We propose to investigate how peripheral immune system cytokines contribute to stress-related alcohol craving and relapse risk in alcohol dependent (AD) individuals with and without high levels of depressive symptomatology. Stress-induced craving in alcoholics is a persistent distress state characterized by elevated negative mood, up-regulated basal adrenal sensitivity and a subsequent dampened arousal response to stress. Notably, this dysregulation is associated with a high susceptibility for relapse, and may be exacerbated in AD individuals with co-morbid depressive and affective symptomology. As chronic stress and alcohol consumption has robust and reciprocal effects on immune system cytokines, we postulate that adaptations in both pro- and anti-inflammatory cytokine levels may contribute to the stress system dysregulation underlying alcohol craving and relapse. Furthermore, that alcohol-related cytokine changes may contribute differentially to the craving state in non-depressed AD individuals compared to those with high co-morbid depressive symptomatology. Our preliminary pilot data shows an increased inflammatory response (high pro-inflammatory cytokines and low anti-inflammatory cytokines) in AD individuals compared with social drinkers (SDs);both at baseline and in response to stress. Moreover, this inflammatory immune system response was shown to be associated with increased stress-induced alcohol craving, negative affect and relapse and was also shown to vary between AD individuals with and without high co-morbid depressive symptomatology. Therefore, our objectives are to investigate the role of pro- and anti- inflammatory cytokine biomarkers in relation to the negative reinforcement processes integral to relapse risk in both non-depressed AD individuals as well as AD individuals with high co-morbid depressive symptomatology (AD+dep VS AD-dep). A 5-year project with a cross-sectional design and a prospective follow-up relapse assessment phase is proposed to study demographically-matched samples of 60 AD (30 +dep / 30 -dep) and 60 SDs (30 +dep / 30 -dep) to address the following specific aims: (1) to examine whether AD subjects and SDs differ with regard to cytokine basal levels and cytokine reactivity following exposure to stress-related imagery. (2) to examine whether AD and SD individuals with and without depressive symptomology will differ with regard to cytokine basal levels and cytokine reactivity following exposure to stress-related imagery. (3) to examine the relationship between stress- induced cytokine adaptations and craving as well as relapse at 14, 30 and 90 days following discharge from inpatient treatment. (4) to explore potential moderators of change in basal and response cytokine levels, including sex and severity of chronic alcohol abuse. As high co-morbid depressive symptomatology is one of the most prevalent psychiatric disorders associated with alcoholism, the identification of new molecular targets for the treatment of alcoholism in both non-depressed individuals as well as those with high depressive symptomatology will be integral to the development of new immune-related, individualized medications for alcohol treatment.

Public Health Relevance

Alcoholism is among the top three causes of preventable death and disease in the US (Mokdad et al., 2004) and is defined by robust stress system dysregulation and a prevalence of high levels of depressive symptomatology. Both factors increase alcohol craving and relapse risk, and have a robust inflammatory effect on immune system processes via adaptations in cytokine mediators, known to modulate mood. The proposed study will provide a greater understanding of the inflammatory immune system mechanisms underlying the development of stress-induced alcohol craving and relapse both in non-depressed AD individuals as well as AD individuals with high levels of depressive symptomatology (CES-D). Findings will therefore elucidate novel biomarkers with the potential for developing new immune-related treatment interventions that target core stress system sensitivity and hence the overlapping pathophysiology of both alcohol dependence and depressive symptomatology.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Grandison, Lindsey
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Yale University
Schools of Medicine
New Haven
United States
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Milivojevic, Verica; Ansell, Emily; Simpson, Christine et al. (2017) Peripheral Immune System Adaptations and Motivation for Alcohol in Non-Dependent Problem Drinkers. Alcohol Clin Exp Res 41:585-595
Fox, Helen C; Milivojevic, Verica; Angarita, Gustavo A et al. (2017) Peripheral immune system suppression in early abstinent alcohol-dependent individuals: Links to stress and cue-related craving. J Psychopharmacol 31:883-892
Milivojevic, Verica; Fox, Helen C; Sofuoglu, Mehmet et al. (2016) Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women. Psychoneuroendocrinology 65:44-53
Bianchi, Renzo; Laurent, Eric (2016) Memory sin: Misattribution, false recognition, and feeling of déjà-vu when reading peers' contributions. Psychoneuroendocrinology 65:34
Seo, Dongju; Sinha, Rajita (2015) Neuroplasticity and Predictors of Alcohol Recovery. Alcohol Res 37:143-52
Fox, Helen; Sofuoglu, Mehmet; Sinha, Rajita (2015) Guanfacine enhances inhibitory control and attentional shifting in early abstinent cocaine-dependent individuals. J Psychopharmacol 29:312-23
Milivojevic, Verica; Sinha, Rajita; Morgan, Peter T et al. (2014) Effects of endogenous and exogenous progesterone on emotional intelligence in cocaine-dependent men and women who also abuse alcohol. Hum Psychopharmacol 29:589-98
Fox, Helen; Sinha, Rajita (2014) The role of guanfacine as a therapeutic agent to address stress-related pathophysiology in cocaine-dependent individuals. Adv Pharmacol 69:217-65
Fox, Helen C; Morgan, Peter T; Sinha, Rajita (2014) Sex differences in guanfacine effects on drug craving and stress arousal in cocaine-dependent individuals. Neuropsychopharmacology 39:1527-37
Fox, Helen C; Tuit, Keri L; Sinha, Rajita (2013) Stress system changes associated with marijuana dependence may increase craving for alcohol and cocaine. Hum Psychopharmacol 28:40-53

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