Chronic Alcohol and Brain Stress Circuit Response

描述（由申请人提供）：慢性酒精和大脑应激回路反应酒精中毒是一种慢性复发性疾病，其中大脑应激和奖赏通路中与酒精相关的神经适应会促进持续的渴望或强迫性的酒精寻求，这是酒精中毒发展和酒精复发易感性的标志症状。在该项目的第一个资助期间，我们发现长期酗酒与一系列与压力相关的变化有关，这些变化伴随着强迫性饮酒状态，而这些变化导致完成住院治疗的酗酒者的复发易感性很高。此外，比较本期研究的中度（MD）、中度暴饮（MB）和重度（HD）非依赖饮酒者的初步结果表明，对压力诱导和提示诱导的酒精渴望的敏感性逐渐增加，以及与大量饮酒和/或暴饮相关的生理和生化变化。这些发现表明，与酒精相关的压力反应以及压力和提示引起的渴望的改变可能有助于强迫性饮酒的发展。因此，在这项竞争性的更新申请中，我们延伸和扩展了当前时期的研究结果，以研究压力在强迫性饮酒发展中的作用以及在非依赖性重度和酗酒者中压力和提示相关酒精消耗增加中的作用。提出了一个为期 5 年的横断面设计项目，该项目将研究 50 名 MD、50 MB 和 50 名 HD 饮酒者的人口统计匹配样本，以实现以下具体目标：（1）检查暴露于压力和酒精暗示是否会增加三个饮酒群体的酒精渴望、负面情绪、行为困扰反应，并差异性地改变生理和生化反应。 (2) 在酒精味觉测试中检查暴露于压力和酒精暗示与中性暗示是否会增加饮酒量，以及饮酒量是否随饮酒群体而变化。 (3) 检查痛苦和强迫性寻求的主观、生理和生化标记是否可以预测每种情况下的饮酒量。 (4) 研究人口统计学和个体差异变量的影响，例如性别、种族、酗酒家族史（FH）、尼古丁的共病使用以及压力和线索相关反应和饮酒水平中的认知/冲动控制不良。解决这些问题将增进对饮酒和压力反应相互作用的机制的理解，从而影响强迫性饮酒的发展和饮酒失控的脆弱性，其结果将对酒精中毒新的预防和治疗干预措施的开发产生重大影响。在美国，酗酒是可预防的死亡和疾病的三大原因之一（Mokdad 等，2004；Room 等，2005）。压力在酗酒的发展和酗酒的高度易感性中起着重要作用。拟议的研究将更好地了解压力和饮酒相互作用的机制，影响强迫性饮酒的发展和压力诱发饮酒的脆弱性，其结果将对酒精中毒新的预防和治疗干预措施的开发产生重大影响。

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.