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）：酒精中毒是一种慢性复发障碍，其特征是强迫使用和失去对摄入的控制。酒精中毒在美国和世界范围内为社会带来了巨大的成本。长期以来，过度使用酒精会对前额叶皮层功能产生不利影响，包括在决策，执行功能以及记忆和学习中的损害。此外，许多研究表明，脑应力系统通过过量饮酒而被激活。然而，很少有研究探讨了慢性酒精和脑应激系统的激活如何与前额叶皮层相互作用，以产生认知功能障碍并有助于强迫性酒精摄入。该项目的总体假设是，前额叶皮层中的大脑应激系统[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，这加剧了与强迫性使用相关的酒精寻求者的强大动机。为了解决这一假设，目前的提案旨在（1）进一步表征过度饮酒的动物模型中认知功能障碍和强迫性饮酒的时间过程。 （2）确定前额叶皮层的压力系统变化在强迫性饮酒中的变化和（3）测试前额叶皮层中应力系统的慢性失活是否会阻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，神经药物和分子技术，以及使用创新的酒精依赖性动物模型，例如升级 - 抑制剂和依赖性诱发的饮酒模型，以及非常具体的强迫性酒精饮酒，工作记忆和持久性响应的措施。了解产生认知缺陷并导致乙醇依赖性强迫性的前额叶皮层内的神经生物学机制将提供关键信息，以了解发展酒精中毒脆弱性的个体差异以及用于治疗和预防酒精中毒的新目标。