Alcoholism is a devastating and costly disease that afflicts approximately one out of every twelve adults in the United States. One of the most pernicious aspects of this disease is the extremely high relapse rate ranging from 50-90%, depending on the form of treatment a dependent individual seeks. Thus, research aimed at the prevention of relapse is of high priority in the alleviation of alcoholism. Stress is the most commonly cited reason for relapse in dependent individuals, and is sufficient to cause alcohol craving and seeking in humans and rodents. A stressful experience or withdrawal from alcohol activates the hypothalamic pituitary adrenal (HPA) axis and leads to the release of glucocorticoids (cortisol in humans and corticosterone in rodents, CORT). The high levels of CORT bind to and activate glucocorticoid receptors (GRs) in the brain and periphery, which then act as transcription factors to initiate or repress the transcription of a large number of stress-responsive genes as well as acting through putative membrane-delimited mechanisms. It has been shown that alcohol consumption and withdrawal both induce the release of CORT and subsequent activation of GRs, and the amount of CORT release following alcohol withdrawal is directly proportional to the severity of withdrawal symptoms. Pharmacological activation of GRs has also been demonstrated to increase preference for alcohol while GR antagonists decrease alcohol preference. Thus, GRs may act as a double-edged sword in the withdrawal-relapse cycle by serving as mediators of the negative affect associated with withdrawal as well being key players in alcohol craving during withdrawal. However, while the importance of systemic GR activation in alcohol preference and withdrawal are apparent, the specific circuitry through which GR is acting in the brain is far less clear. Two brain regions that highly express GRs and are critically involved in alcohol withdrawal behavior and relapse to alcohol seeking following a stressor are the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). Our lab and others have shown that the CeA and the BNST contribute to affective responses to stress. These areas are crucial for stress-induced reinstatement of alcohol seeking, and GR antagonist directed at the CeA blunts reinstatement. GRs are also well known for their ability to alter neuronal excitability and plasticity. Our lab has demonstrated tha stress and alcohol administration are capable of altering synaptic plasticity within the BNST through the examination of long-term potentiation (LTP) induction. We have shown that repeated systemic activation of CORT alters the induction of LTP in the BNST, potentially through GRs within the region. In this proposal, the role of CeA and BNST GRs on alcohol preference, withdrawal anxiety, and LTP induction basally and following alcohol administration will be examined through specific genetic deletion of GR within each of these regions through combined use of mice harboring a floxed GR gene and regional delivery of lentiviral Cre-recombinase.

Public Health Relevance

Alcoholism is hypothesized to be such a devastating disease in large part because of the extremely high relapse rate of 50-90%, and stress is the most commonly cited cause of relapse in individuals with alcohol use disorders. Stress activates glucocorticoid receptors (GRs) within the brain which are known to alter alcohol preference and cause long-term alterations in neuronal excitability, and the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) are two brain regions that are responsive to both stress and alcohol and contain high levels of GRs. It is therefore likely that GRs within these two regions contribute to alterations in neuronal excitability and alcohol preference, and the experiments proposed here will examine this hypothesis through specific genetic deletion of GRs within the BNST and CeA followed by examination of alcohol preference behaviors and neuronal excitability within the two regions.

National Institute of Health (NIH)
Predoctoral Individual National Research Service Award (F31)
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Biomedical Research Review Subcommittee (AA)
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Liu, Qi-Ying
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Vanderbilt University Medical Center
Schools of Medicine
United States
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