Chronic Alcohol, Stress Inflammatory Response and Relapse Risk

描述(由申请人提供)：我们建议调查外周免疫系统细胞因子如何在有和没有高水平抑郁症状的酒精依赖(AD)个体中促进应激相关的酒精渴求和复发风险。酒鬼的压力诱导渴望是一种持续的痛苦状态，其特征是负面情绪升高，基础肾上腺敏感度上调，随后对压力的唤醒反应减弱。值得注意的是，这种调节失调与复发的高易感性有关，在患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和相互作用的影响，我们推测，促炎和抗炎细胞因子水平的适应可能有助于酒精渴望和复发背后的应激系统失调。此外，与酒精相关的细胞因子变化可能对非抑郁AD患者的渴求状态起到不同的作用，而与高度共病的抑郁症状患者相比。我们的初步试验数据显示，与社交饮酒者(SDS)相比，AD患者的炎症反应(高促炎细胞因子和低抗炎细胞因子)增加；在基线和对压力的反应中都是如此。此外，这种炎症免疫系统反应被证明与压力引起的酒精渴望增加、消极情绪和复发有关，而且在有和没有高度共病抑郁症状的AD患者之间也有差异。因此，我们的目标是研究促炎和抗炎细胞因子生物标记物在非抑郁性AD患者以及高共病抑郁症状患者(AD-DEP与AD-DEP)复发风险的负性强化过程中的作用。一项为期5年的横断面设计和前瞻性随访复发评估阶段被提出，以研究人口统计学上匹配的60例AD(30dep/30-dep)和60例抑郁(30dep/30-dep)样本，以解决以下具体目标：(1)考察AD受试者和抑郁障碍患者在暴露于应激相关图像后在细胞因子基础水平和细胞因子反应性方面是否存在差异。(2)研究有抑郁症状的AD患者和无抑郁症状的SD患者在暴露于应激相关图像后，在细胞因子基础水平和细胞因子反应性方面是否存在差异。(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)探索基础和反应性细胞因子水平变化的潜在调节因素，包括性别和慢性酒精滥用的严重程度。由于高共病抑郁症状是与酒精中毒相关的最常见的精神障碍之一，为非抑郁患者和高度抑郁症状患者确定治疗酒精中毒的新分子靶点将是开发新的免疫相关的个性化酒精治疗药物不可或缺的一部分。

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.