Alcohol-induced alterations in orbitofrontal cortex serotonin signaling

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Project Summary Excessive alcohol consumption is a leading cause of mortality and economic burden in the United States. Of the patterns of excessive intake, binge drinking is the most common and accounts for approximately half of the deaths attributable to alcohol. In addition to high rates of mortality, repeated cycles of binge alcohol intake and withdrawal cause persistent adaptations in brain regions that increase the risk of psychiatric symptoms and subsequent excessive alcohol consumption. This places individuals at greater risk for developing alcohol dependence. These outcomes may be driven by dysregulation in serotonin (5-hydroxytryptamine, 5-HT) systems originating in the dorsal raphe nucleus (DR). Although involvement of 5-HT has been well established in alcohol use disorder, we lack a thorough understanding of the neural circuits and precise signaling mechanisms that underlie this dysregulation. In this proposal, I will examine the adaptations in a 5-HT circuit from the DR to the orbitofrontal cortex (OFC) that result from repeated episodes of binge-like alcohol intake. I will accomplish this using a series of converging and highly innovative ex vivo and in vivo techniques that will allow me to measure binge alcohol-induced changes in 5-HT release and signaling dynamics in the DR and the OFC. Further, I will probe the causal role of 5-HT signaling in the DR-OFC circuit in promoting excessive alcohol intake. In addition to providing me with advanced technical training and professional development activities, this proposal will provide essential information concerning the actions of binge-like alcohol drinking on 5-HT neural circuitry and signaling. Ultimately, this proposal will identify a circuit-based signaling mechanism that can be used for the targeted treatment of alcohol use disorder. !