Binge-like ethanol drinking activates anaplastic lymphoma kinase signaling and increases the expression of STAT3 target genes in the mouse hippocampus and prefrontal cortex.

Autor: Hamada K; Graduate Program in Neuroscience, University of Illinois at Chicago, Chicago, Illinois, USA.; Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA., Ferguson LB; Waggoner Center for Alcohol Addiction Research and Department of Neuroscience, University of Texas at Austin, Austin, Texas, USA.; Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, Texas, USA., Mayfield RD; Waggoner Center for Alcohol Addiction Research and Department of Neuroscience, University of Texas at Austin, Austin, Texas, USA., Krishnan HR; Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA., Maienschein-Cline M; Research Informatics Core, University of Illinois at Chicago, Chicago, Illinois, USA., Lasek AW; Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.
Jazyk: angličtina
Zdroj: Genes, brain, and behavior [Genes Brain Behav] 2021 Feb 28, pp. e12729. Date of Electronic Publication: 2021 Feb 28.
DOI: 10.1111/gbb.12729
Abstrakt: Alcohol use disorder (AUD) has a complex pathogenesis, making it a difficult disorder to treat. Identifying relevant signaling pathways in the brain may be useful for finding new pharmacological targets to treat AUD. The receptor tyrosine kinase anaplastic lymphoma kinase (ALK) activates the transcription factor STAT3 in response to ethanol in cell lines. Here, we show ALK activation and upregulation of known STAT3 target genes (Socs3, Gfap and Tnfrsf1a) in the prefrontal cortex (PFC) and ventral hippocampus (HPC) of mice after 4 days of binge-like ethanol drinking. Mice treated with the STAT3 inhibitor stattic drank less ethanol than vehicle-treated mice, demonstrating the behavioral importance of STAT3. To identify novel ethanol-induced target genes downstream of the ALK and STAT3 pathway, we analyzed the NIH LINCS L1000 database for gene signature overlap between ALK inhibitor (alectinib and NVP-TAE684) and STAT3 inhibitor (niclosamide) treatments on cell lines. These genes were then compared with differentially expressed genes in the PFC of mice after binge-like drinking. We found 95 unique gene candidates, out of which 57 had STAT3 binding motifs in their promoters. We further showed by qPCR that expression of the putative STAT3 genes Nr1h2, Smarcc1, Smarca4 and Gpnmb were increased in either the PFC or HPC after binge-like drinking. Together, these results indicate activation of the ALK-STAT3 signaling pathway in the brain after binge-like ethanol consumption, identify putative novel ethanol-responsive STAT3 target genes, and suggest that STAT3 inhibition may be a potential method to reduce binge drinking in humans.
(© 2021 International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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