DOI
https://doi.org/10.25772/F13K-5169
Author ORCID Identifier
https://orcid.org/0000-0002-2342-0900
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Michael F. Miles
Abstract
Alcohol use disorder (AUD) is a complex neuropsychiatric condition where initial exposure to alcohol progresses to pathological levels which results in excessive and compulsive consumption. Cell-to-cell signaling, cellular responsiveness, and lasting modulations in gene expression have been implicated in the shift from first ethanol exposure to dependence. Despite the high prevalence and clear burdens on the individual and society which stem from AUD, few effective, long-term treatments are currently available. Glycogen synthase kinase 3 beta (GSK3β) has been implicated in ethanol behaviors and poses as a potential therapeutic target in the treatment of AUD. Here we investigated the regional and cellular specificity of GSK3β regulation of voluntary ethanol consumption. We hypothesized GSK3β activity within mPFC CaMKIIα+ cells promotes ethanol consumption. As such, increased GSK3β protein levels would increase ethanol consumption and preference and decreased GSK3β would decrease these ethanol drinking behaviors. These experiments identified a potential role of GSK3β activity in regulating the balance between ethanol and water consumption as well as mediating the anxiolytic response to ethanol. We next sought to preclinically characterize the selective GSK3β inhibitor tideglusib and assess its therapeutic potential for AUD treatment, laying the groundwork for future clinical trial. Tideglusib significantly decreased voluntary ethanol consumption in multiple models of rodent drinking behavior. Transcriptomic analysis revealed clusters of ethanol-regulated gene expression that were no longer differentially expressed compared to water-drinking animals in a group treated with tideglusib. Further, we have shown specific gene expression networks regulated by chronic ethanol exposure which are no longer significant with tideglusib treatment. This elucidates a potential mechanism through which GSK3β inhibition protects against ethanol-induced gene transcriptional responses and provides insight on novel gene networks which may be targetable in AUD treatment. Collectively this dissertation implicates GSK3β as a mediator of voluntary ethanol consumption and its resultant maladaptive gene expression, and support GSK3β as a viable therapeutic target for AUD.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
9-13-2024
Included in
Behavioral Neurobiology Commons, Medical Pharmacology Commons, Molecular and Cellular Neuroscience Commons, Molecular Genetics Commons, Neurosciences Commons