The Role of Brain Stress Systems in the Prefrontal Cortex in Compulsive Drinking

描述（由申请人提供）：酒精中毒是一种慢性复发性疾病，其特征是强迫性使用和对摄入失去控制。酗酒给美国乃至全世界的社会造成了巨大的损失。长期以来，过量饮酒被证明对前额皮质功能有不利影响，包括决策、执行功能、记忆和学习功能的损害。此外，许多研究已经证实，过量饮酒会激活大脑应激系统。然而，很少有研究探索慢性酒精和大脑应激系统的激活如何与前额叶皮层相互作用，产生认知功能障碍，并导致强迫性酒精摄入。这个项目的总体假设是，前额皮质的大脑应激系统[促肾上腺皮质激素释放因子（CRF）和去甲肾上腺素（NE）]的激活破坏了认知功能，从而加剧了与强迫性饮酒相关的强烈的寻求酒精的动机。为了解决这一假设，本研究的目的是：(1)在过度饮酒的动物模型中进一步表征认知功能障碍和强迫性饮酒发展的时间过程。(2)确定强迫性饮酒发展过程中前额叶皮层应激系统的变化模式；(3)测试前额叶皮层应激系统的慢性失活是否能防止认知缺陷和强迫性饮酒的发展。该方法结合了神经解剖学、神经药理学和分子技术，并使用了创新的酒精依赖动物模型，如升级狂欢和依赖诱导饮酒模型，结合了强迫性饮酒、工作记忆和持续性反应的非常具体的测量。了解前额叶皮层中产生认知缺陷并导致酒精依赖强迫性的神经生物学机制，将为理解酒精中毒易感性的个体差异以及治疗和预防酒精中毒的新目标提供关键信息。

DESCRIPTION (provided by applicant): Alcoholism is a chronic relapsing disorder characterized by compulsive use and loss of control over intake. Alcoholism produces significant cost to society in the United States and worldwide. The excessive use of alcohol has long been shown to have detrimental effects on prefrontal cortex function including impairment in decision making, executive function, and memory and learning. In addition, many studies have established that brain stress systems are activated by excessive drinking. However, few studies have explored how chronic alcohol and activation of the brain stress system interacts with the prefrontal cortex to produce cognitive dysfunction and contribute to compulsive alcohol intake. The overall hypothesis of this project is that activation of the brain stress systems [corticotropin releasing factor (CRF) and norepinephrine (NE)] in the prefrontal cortex disrupts cognitive function that exacerbates the powerful motivation for alcohol seeking associated with compulsive use. To address this hypothesis, the present proposal has been designed to (1) To further characterize the time course of development of cognitive dysfunction and compulsive drinking in animal models of excessive drinking. (2) To determine the pattern of changes in the stress systems in the prefrontal cortex in the development of compulsive drinking and (3) To test if chronic inactivation of the stress systems in the prefrontal cortex prevents cognitive deficits and the development of compulsive alcohol drinking. The approach combines neuroanatomical, neuropharmacological, and molecular techniques and the use of innovative animal models of alcohol dependence, such as the escalation-binge and dependence-induced drinking models, combined with very specific measures of compulsive alcohol drinking, working memory and perseverative responding. Understanding the neurobiological mechanisms within the prefrontal cortex that produce cognitive deficits and contribute to the compulsivity of ethanol dependence will provide key information for understanding the individual differences in vulnerability to develop alcoholism and new targets for the treatment and prevention of alcoholism.