Chronic Alcohol, Stress Inflammatory Response and Relapse Risk

描述（由申请人提供）：我们建议研究有或没有高水平抑郁症状的酒精依赖（AD）个体中，外周免疫系统细胞因子如何促进与压力相关的酒精渴望和复发风险。酗酒者的压力诱发渴望是一种持续的痛苦状态，其特征是负性情绪升高，基底肾上腺敏感性上调，随后对压力的觉醒反应减弱。值得注意的是，这种失调与复发的高易感性相关，并且在伴有抑郁和情感症状的AD患者中可能会加剧。由于慢性应激和饮酒对免疫系统细胞因子具有强大的相互作用，我们假设促炎性和抗炎性细胞因子水平的适应可能导致应激系统失调，从而导致酒精渴望和复发。此外，酒精相关的细胞因子变化可能对非抑郁AD个体的渴望状态有不同的贡献，与那些有高共病抑郁症状的个体相比。我们的初步试验数据显示，与社交饮酒者（SDs）相比，AD个体的炎症反应（高促炎细胞因子和低抗炎细胞因子）增加；无论是基线还是应激反应。此外，这种炎症性免疫系统反应被证明与压力诱导的酒精渴望增加、负面影响和复发有关，并且还被证明在有和没有高共病抑郁症状的AD个体之间有所不同。因此，我们的目标是研究促炎和抗炎细胞因子生物标志物在非抑郁性AD个体以及具有高共病抑郁症状（AD+ deep VS AD- deep）的AD个体中与复发风险相关的负强化过程中的作用。一项为期5年的项目，采用横断面设计和前瞻性随访复发评估阶段，研究人口统计学匹配的60例AD（30 +深度/ 30 -深度）和60例SDs（30 +深度/ 30 -深度）样本，以解决以下具体目标：(1)检查AD受试者和SDs在暴露于压力相关图像后细胞因子基础水平和细胞因子反应性是否存在差异。(2)研究有抑郁症状和无抑郁症状的AD和SD个体在应激相关图像暴露后，细胞因子基础水平和细胞因子反应性是否存在差异。(3)探讨应激诱导的细胞因子适应与渴求及出院后14、30、90天复发的关系。(4)探讨慢性酒精滥用的基础和应答细胞因子水平变化的潜在调节因子，包括性别和严重程度。由于高共病性抑郁症状是与酒精中毒相关的最普遍的精神疾病之一，在非抑郁个体和高抑郁症状个体中发现酒精中毒治疗的新分子靶点，将是开发新的免疫相关的、个体化的酒精治疗药物的组成部分。

DESCRIPTION (provided by applicant): 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.