample to test the association with alcohol dependence (AD) of single nucleotide polymorphisms in the genes encoding two key enzymes required for the generation of endogenous neuroactive steroids: 5α-reductase, type I (5α-R), and 3α-hydroxysteroid dehydrogenase, type 2 (3α-HSD), both of which are expressed in human brain. METHODS: We focused on markers previously associated with a biological phenotype. For 5α-R, we examined the synonymous SRD5A1 exon 1 SNP rs248793, which has been associated with the ratio of dihydrotestosterone to testosterone. For 3α-HSD, we examined the nonsynonymous AKR1C3 SNP rs12529 (H5Q), which has been associated with bladder cancer. The SNPs were genotyped in a sample of 1,083 non-Hispanic Caucasians including 552 controls and 531 subjects with AD. RESULTS: The minor allele for both SNPs was more common among controls than subjects with AD: SRD5A1 rs248793 C-allele (χ(2)(1) = 7.6, p = 0.006) and AKR1C3 rs12529 G-allele (χ(2)(1) = 14.6, p = 0.0001). There was also an interaction of these alleles such that the "protective" effect of the minor allele at each marker for AD was conditional on the genotype of the second marker. CONCLUSIONS: We found evidence of an association with AD of polymorphisms in two genes encoding neuroactive steroid biosynthetic enzymes, providing indirect evidence that neuroactive steroids are important mediators of alcohol effects in humans.

Moderation of Prazosin's Efficacy by Alcohol Withdrawal Symptoms.

OBJECTIVE: Alcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated secondary outcomes of alcohol craving and mood, anxiety, and sleep disturbances, which are predictive of poor treatment outcomes. The authors examined whether alcohol withdrawal symptoms moderate the efficacy of prazosin in reducing alcohol intake and associated secondary outcomes. METHODS: A 12-week, double-blind, randomized, controlled proof-of-concept trial of prazosin (16 mg/day, with a 2-week titration) was conducted in community-recruited adults with current alcohol dependence (N=100) with varying levels of alcohol withdrawal symptoms assessed at treatment entry. Primary outcomes were daily self-reported drinking days and heavy drinking days, and secondary outcomes were average drinks/day and mood, anxiety, craving, and sleep quality ratings. RESULTS: Modified intent-to-treat analyses indicated a significant interaction of alcohol withdrawal symptom score by treatment by full-dose treatment period (weeks 3-12) for drinking days, heavy drinking days, and average drinks/day. By week 12, participants with high alcohol withdrawal symptoms on prazosin reported 7.07% heavy drinking days and 27.46% drinking days, while those on placebo had 35.58% heavy drinking days and 58.47% drinking days (heavy drinking days: odds ratio=0.14, 95% CI=0.058, 0.333; drinking days: odds ratio=0.265, 95% CI=0.146, 0.481). No such benefit of prazosin was observed in those reporting low or no alcohol withdrawal symptoms. Individuals with high alcohol withdrawal symptoms on prazosin compared with placebo also showed significantly improved anxiety, depression, and alcohol craving over the course of the trial. CONCLUSIONS: The findings indicate that alcohol withdrawal symptoms are a significant moderator of prazosin treatment response for alcohol use outcomes and for associated symptoms of alcohol craving, anxiety, and mood symptoms. These data support further evaluation of alcohol withdrawal symptoms as a prognostic indicator of prazosin's efficacy in the treatment of AUD.

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.

Central and Peripheral Biomarkers of Stress Response for Addiction Risk and Relapse Vulnerability.

Substance use disorders (SUDs) are marked by heterogeneity in clinical symptomatology and high relapse rates following treatment. Here, we describe specific peripheral and central stress responses associated with the pathophysiology of SUDs. We outline potential stress response measures, including hypothalamus-pituitary-adrenal axis markers, autonomic responses, and central structural and functional brain alterations that could be exploited as putative biomarkers in SUDs. We posit that stress responses can be predictive of both the development of SUDs and their high relapsing nature. We examine their potential as candidate biomarkers, as well as the remaining challenges in developing and implementing their application for the prevention and treatment of SUDs.

Sexual dimorphism in the neural impact of stress and alcohol.

Alcohol use disorder is a widespread mental illness characterized by periods of abstinence followed by recidivism, and stress is the primary trigger of relapse. Despite the higher prevalence of alcohol use disorder in males, the relationship between stress and behavioral features of relapse, such as craving, is stronger in females. Given the greater susceptibility of females to stress-related psychiatric disorders, understanding sexual dimorphism in the relationship between stress and alcohol use is essential to identifying better treatments for both male and female alcoholics. This review addresses sex differences in the impact of stressors on alcohol drinking and seeking in rodents and humans. As these behavioral differences in alcohol use and relapse originate from sexual dimorphism in neuronal function, the impact of stressors and alcohol, and their interaction, on molecular adaptations and neural activity in males and females will also be discussed. Together, the data reviewed herein, arising from a symposium titled "Sex matters in stress-alcohol interactions" presented at the Fourth Volterra Conference on Stress and Alcohol, will highlight the importance of identifying sex differences to improve treatments for comorbid stress and alcohol use disorder in both sexes.

Sex differences in guanfacine effects on stress-induced stroop performance in cocaine dependence.

AIMS: Chronic drug abuse leads to sex-specific changes in drug cue and stress physiologic and neuroendocrine reactivity as well as in neural responses to stress and cue-related challenges and in executive function such as inhibitory control, cognitive flexibility and self control. Importantly, these functions have been associated with high risk of relapse and treatment. Alpha-2 agonism may enhance inhibitory cognitive processes in the face of stress with sex-specific effects, however this has not been previously assessed in cocaine dependence. METHOD: Forty inpatient treatment-seeking cocaine dependent individuals (13F/27M) were randomly assigned to receive either placebo or up to 3mgs of Guanfacine. Three laboratory sessions were conducted following 3-4 weeks of abstinence, where patients were exposed to three 10-min personalized guided imagery conditions (stress, drug cue, combined stress/cue), one per day, on consecutive days in a random, counterbalanced order. The Stroop task was administered at baseline and immediately following imagery exposure. RESULTS: Guanfacine treated women improved their performance on the Stroop task following exposure to all 3 imagery conditions compared with placebo women (p=0.02). This improvement in cognitive inhibitory performance was not observed in the men. CONCLUSIONS: Enhancing the ability to cognitively regulate in the face of stress, drug cues and combined stress and drug cue reactivity may be key targets for medications development in cocaine dependent women.