The Role of Serotonin in Alcohol-Withdrawal Induced Anxiety

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Abstract Alcohol abuse is an enormous public health problem. While there have been significant gains in our knowledge of this disorder, we lack fundamental knowledge pertaining to the biological mechanisms that contribute to the chronic relapsing pathology of alcohol abuse. It has been hypothesized that alcohol exposure modifies function in brain regions critical for regulation of emotion, and that these changes underlie persistent alterations in behavior. The serotonin (5HT) system has been implicated in the pathophysiology of a range of psychiatric conditions, most notably anxiety disorders and depression (two conditions co-morbid with alcohol use disorders). Altered 5HT signaling has been suggested to contribute to cravings and relapses, as well as the increased negative affective state, manifested as the anxiety-like behavior and dysphoria, associated with alcohol abuse. In the previous submission, we found that chronic intermittent ethanol exposure drives changes in 5HT systems in the BNST, one brain region linked with anxiety-like behavior. Additionally, we identified a 5HT sensitive micro-circuit in the BNST that regulates anxiety-like behavior. We propose here to use multiple converging approaches to test the impact of alcohol exposure on discrete aspects of this 5HT sensitive circuit. We further propose to explore the impact of disruption of these processes on alcohol-induced anxiety-like behaviors and alcohol drinking. We will test the central hypothesis that chronic intermittent alcohol exposure leads to persistent adaptations in this 5HT sensitive circuit in the BNST to drive increased anxiety-like behavior and alcohol consumption.