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 (GSK3β) has been implicated in ethanol behaviours and poses as a potential therapeutic target in the treatment of AUD. Here, we investigated the preclinical evidence for tideglusib, a clinically available selective GSK3β inhibitor, in modulating chronic and binge ethanol consumption. Tideglusib decreased ethanol consumption in both a model of daily, progressive ethanol intake (two-bottle choice, intermittent ethanol access) and binge-like drinking behaviour (drinking in the dark) without effecting water intake. With drinking in the dark, tideglusib was more potent in males (ED50 = 64.6, CI = 58.9-70.8) than females (ED50 = 79.4, CI = 70.8-93.3). Further, we found tideglusib had no effect on ethanol pharmacokinetics, taste preference or anxiety-like behaviour, although there was a transient increase in total locomotion following treatment. Additionally, tideglusib treatment did not alter liver function as measured by serum activity of alanine aminotransferase and aspartate aminotransferase but did cause a decrease in serum alkaline phosphatase activity. RNA sequencing analysis of tideglusib actions on ethanol consumption revealed alterations in genes involved in synaptic plasticity and transmission, as well as genes downstream of the canonical Wnt signalling pathway, suggesting tideglusib may modulate ethanol consumption via β-catenin binding to the transcription factors TCF3 and LEF1. The data presented here further implicate GSK3β in alcohol consumption and support the use of tideglusib as a potential therapeutic in the treatment of AUD.