Abstract
Understanding how ethanol actions on brain signal transduction and gene expression lead to excessive consumption and addiction could identify new treatments for alcohol dependence. We previously identified glycogen synthase kinase 3-beta (Gsk3b) as a member of a highly ethanol-responsive gene network in mouse medial prefrontal cortex (mPFC). Gsk3b has been implicated in dendritic function, synaptic plasticity and behavioral responses to other drugs of abuse. Here, we investigate Gsk3b in rodent models of ethanol consumption and as a risk factor for human alcohol dependence. Stereotactic viral vector gene delivery overexpression of Gsk3b in mouse mPFC increased 2-bottle choice ethanol consumption, which was blocked by lithium, a known GSK3B inhibitor. Further, Gsk3b overexpression increased anxiety-like behavior following abstinence from ethanol. Protein or mRNA expression studies following Gsk3b over-expression identified synaptojanin 2, brain-derived neurotrophic factor and the neuropeptide Y Y5 receptor as potential downstream factors altering ethanol behaviors. Rat operant studies showed that selective pharmacologic inhibition of GSK3B with TDZD-8 dose-dependently decreased motivation to self-administer ethanol and sucrose and selectively blocked ethanol relapse-like behavior. In set-based and gene-wise genetic association analysis, a GSK3b-centric gene expression network had significant genetic associations, at a gene and network level, with risk for alcohol dependence in humans. These mutually reinforcing cross-species findings implicate GSK3B in neurobiological mechanisms controlling ethanol consumption, and as both a potential risk factor and therapeutic target for alcohol dependence.
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Acknowledgements
This work is dedicated to the memory of Dr. Matthew Riley of the National Institute for Alcohol Abuse and Alcoholism (NIAAA), who consistently encouraged and challenged the investigators involved in this work. We thank Dr. Kenneth S. Kendler for reviewing the manuscript, Dr. Steve Negus for discussions on behavioral economics analysis and members of the Miles laboratory for many helpful discussions during the course of this work. Additional support was provided by the COGA Consortium for the use of genotype data. A full acknowledgement of COGA investigators is included in Supplementary Methods and Materials. The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut, includes ten different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, A. Goate, J. Rice, K. Bucholz); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield); Southwest Foundation (L. Almasy), Howard University (R. Taylor) and Virginia Commonwealth University (D. Dick). Other COGA collaborators include: L. Bauer (University of Connecticut); D. Koller, S. O’Connor, L. Wetherill, X. Xuei (Indiana University); Grace Chan (University of Iowa); N. Manz, M. Rangaswamy (SUNY Downstate); A. Hinrichs, J. Rohrbaugh, J-C Wang (Washington University in St. Louis); A. Brooks (Rutgers University); and F. Aliev (Virginia Commonwealth University). A. Parsian and M. Reilly are the NIAAA Staff Collaborators. COGA investigators continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, currently a consultant with COGA, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). Funding support for GWAS genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the National Institute on Alcohol Abuse and Alcoholism, the NIH GEI (U01HG004438), and the NIH contract “High throughput genotyping for studying the genetic contributions to human disease” (HHSN268200782096C). Kim Doheny and Elizabeth Pugh from CIDR and Justin Paschall from the NCBI dbGaP staff provided valuable assistance with genotyping and quality control in developing the dataset available at dbGaP. This work was supported by NIAAA grants U01AA016667 (MFM), P50 AA022537 (DD, SB, MFM), K02 AA018755 (DD) and F30 AA024382 (ADV).
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van der Vaart, A., Meng, X., Bowers, M.S. et al. Glycogen synthase kinase 3 beta regulates ethanol consumption and is a risk factor for alcohol dependence. Neuropsychopharmacol 43, 2521–2531 (2018). https://doi.org/10.1038/s41386-018-0202-x
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DOI: https://doi.org/10.1038/s41386-018-0202-x
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