Chronic Alcohol and Brain Stress Circuit Response

描述(申请人提供)：慢性酒精和大脑压力回路反应酒精中毒是一种慢性复发性疾病，在这种疾病中，大脑压力和奖励通路中与酒精相关的神经适应已知会促进持续的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症状。在这个项目的第一个资助期，我们发现慢性酒精滥用与一系列与压力相关的变化有关，这些变化伴随着强迫性酒精寻求状态，这些变化导致完成住院治疗的酒精患者的高复发易感性。此外，对当前研究中研究的中度(MD)、中度酗酒(MB)和重度(HD)非依赖饮酒者的初步结果表明，他们对压力诱导和暗示诱导的酒精渴望以及与大量饮酒和/或酗酒相关的生理生化变化的敏感性逐渐增加。这些发现表明，与酒精相关的应激反应变化以及压力和线索诱导的渴望可能有助于强迫性饮酒的发展。因此，在这个竞争性的更新申请中，我们扩展和扩展了当前时期的发现，以检查压力在强迫性酒精寻求的发展中的作用，以及在非依赖型重度和酗酒者中压力和线索相关的酒精消费增加的作用。一项为期5年的横断面设计项目将研究人口统计学上匹配的50名MD、50 MB和50名HD饮酒者的样本，以解决以下具体目标：(1)检查暴露在压力和酒精线索下是否会增加酒精渴望、负面情绪、行为痛苦反应，并在三个饮酒组之间差异地改变生理和生化反应。(2)考察在酒精品尝测试中，暴露于压力和酒精线索与中性线索是否会增加饮酒量，以及饮酒量是否随饮酒组的不同而不同。(3)检验苦恼和强迫寻求的主观、生理和生化指标是否能预测每种情况下的饮酒量。(4)探讨性别、种族、酗酒家族史、尼古丁共病、认知/冲动控制不良等人口统计学和个体差异变量对应激和线索相关反应及饮酒水平的影响。解决这些问题将增加对酒精消费和应激反应相互作用影响强迫性饮酒和失控饮酒易感性的机制的理解，研究结果将对开发新的酒精中毒预防和治疗干预措施具有重要意义。在美国，酒精中毒是可预防的死亡和疾病的三大原因之一(Mokda等人，2004年；Room等人，2005年)。压力在酒精中毒的发展和对酒精复发的高度易感性中起着重要的作用。这项拟议的研究将更好地理解压力和饮酒相互作用影响强迫性饮酒和压力饮酒易感性的发展机制，研究结果将对开发新的酒精中毒预防和治疗干预措施具有重要意义。

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.