A Selective GSK3β Inhibitor, Tideglusib, Decreases Intermittent Access and Binge Ethanol Self-Administration in...

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Alcohol use disorder (AUD) affects over 10% of US adults, with limited effective long-term treatments.
• Glycogen synthase kinase 3-beta (GSK3β) is implicated in alcohol-related behaviors, presenting a potential therapeutic target for AUD.

Purpose of the Study:

• To investigate the preclinical efficacy of tideglusib, a selective GSK3β inhibitor, in modulating chronic and binge ethanol consumption.
• To explore the underlying molecular mechanisms of tideglusib's action on ethanol intake.

Main Methods:

• Utilized rodent models for chronic (two-bottle choice, intermittent access) and binge (drinking in the dark) ethanol consumption.
• Assessed effects on water intake, ethanol pharmacokinetics, anxiety-like behavior, locomotion, and liver function markers (ALT, AST, ALP).
• Conducted RNA sequencing to analyze gene expression changes in response to tideglusib treatment.

Main Results:

• Tideglusib significantly decreased ethanol consumption in both chronic and binge drinking models, without affecting water intake.
• The drug showed greater potency in males than females during binge drinking.
• No adverse effects on liver function were observed, though alkaline phosphatase activity decreased; transient locomotion increase noted. RNA sequencing revealed modulation of synaptic plasticity and Wnt signaling pathways.

Conclusions:

• Tideglusib demonstrates significant potential as a therapeutic agent for alcohol use disorder (AUD) by reducing ethanol consumption.
• GSK3β inhibition by tideglusib may exert its effects through the Wnt signaling pathway, impacting synaptic function.
• Further research into tideglusib for AUD treatment is warranted based on these preclinical findings.