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)
April 2, 2018
115 (16) 4282-4287

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.

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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.

Supporting Information

Supporting Information (PDF)

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 115 | No. 16
April 17, 2018
PubMed: 29610348

Classifications

Submission history

Published online: April 2, 2018
Published in issue: April 17, 2018

Keywords

  1. nicotine
  2. metformin
  3. 5′ AMP-activated protein kinase
  4. CREB

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.

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Julia K. Brynildsen1
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Bridgin G. Lee1
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Isaac J. Perron
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Sunghee Jin
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224;
Sangwon F. Kim2 [email protected]
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224;
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21224
Julie A. Blendy2 [email protected]
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Present address: Department of Systems Pharmacology and Translational Therapeutics, Translational Research Laboratory, Philadelphia, PA 19104.

Notes

2
To whom correspondence may be addressed. Email: [email protected] or [email protected].
Author contributions: B.G.L. and J.A.B. designed research; J.K.B., B.G.L., I.J.P., S.J., and S.F.K. performed research; S.F.K. contributed new reagents/analytic tools; J.K.B., B.G.L., S.F.K., and J.A.B. analyzed data; and B.G.L., S.F.K., and J.A.B. wrote the paper.
1
J.K.B. and B.G.L. contributed equally to this work.

Competing Interests

The authors declare no conflict of interest.

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    Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal
    Proceedings of the National Academy of Sciences
    • Vol. 115
    • No. 16
    • pp. 3985-E3862

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