Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 16, Pages 4282-4287Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1707047115
Keywords
nicotine; metformin; 5 ' AMP-activated protein kinase; CREB
Categories
Funding
- National Institutes of Health [T32-GM008076, R01 DA041180, DK084336]
- National Center for Advancing Translational Sciences Award [TL1TR000138]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [TL1TR000138] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK084336] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008076] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA041180] Funding Source: NIH RePORTER
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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 AMPK alpha 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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