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Purpose: We previously identified glycogen synthase kinase-3 beta (Gsk3b) as a central member of a gene network highly regulated by acute ethanol in medial prefrontal cortex (mPFC) and associated with risk for alcohol dependence in humans. Further, we have demonstrated modulation of Gsk3b alters ethanol consumption in rodent models. GSK3B could thus represent a potential new therapeutic target for the treatment of alcohol use disorder (AUD). Here, we investigate the mechanisms of Gsk3b action in ethanol consumption and report preclinical evidence for the selective GSK3B inhibitor, tideglusib, as a therapeutic agent for AUD.
Methods: (1) Selective Cre-induced Gsk3b deletion in Camk2a-neurons within the forebrain using transgenic Camk2a-CreER/Gsk3b floxed mice bred with Gsk3b fl/fl mice to produce Cre/Gsk3b fl/fl mice, which were injected with tamoxifen to induce Gsk3b deletion or (2) selective pharmacological antagonism of GSK3B using Tideglusib delivered via gavage in a corn oil vehicle. Actions on drinking behavior were measured using mouse intermittent ethanol, two-bottle choice self-administration models in C57BL/6J mice.
Results: Deletion of Gsk3b in Camk2a-neurons decreased ethanol consumption and preference. There was no significant effects of sex or sex*genotype on either consumption or preference, so sexes were pooled. Gsk3b deletion did not alter basal locomotor activity, anxiety-like behavior (light-dark box), taste preference for quinine or saccharin, or ethanol pharmacokinetics. Initial administration of tideglusib (100mg/kg twice daily) or corn oil vehicle via gavage decreased total fluid consumption in all groups, regardless of ethanol drinking history or tideglusib treatment. However, following prolonged tideglusib, mice decreased binge (2hr) and daily (24hr) ethanol consumption and preference after three weeks of administration relative to vehicle controls. Tideglusib studies were only performed in male mice. Control studies showed no effect of tideglusib on liver fat accumulation in ethanol consuming animals. Ongoing work is assessing alternative oral tideglusib delivery methods in decreasing ethanol consumption.
Conclusion: These results suggest GSK3B may be a therapeutic target for treatment of AUD. Deletion of Gsk3b in forebrain Camk2a-neurons showed a regional and cell-type specificity in GSK3B’s modulation of ethanol consumption and preference, providing insight into the mechanisms of Gsk3b action in ethanol consumption. Targeting GSK3B using tideglusib, a selective GSK3B inhibitor, also produced a decrease in ethanol consumption and preference over water during the fourth week of treatment. These findings were consistent with previous work in our lab investigating the delivery of tideglusib through intraperitoneal injections, though these studies were limited to a shorter drug-administration period. Here we have used a more therapeutically translatable route of administration via oral gavage and begun to investigate the longer-term effects of tideglusib on ethanol behaviors and toxicity. Tideglusib is a clinically available agent that warrants investigation in the treatment of AUD.
Supported by NIAAA grants P50AA022537 and R01AA027581.
ethanol, GSK3B, glycogen synthase kinase 3 beta, tideglusib, Camk2a, CamkIIa, calcium calmodulin dependent protein kinase
Medical Neurobiology | Medical Pharmacology | Medicine and Health Sciences | Neurosciences | Substance Abuse and Addiction
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