Alcohol abuse is an enormous public health problem and while there have been significant gains in our knowledge of this disorder, there remains a gap in our knowledge of the fundamental biological mechanisms that contribute to its chronic relapsing nature. It has been hypothesized that alcohol exposure modifies function in brain regions critical for regulation of emotion, and that these changes underlie the persistent alterations in behavior. The 5HT system has been implicated in the pathophysiology of a range of psychiatric conditions, most notably anxiety disorders and depression. In keeping with the co-morbidity of these conditions, the 5HT system is proposed to be involved in the development of alcoholism. Altered 5HT signaling has been suggested to contribute to cravings and relapses as well as the increased negative affect, manifested as increased anxiety-like behavior and dysphoria, that is associated with alcohol abuse. The BNST is a structure that has been proposed to be a site of neuroadaptations underlying these behavioral alterations. Further, 5HT signaling within the BNST has been associated with anxiety-like behavior. The ability of 5HT to modulate synaptic transmission in the BNST, and the possibility that this modulation may be altered following ethanol exposure, however, has not been studied in depth. A thorough understanding of the effects of alcohol exposure on 5HT function in the BNST will provide critical mechanistic insight in to alcohol-withdrawal induced anxiety. In preliminary studies, we show that 5HT modulates synaptic transmission in the BNST via activation of 5HT2C-R and that alcohol exposure alters 5HT levels and receptor expression in the BNST. These results support our central hypothesis that: Dysregulation of 5HT2C-R signaling in the BNST following chronic ethanol exposure is associated with alcohol withdrawal induced behavioral deficits. The following three separate but integrated Specific Aims are proposed to test our central hypothesis: SA#1. Test the hypothesis that 5HT2C-R increases GABA release on to an important population of feed- forward inhibitory neurons. SA#2. Test the hypothesis that alcohol exposure enhances 5HT2C-R function in the BNST. SA#3. Test the hypothesis that anxiety-like behavior is increased following alcohol exposure through activation of 5HT2C-R. In total, the proposed research will provide essential information concerning the role that the 5HT2C-R plays in alcohol-induced dysregulation of neuronal function and behavior. Further, given the ability of the 5HT2 agonist, mCPP, to increase craving in alcoholics, this study could shed important light on both craving and relapse. Understanding molecular mechanisms that underlie these processes could lead to more effective therapeutic interventions.
The focus of this project is to understand how alcohol exposure alters emotional behavior. Successful completion of this project will result in a greater understanding of how alcohol changes brain function. Further, these studies may provide insight as to how to develop more useful treatments for alcoholism and anxiety disorders.
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