Chronic Alcohol and Brain Stress Circuit Response

描述（由申请人提供）：慢性酒精和脑应激回路反应酒精中毒是一种慢性复发性疾病，其中已知脑应激和奖励通路中的酒精相关神经适应性促进持续渴望或强迫性酒精寻求，这是酒精中毒发展和酒精复发易感性的标志性症状。在该项目的第一个资助期，我们发现慢性酒精滥用与一系列伴随强迫性酒精寻求状态的压力相关改变有关，这些变化有助于完成住院治疗的酗酒者的高复发易感性。此外，初步结果比较中度（MD），中度暴饮暴食（MB）和重度（HD）的非依赖性饮酒者在当前阶段的研究表明，逐步增加的敏感性，压力诱导和线索诱导的酒精渴望和相关的生理和生化变化与酗酒和/或暴饮。这些研究结果表明，酒精相关的改变，压力反应和压力和线索诱导的渴望可能有助于发展的强迫性酒精寻求。因此，在这个竞争性的更新应用程序中，我们扩展和扩大了当前阶段的研究结果，以研究压力在强迫性酒精寻求发展中的作用，以及在非依赖性重度和酗酒者中增加压力和线索相关的酒精消费。本研究拟以50名MD、50名MB和50名HD饮酒者为研究对象，采用横断面设计，研究以下几个方面：（1）研究压力和酒精刺激是否会增加饮酒者的饮酒欲望、消极情绪和行为反应，并改变三组饮酒者的生理和生化反应。(2)研究暴露于压力和酒精线索与中性线索是否会增加酒精口味测试中的酒精消耗量，以及消耗量是否随饮酒组而变化。(3)检查是否主观，生理和生化标记的痛苦和强迫性寻求是预测量的酒精消耗在每一个条件。(4)研究人口统计学和个体差异变量的影响，如性别、种族、酒精中毒（FH）家族史、尼古丁的共病使用和对压力和线索相关反应的认知/冲动控制不良以及饮酒水平。解决这些问题将增加对酒精消费和压力反应相互作用的机制的理解，以影响强迫性酒精寻求和对失控饮酒的脆弱性的发展，其结果将对开发新的预防和治疗酒精中毒的干预措施产生重大影响。酒精中毒是美国可预防的死亡和疾病的三大原因之一（Mokdad等人，2004; Room等人，2005年）。压力在酒精中毒的发展和酒精复发的高度脆弱性中起着重要作用。这项拟议的研究将提供一个更好的理解的机制，压力和酒精消费相互作用，以影响发展的强迫性酒精寻求和脆弱性的压力诱导饮酒，其结果将有重大意义的发展新的预防和治疗干预酗酒。

DESCRIPTION (provided by applicant): Chronic Alcohol and Brain Stress Circuit Response Alcoholism is a chronic relapsing illness in which alcohol-related neuroadaptations in brain stress and reward pathways are known to promote persistent craving or compulsive alcohol seeking, a hallmark symptom in both the development of alcoholism and in alcohol relapse susceptibility. In the first funding period of this project, we found that chronic alcohol abuse is associated with a series of stress-related alterations that accompany the compulsive alcohol seeking state, and these changes contribute to high relapse susceptibility in alcoholics completing inpatient treatment. Furthermore, preliminary results comparing moderate (MD), moderate bingeing (MB) and heavy (HD) non-dependent drinkers studied in the current period suggested a progressive increase in sensitivity to stress-induced and cue-induced alcohol craving and associated physiological and biochemical alterations associated with heavy drinking and/or binge drinking. These findings suggest that alcohol-related alterations in stress responses and stress and cue-induced craving may contribute to the development of compulsive alcohol seeking. Therefore, in this competing renewal application, we extend and expand the findings from the current period to examine the role of stress in the development of compulsive alcohol seeking and in increased stress and cue-related alcohol consumption in non-dependent heavy and binge drinkers. A 5-year project with a cross-sectional design is proposed that will study demographically-matched samples of 50 MD, 50 MB and 50 HD drinkers, to address the following specific aims: (1) To examine whether exposure to stress and to alcohol cues increases alcohol craving, negative emotions, behavioral distress responses and alters physiological and biochemical responses differentially across the three drinking groups. (2) To examine whether exposure to stress and to alcohol cues vs. neutral cues increases alcohol consumption in the alcohol taste test, and if amount consumed vary as a function of drinking group. (3) To examine whether subjective, physiological and biochemical markers of distress and compulsive seeking is predictive of amounts of alcohol consumed in each condition. (4) To examine the influence of demographic and individual differences variables, such as gender, race, family history of alcoholism (FH), co-morbid use of nicotine and poor cognitive/impulse control in stress and cue-related responses and level of alcohol consumption. Addressing these questions will increase an understanding of the mechanisms by which alcohol consumption and stress responses interact to influence development of compulsive alcohol seeking and vulnerability to loss of control drinking, and the results will have significant implications for the development of new prevention and treatment interventions for alcoholism. Alcoholism is among the top three causes of preventable death and disease in the US (Mokdad et al., 2004; Room et al., 2005). Stress plays an important role in the development of alcoholism and in high vulnerability to alcohol relapse. The proposed study will provide a greater understanding of the mechanism by which stress and alcohol consumption interacts to influence development of compulsive alcohol seeking and vulnerability to stress-induced drinking, and the results will have significant implications for the development of new prevention and treatment interventions for alcoholism.