Role of CRF in the affective symptoms of acute and protracted ethanol withdrawal

CRF 在急性和长期乙醇戒断情感症状中的作用

• 批准号: 7072389
• 负责人: Adriaan Willem Bruijnzeel
• 金额: $ 7.33万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7072389
• 关键词: alcoholism /alcohol abuse; amygdala; anxiety; behavior test; behavioral /social science research tag; corticotropin releasing factor; depression; drug withdrawal; emotions; ethanol; hormone receptor; laboratory mouse; laboratory rat; pathogenic diet; psychopharmacology; reinforcer; sign /symptom; substance abuse related behavior

DESCRIPTION (provided by applicant): Ethanol dependence is a chronic mental illness that is characterized by loss of control over ethanol intake, the appearance of withdrawal symptoms upon the discontinuation of ethanol use, and relapse to ethanol use after periods of abstinence. Prolonged ethanol use has been shown to cause organ damage, and to increase the risk for a variety of cancers. It has been estimated that ethanol use and abuse leads to the death of 85,000 Americans each year, and is thereby the third-leading preventable cause of death in the United States. The acute and protracted negative affective state (i.e. anxiety and depression) associated with the discontinuation of ethanol use has been shown to contribute to craving and relapse. Therefore, treatments that reverse the negative affective state associated with ethanol withdrawal may help recovering alcoholics to maintain abstinence. The overall aim of our studies is to investigate the neuronal substrates that mediate the negative affective state of acute and protracted ethanol withdrawal. The rat intracranial self-stimulation paradigm will be used to assess the depressive-like signs of acute and protracted ethanol withdrawal. Ethanol withdrawal in rats is associated with elevations in brain reward thresholds (i.e. deficit in brain reward function) that are analogous to the anhedonia experienced by ethanol dependent patients after the discontinuation of ethanol use. The elevated plus-maze test will be used to assess anxiety-like behavior associated with acute and protracted abstinence. Acute ethanol withdrawal will be investigated immediately after the discontinuation of the ethanol liquid diet, and protracted abstinence will be investigated 6 weeks later. The first specific aim is to examine the role of the "stress" peptide corticotropin-releasing factor (CRF) in subcomponents of the extended amygdala in the acute negative affective signs of ethanol withdrawal. The second specific aim investigates the role of CRF in subcomponents of the extended amygdala in the protracted negative affective signs of ethanol withdrawal. The extended amygdala is a large brain structure involved in emotion and motivation. It is expected that antagonism of CRF receptors in subcomponents of the extended amygdala reverse the acute and protracted negative affective signs of ethanol withdrawal in rats. These proposed studies will provide information about the neuronal systems underlying acute and protracted ethanol abstinence, and thereby contribute to the development of new and improved pharmacotherapies for ethanol use-disorders.

描述（由申请人提供）：乙醇依赖性是一种慢性精神疾病，其特征在于失去对乙醇摄入的控制，戒断乙醇使用后出现戒断症状的出现，以及在戒酒期间后对乙醇的复发。长时间的乙醇使用已被证明会造成器官损伤，并增加了各种癌症的风险。据估计，乙醇的使用和滥用每年导致85,000名美国人死亡，因此是美国第三条可预防的死亡原因。与使用乙醇使用相关的急性和旷日持久的负面情感状态（即焦虑和抑郁症）已证明有助于渴望和复发。因此，扭转与乙醇戒断相关的负面情感状态的治疗可能有助于恢复酗酒者维持戒酒。我们研究的总体目的是研究介导急性和长期乙醇戒断的负面情感状态的神经元底物。大鼠颅内自刺激范式将用于评估急性和旷日持久的乙醇戒断的抑郁样迹象。大鼠的乙醇戒断与脑奖励阈值的升高（即脑奖励功能的缺陷）相似，这些乙醇与乙醇使用后相关的患者所经历的Anhedonia类似。升高的迷宫测试将用于评估与急性和持久禁欲有关的焦虑样行为。乙醇液体饮食中断后，将立即研究急性乙醇的戒断，并将在6周后研究持久的节制。第一个具体目的是检查“胁迫”肽皮质激素释放因子（CRF）在延伸杏仁核的亚组成部分中的作用。第二个特定目的调查了CRF在延长的杏仁核的亚组成部分中的作用，在延长的乙醇戒断的负面情感迹象中。扩展的杏仁核是参与情感和动机的大脑结构。可以预期，杏仁核的子组件中CRF受体的拮抗作用逆转了大鼠乙醇戒断的急性和持久的负面情感迹象。这些拟议的研究将提供有关急性和旷日持久的乙醇屈服基础神经元系统的信息，从而有助于开发用于乙醇使用疾病的新的和改进的药物治疗。