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

描述（由申请方提供）：乙醇依赖是一种慢性精神疾病，其特征为对乙醇摄入失去控制，停止使用乙醇后出现戒断症状，以及在戒酒期后复发使用乙醇。长期使用乙醇已被证明会导致器官损伤，并增加患多种癌症的风险。据估计，乙醇的使用和滥用每年导致85，000名美国人死亡，因此是美国第三大可预防的死亡原因。与停止使用乙醇相关的急性和长期负面情感状态（即焦虑和抑郁）已被证明有助于渴望和复发。因此，逆转与酒精戒断相关的负面情感状态的治疗可能有助于恢复酗酒者保持禁欲。我们研究的总体目标是调查神经基质介导的急性和长期乙醇戒断的负性情感状态。将使用大鼠颅内自我刺激范例评估急性和长期乙醇戒断的抑郁样体征。大鼠的乙醇戒断与脑奖励阈值升高（即脑奖励功能缺陷）相关，这类似于乙醇依赖患者在停止使用乙醇后经历的快感缺失。高架十字迷宫试验将用于评估与急性和长期禁欲相关的焦虑样行为。停止乙醇液体饮食后立即研究急性乙醇戒断，6周后研究长期戒酒。第一个具体的目的是研究的作用，“压力”肽促肾上腺皮质激素释放因子（CRF）的子组件的扩展杏仁核的急性负性情感的迹象，乙醇戒断。第二个具体的目标调查CRF在延长杏仁核的子成分中的作用，在长期的负面情绪迹象的乙醇戒断。延伸杏仁核是一个涉及情感和动机的大型大脑结构。预期在大鼠中，扩展杏仁核的亚组分中CRF受体的拮抗作用逆转了乙醇戒断的急性和长期负面情感体征。这些拟议的研究将提供有关急性和长期乙醇戒断的神经系统的信息，从而有助于开发新的和改进的乙醇使用障碍的药物疗法。

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.