A selective GSK3β inhibitor, tideglusib, decreases intermittent access and binge ethanol self-administration in C57BL/6J mice

Gottlieb, S.; van der Vaart, A.; Hassan, A.; Bledsoe, D.; Morgan, A.; O'Rourke, B.; Rogers, W. D.; Wolstenholme, J. T.; Miles, M. F.

doi:10.1101/2024.05.13.593949

bioRxiv · 10.1101/2024.05.13.593949

A selective GSK3β inhibitor, tideglusib, decreases intermittent access and binge ethanol self-administration in C57BL/6J mice

Gottlieb, S.·van der Vaart, A.·Hassan, A.·Bledsoe, D.·Morgan, A.·O'Rourke, B.·Rogers, W. D.·Wolstenholme, J. T.·Miles, M. F.

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Abstract

Over 10% of the US population over 12 years old meets criteria for Alcohol Use Disorder (AUD), yet few effective, long-term treatments are currently available. Glycogen synthase kinase 3 beta (GSK3{beta}) has been implicated in ethanol behaviors and poses as a potential therapeutic target in the treatment of AUD. Here we investigate the role of tideglusib, a selective GSK3{beta} inhibitor, in ethanol consumption and other behaviors. We have shown tideglusib decreases ethanol consumption in both a model of daily, progressive ethanol intake (two-bottle choice, intermittent ethanol access) and binge-like drinking behavior (drinking-in-the-dark) without effecting water intake. Further, we have shown tideglusib to have no effect on ethanol pharmacokinetics, taste preference, or anxiety-like behavior, though there was a transient increase in total locomotion following treatment. Additionally, we assessed liver health following treatment via serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and showed no effect on aminotransferase levels though there was a decrease in alkaline phosphatase. RNA sequencing studies revealed a role of GSK3{beta} inhibition via tideglusib on the canonical Wnt signaling pathway, suggesting tideglusib may carry out its effects on ethanol consumption through effects on {beta}-catenin binding to the transcription factors TCF3 and LEF1. The data presented here further implicate GSK3{beta} in alcohol consumption and support the use of tideglusib as a potential therapeutic in the treatment of AUD.

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Gottlieb, S., van der Vaart, A., Hassan, A., Bledsoe, D., Morgan, A., O'Rourke, B., Rogers, W. D., Wolstenholme, J. T., Miles, M. F.. 2024-05-15. A selective GSK3β inhibitor, tideglusib, decreases intermittent access and binge ethanol self-administration in C57BL/6J mice. https://doi.org/10.1101/2024.05.13.593949

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