This project aims to elucidate a biological pathway which convergent evidence has implicated in ethanol response. At the center of the pathway is glycogen synthase kinase-3 beta (GSK3B), which has been shown to be inhibited via phosphorylation in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of rodents after acute ethanol exposure. GSK3B has also been shown to regulate GABA receptor clustering via its action on gephyrin, which may represent a plasticity-related pathway relevant to ethanol exposure. Studies on rodent drinking behavior have indicated that inhibition of GSK3B with specific pharmacologic inhibitors decrease ethanol drinking, possibly through altering the typical ethanol response. Using a specific inhibitor, Tideglusib, we will further investigate inhibition of GSK3B in relation to drinking behavior, as well as anxiety-like behavior, to determine whether drug treatment influences the usual anxiolytic effect of ethanol, or the anxiety-inducing effect of ethanol withdrawal. In conjunction, we will examine changes in the phosphorylation state of GSK3B following chronic ethanol exposure as well as withdrawal. Additionally, we will use a Cre-LoxP system to selectively knock out Gsk3b in specific brain regions to assess potentially localized or differential effects of the GSK3B pathway in the PFC vs. NAc on drinking behavior. RNASeq analysis will be performed on the knockout samples following chronic ethanol exposure to assess for downstream effects of Gsk3b deletion with particular attention to gephyrin and GABA receptor subunit transcripts.
Despite the prevalence (US population frequency ~ 7%) and devastating impact of Alcohol Use Disorders (AUDs) on individual patients and society, a reliably successful long-term treatment is lacking even in motivated patients. Based on recent evidence implicating glycogen synthase kinase-3 beta (GSK3B) in neuronal alcohol response and synaptic plasticity, we propose to explore the nature and effect of inhibition of the GSK3B pathway in animal models, with the hope that we may gain insight into potential applicability of GSK3B inhibitors in human AUDs.
|van der Vaart, Andrew; Meng, Xianfang; Bowers, M Scott et al. (2018) Glycogen synthase kinase 3 beta regulates ethanol consumption and is a risk factor for alcohol dependence. Neuropsychopharmacology 43:2521-2531|
|van der Vaart, Andrew D; Wolstenholme, Jennifer T; Smith, Maren L et al. (2017) The allostatic impact of chronic ethanol on gene expression: A genetic analysis of chronic intermittent ethanol treatment in the BXD cohort. Alcohol 58:93-106|