Chronic Alcohol, Stress Inflammatory Response and Relapse Risk

描述（由申请人提供）：我们建议研究外周免疫系统细胞因子如何影响有或没有高水平抑郁症状的酒精依赖（AD）个体与压力相关的酒精渴望和复发风险。酗酒者压力引起的渴望是一种持续的痛苦状态，其特征是负面情绪升高、基础肾上腺敏感性上调以及随后对压力的唤醒反应减弱。值得注意的是，这种失调与复发的高度易感性相关，并且在患有共病抑郁和情感症状的 AD 个体中可能会加剧。由于慢性压力和饮酒对免疫系统细胞因子具有强大且相互影响，因此我们假设促炎和抗炎细胞因子水平的适应可能导致酒精渴望和复发的压力系统失调。此外，与患有高共病抑郁症状的人相比，酒精相关的细胞因子变化可能对非抑郁 AD 个体的渴望状态产生不同的影响。我们的初步试验数据显示，与社交饮酒者 (SD) 相比，AD 个体的炎症反应增强（促炎细胞因子高，抗炎细胞因子低）；无论是在基线还是在应对压力时。此外，这种炎症免疫系统反应与压力引起的酒精渴望增加、负面影响和复发有关，并且在患有和不患有高共病抑郁症状的 AD 个体之间也存在差异。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的 AD 个体（AD dep VS AD-dep）中与复发风险不可分割的负强化过程相关的作用。提出一个为期 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 60 个 AD（30 个深度/30 个深度）和 60 个 SD（30 个深度/30 个深度）的人口统计学匹配样本，以实现以下具体目标：（1）检查 AD 受试者和 SD 受试者在暴露于压力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) 检查有或没有抑郁症状的 AD 和 SD 个体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会有所不同。 (3)检查应激诱导的细胞因子适应与渴望以及住院治疗出院后14、30和90天复发之间的关系。 (4)探索基础和反应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酗酒相关的最常见的精神疾病之一，因此确定用于治疗非抑郁个体和具有高抑郁症​​状的酗酒患者的新分子靶点将是开发新的免疫相关的个体化酒精治疗药物的一部分。

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.