Chronic Alcohol, Stress Inflammatory Response and Relapse Risk

长期酗酒、应激性炎症反应和复发风险

• 批准号: 8515902
• 负责人: Helen Cecilia Fox
• 金额: $ 32.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515902
• 关键词: Address; Adrenal Glands; Affect; Affective; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Anti-Inflammatory Agents; Anti-inflammatory; Anxiety; Arousal; Biological Markers; Brain; Cessation of life; Chronic; Chronic stress; Clinical; Comorbidity; Data; Development; Disease; Distress; Exposure to; Family; Foxes; Functional disorder; Gender; Guided imagery; Healthcare; High Prevalence; Imagery; Immune; Immune system; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Inpatients; Interleukin-10; Interleukin-12; Interleukin-4; Interleukin-6; Intervention; Interview; Laboratories; Measures; Mediator of activation protein; Mental disorders; Molecular Target; Mood Disorders; Moods; Negative Reinforcements; Participant; Patient Discharge; Patients; Peripheral; Pharmaceutical Preparations; Phase; Physiological; Plasma; Predisposition; Prevalence; Process; Recording of previous events; Recovery; Recruitment Activity; Relapse; Research; Risk; Role; Sampling; Severities; Smoker; Stress; System; TNF gene; Up-Regulation; Withdrawal Symptom; Work; alcohol abuse therapy; alcohol craving; alcohol relapse; alcoholism therapy; anakinra; biological adaptation to stress; care burden; chronic alcohol ingestion; craving; cytokine; depressive symptoms; design; drinking; follow-up; negative emotional state; negative mood; novel; problem drinker; prospective; response; sex; social; social group

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.

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促进酒精依赖（AD）个体（有或无高水平抑郁性精神障碍）的应激相关酒精渴求和复发风险。酗酒者的应激性渴求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，随后对应激的唤醒反应减弱。值得注意的是，这种失调与复发的高度易感性相关，并且可能在患有共病抑郁症和情感障碍的AD个体中加剧。由于慢性压力和饮酒对免疫系统细胞因子具有强大的相互作用，我们推测促炎和抗炎细胞因子水平的适应可能导致压力系统失调，导致酒精渴望和复发。此外，酒精相关的细胞因子的变化可能有助于差异的渴求状态，在非抑郁症的AD个人相比，那些高共病抑郁症。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（高促炎细胞因子和低抗炎细胞因子）增加;无论是在基线还是对压力的反应。此外，这种炎症性免疫系统反应显示与增加的应激诱导的酒精渴望、负面影响和复发相关，并且还显示在具有和不具有高共病抑郁症的AD个体之间变化。因此，我们的目的是研究促炎和抗炎细胞因子生物标志物在非抑郁AD个体以及具有高共病抑郁症的AD个体（AD+dep VS AD-dep）中与复发风险不可或缺的负强化过程相关的作用。本研究拟采用横断面设计和前瞻性随访复发评估阶段，对60例AD患者的人口统计学匹配样本进行为期5年的研究（30 +dep / 30 -dep）和60 SD（30 +dep / 30 -dep），以实现以下具体目标：（1）检查AD受试者和SD受试者在暴露于应激相关图像后的细胞因子基础水平和细胞因子反应性方面是否不同。(2)研究是否AD和SD个体与抑郁症和不抑郁症将不同方面的细胞因子基础水平和细胞因子反应性暴露于压力相关的图像。(3)研究应激诱导的细胞因子适应与渴求之间的关系，以及出院后14、30和90天的复发。(4)探索基础和应答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。由于高共病抑郁症是与酒精中毒相关的最常见的精神疾病之一，因此在非抑郁个体以及高抑郁症患者中识别用于治疗酒精中毒的新分子靶点将是开发新的免疫相关的个体化药物用于酒精治疗的组成部分。