Alcohol abuse is a significant public health burden that is often difficult to manage with current treatment options. Chronic intermittent ethanol (CIE can induce adaptations in neural circuits that govern anxiety and motivated behavior and may have relevance for ethanol dependence. The goal of this application is to dissect neural circuits that are critically involved in dependence induced escalations in ethanol drinking. Recent evidence indicates that both 5-HT2CR and kappa opioid receptor (KOR) in the nucleus accumbens (NAc) shell contribute to CIE enhanced drinking. My central hypothesis is that chronic intermittent ethanol (CIE) augments 5-HT release in the NAc, which activate local dynorphin neurons that in turn reduce dopamine release. This degrades the reward value of ethanol and leads to increased ethanol consumption.
In Specific Aim 1, I will use a multiplexed DREADD strategy to delineate the role of 5HT inputs to the NAc shell in CIE induced elevations in voluntary ethanol drinking.
In Specific Aim 2, I will examine the impact of CIE on excitability f dynorphin neurons using slice electrophysiology. Based on preliminary data that stimulation of NAc dynorphin neurons modulates dopamine release in the NAc, I will also use slice voltammetry to examine how CIE shapes dynorphin-dopamine interactions in the NAc.
Specific Aim 3 is designed to clarify the role of these NAc dynorphin neurons in excessive ethanol drinking after CIE. In total, the proposed research will provide essential information concerning the actions of CIE on the 5-HT-dynorphin circuits in the NAc that specifically drive excessive alcohol consumption.
This project will help to elucidate the role of serotonin inputs to the nucleus accumbens in alcohol dependence and excessive alcohol drinking. The goal of these studies is to determine if these inputs to the accumbens are necessary and sufficient to drive escalations in alcohol and to examine the impact of ethanol induced remodeling of these inputs on the pathogenesis of alcoholism. Ultimately, this investigation may identify new potential targets for the treatment of alcohol use disorders.
