Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal
Edited by Susan G. Amara, National Institutes of Health, Bethesda, MD, and approved March 15, 2018 (received for review April 28, 2017)
Significance
Cigarette smoking is the leading cause of preventable disease and death in the United States. Severe withdrawal symptoms are the reason most people have a hard time quitting smoking. AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis and is activated in response to cellular stressors. We discovered that the AMPK pathway is activated following chronic nicotine use but is repressed following nicotine withdrawal. We reasoned that increasing pAMPK levels pharmacologically might reduce symptoms of nicotine withdrawal. After giving mice metformin, an AMPK activator, we were able to reduce nicotine withdrawal, and found that this was dependent on the presence of the AMPK protein in the hippocampus. This study suggests that AMPK activation could be a target for smoking cessation.
Abstract
Cigarette smoking is the leading cause of preventable disease and death in the United States, with more persons dying from nicotine addiction than any other preventable cause of death. Even though smoking cessation incurs multiple health benefits, the abstinence rate remains low with current medications. Here we show that the AMP-activated protein kinase (AMPK) pathway in the hippocampus is activated following chronic nicotine use, an effect that is rapidly reversed by nicotine withdrawal. Increasing pAMPK levels and, consequently, downstream AMPK signaling pharmacologically attenuate anxiety-like behavior following nicotine withdrawal. We show that metformin, a known AMPK activator in the periphery, reduces withdrawal symptoms through a mechanism dependent on the presence of the AMPKα subunits within the hippocampus. This study provides evidence of a direct effect of AMPK modulation on nicotine withdrawal symptoms and suggests central AMPK activation as a therapeutic target for smoking cessation.
Acknowledgments
We thank Dr. Benoit Viollet for providing the AMPKα1loxP/loxP;AMPKα2loxP/loxP mice, and Gavin Huang for assisting with the experiments. This work was supported by National Institutes of Health Grants T32-GM008076 (to B.G.L.), R01 DA041180 (to J.A.B.), DK084336 (to S.F.K.), and National Center for Advancing Translational Sciences Award TL1TR000138.
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Copyright © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
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Published online: April 2, 2018
Published in issue: April 17, 2018
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Acknowledgments
We thank Dr. Benoit Viollet for providing the AMPKα1loxP/loxP;AMPKα2loxP/loxP mice, and Gavin Huang for assisting with the experiments. This work was supported by National Institutes of Health Grants T32-GM008076 (to B.G.L.), R01 DA041180 (to J.A.B.), DK084336 (to S.F.K.), and National Center for Advancing Translational Sciences Award TL1TR000138.
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This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal, Proc. Natl. Acad. Sci. U.S.A.
115 (16) 4282-4287,
https://doi.org/10.1073/pnas.1707047115
(2018).
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