The Functional Implications of Astrocytic GPCR-signaling on Alcohol Abuse

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Project Description Problematic alcohol consumption is a major health and socio-economic issue within the United States, but much of the economic burden and pathological consequences from alcohol misuse is associated with binge drinking. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has defined binge drinking as a pattern of drinking that results in a blood ethanol concentration (BEC) of greater than 80mg/dL. Repetitive binge drinking episodes greatly increases the likelihood of developing ethanol dependence. As such, it is critical to consider the neurobiological mechanisms that modulate binge drinking in order to develop novel therapeutic areas to curb alcohol misuse. The neuroimmune system has become of increasing interest as alcohol abuse can elicit neuroinflammatory cascades that can contribute to alcohol-induced neurodegeneration, but of more relevance to this study, alcohol can alter the neuroimmune systems role in neurotransmission and therein contribute to alcohol-related behaviors. This grant furthers our previous studies of binge-like alcohol’s effects on cytokines in the amygdala by specifically determining the impacts of alcohol misuse on astrocyte activation and expression patterns (Aim 1). Moreover, the impact of repeated binge-like drinking episodes on the permanence or plasticity of an altered astrocyte population will be ascertained (Aim 1). Secondly, these studies will determine the role of astrocytic signaling on ethanol consumption and alcohol- induced anxiolytic behavior (Aim 2), but Aim 3 will also determine whether alcohol’s impact on astrocytic glutamate and cytokine regulation is related to changes in alcohol consumption and pharmacologic properties. This will be accomplished by manipulating G-protein coupled receptors specifically in astrocytes using DREADDs under a GFAP promoter. Because sex-differences can alter neuroimmune responses, these studies will elucidate the impact of sex on both astrocytes effects on behavior and binge drinking on astrocytes. Together these three aims will test the overall hypothesis that there is a reciprocal and reinforcing relationship between alcohol and astrocyte activation associated with the impact of astrocytes on glutamatergic tone and cytokine production. These innovative studies will provide insight into the role of astrocytes in the transition to alcohol dependence, novel information regarding the impact of sex on alcohol-induced neuroimmune changes, and a shift in our understanding of the relationship between alcohol misuse and neuroimmune dysregulation.