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

描述(申请人提供)：酒精依赖是一种慢性精神疾病，其特征是对酒精摄入量失去控制，在停止使用酒精时出现戒断症状，并在戒酒一段时间后再次使用酒精。长期使用乙醇已被证明会导致器官损伤，并增加患各种癌症的风险。据估计，乙醇的使用和滥用每年导致8.5万美国人死亡，因此是美国第三大可预防的死亡原因。与停止使用酒精有关的急性和持久的负面情绪状态(即焦虑和抑郁)已被证明有助于渴求和复发。因此，逆转与戒酒相关的负面情绪状态的治疗可能有助于恢复酗酒者的戒酒。我们研究的总体目标是调查调节急性和长期酒精戒断的负面情绪状态的神经元底物。大鼠颅内自我刺激范式将被用来评估急性和长期酒精戒断的抑郁样迹象。大鼠戒断酒精与大脑奖赏阈值升高(即大脑奖赏功能缺陷)有关，这类似于酒精依赖患者在停止使用酒精后经历的快感丧失。高架正迷宫测试将被用来评估与急性和长期戒断相关的焦虑样行为。在停止流质酒精饮食后，将立即调查急性酒精戒断情况，并将在6周后调查长期戒酒情况。第一个特别的目的是研究在酒精戒断的急性负面情绪症状中，杏仁核亚成分中的“应激”多肽促肾上腺皮质激素释放因子(CRF)的作用。第二个具体目的是研究CRF在延长的酒精戒断负面情绪征象中杏仁核亚成分中的作用。延伸的杏仁核是一个巨大的大脑结构，与情绪和动机有关。预计CRF受体在延伸杏仁核亚成分中的拮抗作用可以逆转大鼠酒精戒断的急性和持久的负面情感症状。这些拟议的研究将提供关于急性和长期酒精戒断的神经系统的信息，从而有助于开发新的和改进的酒精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.