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

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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.