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

Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):4282-4287. doi: 10.1073/pnas.1707047115. Epub 2018 Apr 2.

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.

Keywords: 5′ AMP-activated protein kinase; CREB; metformin; nicotine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases / drug effects*
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / physiology
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Anxiety Disorders / chemically induced
  • Anxiety Disorders / drug therapy*
  • Anxiety Disorders / enzymology
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Feeding Behavior / drug effects
  • Gene Knockdown Techniques
  • Hippocampus / drug effects*
  • Hippocampus / enzymology
  • Male
  • Metformin / pharmacology
  • Metformin / therapeutic use*
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / drug effects*
  • Nerve Tissue Proteins / physiology
  • Nicotine / adverse effects*
  • Ribonucleotides / pharmacology
  • Signal Transduction / drug effects
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / enzymology
  • Tobacco Use Disorder / enzymology
  • Tobacco Use Disorder / psychology

Substances

  • Nerve Tissue Proteins
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Nicotine
  • Metformin
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide