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

前额皮质大脑压力系统在强迫性饮酒中的作用

• 批准号: 8308410
• 负责人: George F. Koob
• 金额: $ 37.98万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308410
• 关键词: Address; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Biological Neural Networks; Brain; Brain Mapping; Chronic; Cognition; Cognitive; Cognitive deficits; Corticotropin-Releasing Hormone; Decision Making; Dependence; Development; Disease; Ethanol dependence; Exhibits; Functional disorder; Goals; Heavy Drinking; Human; Impaired cognition; Impairment; Individual Differences; Intake; Learning; Link; Measures; Memory; Modeling; Molecular; Motivation; Nerve Degeneration; Neurons; Neurotransmitters; Norepinephrine; Obsessive compulsive behavior; Pattern; Pharmaceutical Preparations; Prefrontal Cortex; Prevention; Rattus; Recording of previous events; Relapse; Rodent; Role; Self-Administered; Short-Term Memory; Site; Societies; Stress; Structure; Substance Addiction; System; Techniques; Testing; Time; United States; Withdrawal; alcohol exposure; alcohol seeking behavior; alcoholism prevention; base; chronic alcohol ingestion; cingulate cortex; cognitive function; cost; design; drinking; executive function; innovation; motivated behavior; neurobiological mechanism; norepinephrine system; novel; prevent

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.

描述（由申请人提供）：酗酒是一种慢性复发性疾病，其特征是强迫性使用和失去对摄入的控制。酗酒给美国和全世界的社会带来了巨大的代价。长期以来，过量饮酒已被证明会对前额皮质功能产生有害影响，包括损害决策、执行功能以及记忆和学习。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，很少有研究探讨长期饮酒和大脑应激系统的激活如何与前额皮质相互作用，从而产生认知功能障碍并导致强迫性饮酒。该项目的总体假设是，前额皮质中大脑压力系统[促肾上腺皮质激素释放因子（CRF）和去甲肾上腺素（NE）]的激活会扰乱认知功能，从而加剧与强迫性使用相关的饮酒的强烈动机。为了解决这一假设，本提案旨在 (1) 进一步描述过量饮酒动物模型中认知功能障碍和强迫性饮酒发展的时间过程。 (2) 确定前额皮质压力系统在强迫性饮酒发展过程中的变化模式；(3) 测试前额叶皮质压力系统的长期失活是否可以预防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以及创新的酒精依赖动物模型的使用，例如升级暴饮暴食和依赖诱发的饮酒模型，以及对强迫性饮酒、工作记忆和持久反应的非常具体的测量。了解前额皮质内产生认知缺陷并导致乙醇依赖的强迫性的神经生物学机制，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目标提供关键信息。