Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal

Julia K. Brynildsen, Bridgin G. Lee, Isaac J. Perron, Sunghee Jin, Sangwon F. Kim, Julie A. Blendy

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)4282-4287
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number16
StatePublished - Apr 17 2018


  • 5′ AMP-activated protein kinase
  • CREB
  • Metformin
  • Nicotine

ASJC Scopus subject areas

  • General


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