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

描述(申请人提供)：酒精中毒是一种慢性复吸障碍，特征是强迫性使用和对摄取失去控制。酗酒在美国和世界范围内给社会造成了巨大的代价。长期以来，过量饮酒被证明对前额叶皮质功能有不利影响，包括决策、执行功能以及记忆和学习方面的损害。此外，许多研究已经证实，过量饮酒会激活大脑压力系统。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质相互作用，产生认知功能障碍，并导致强制饮酒。该项目的总体假设是，激活前额叶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)]会扰乱认知功能，从而加剧与强迫使用相关的强大的饮酒动机。为了解决这一假说，本研究旨在(1)进一步描述过度饮酒动物模型中认知功能障碍和强迫性饮酒的发展过程。(2)确定强迫性饮酒发展过程中前额叶皮质应激系统的变化模式；(3)测试额叶皮质应激系统的慢性失活是否能阻止认知障碍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，使用了酒精依赖的创新动物模型，如升级狂欢和依赖诱导饮酒模型，并结合了非常具体的强制饮酒、工作记忆和持之以恒反应的措施。了解前额叶皮质内产生认知缺陷并导致酒精依赖强迫的神经生物学机制将为了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靶点提供关键信息。

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.