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Background: We have shown modulations in glycogen synthase kinase 3 beta (GSK3B) abundance or activity regulate ethanol consumption, suggesting potential as a therapeutic target for alcohol use disorder (AUD). Here we report the GSK3B inhibitor tideglusib’s actions on ethanol consumption, basal behaviors, and modulation of GSK3B targets.
Methods: C57BL/6J males and females received i.g. 200mg/kg tideglusib, except drinking-in-the-dark (males;100mg/kg i.p.). Drinking-in-the-dark (DID): Mice given 20% ethanol 4-hours, 4-days/week x 3 weeks and then i.p. tideglusib or vehicle x 4 days in a Latin Square design with ethanol consumption measured daily. Light/Dark Box: Mice gavaged with tideglusib or vehicle and i.p. injected with 1.8g/kg ethanol or saline then tested for 10-min. Taste Preference: Mice received tideglusib x 6 days and then tested daily for saccharin or quinine taste preference. Western Blots: Mice received tideglusib or vehicle i.g. 3x/week for 2-weeks and mPFC assayed for phosphorylated and total GSK3B, Dynamin1, and PSD-95.
Results: Tideglusib decreased ethanol DID consumption, transiently increased locomotion, and had no effect on anxiety-like behaviors or taste preference. Only total Dynamin1 showed tideglusib-induced modulation where females had increased Dynamin1 and decreased pDynamin1/total Dynamin1.
Conclusion: Tideglusib is a promising AUD therapeutic, rapidly decreasing ethanol consumption in a binge-drinking model. Tideglusib is likely not reducing consumption by altering taste or anxiety-like behaviors. Dynamin1 is integral in activity-dependent bulk endocytosis and requires GSK3B-induced rephosphorylation. Tideglusib increased Dynamin1 levels likely represent a compensatory response to decreased GSK3B activity, providing insight to tideglusib’s mechanism in ethanol behaviors. Funded by NIAAA grant R01AA027581.
AUD, ethanol, GSK3B, glycogen synthase kinase 3 beta, tideglusib, PSD-95, Dynamin1, anxiety, drinking in the dark
Behavior and Behavior Mechanisms | Chemical Actions and Uses | Medical Pharmacology | Mental Disorders | Neurosciences
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