Metformin quells nicotine withdrawal symptoms in mouse model

John Murphy, MDLinx | April 13, 2018

A new study suggests that metformin—the first-line therapy for type 2 diabetes—may be an effective aid to quitting smoking. Researchers have shown that mice given metformin had reduced symptoms of anxiety during nicotine withdrawal.

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Metformin reduces the anxiety symptoms of nicotine withdrawal by activating AMPK in the hippocampus (green). (Image: J Blendy, et al/PNAS)

“Although we are just beginning to characterize this new role for metformin, our study suggests that the protein it acts on could be a new target for smoking cessation treatment,” said senior author Julie Blendy, PhD, professor, Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Dr. Blendy and coauthors recently reported their results in the Proceedings of the National Academy of Sciences.

Cigarette smoking is the leading cause of preventable disease and death in the United States. But quitting isn’t easy, very often because of severe withdrawal symptoms, the researchers noted. Recent studies have linked AMP-activated protein kinase (AMPK) to behaviors that contribute to relapse during nicotine withdrawal.

“We discovered that the AMPK pathway is activated following chronic nicotine use, but is repressed following nicotine withdrawal,” Dr. Blendy and coauthors wrote.

Metformin is known to have multiple targets, one of which is AMPK activation in the liver. So, the researchers reasoned that metformin might also activate AMPK in the brain (specifically the hippocampus) to reduce symptoms of nicotine withdrawal.

The researchers regularly administered nicotine to mice, then tested them with either systemic metformin or saline for a week. After stopping the nicotine, the researchers found that the AMPK pathway in the hippocampus was activated in the mice given metformin compared with the mice given saline.

“Strikingly, systemic metformin also completely prevented anxiety-like behaviors caused by nicotine withdrawal at a dose that did not impact body weight, food consumption, or glucose levels under both fed and fasted conditions,” Dr. Blendy and coauthors wrote.

They concluded: “We propose that AMPK activation in the brain via metformin can be repurposed as a novel pharmacotherapy for nicotine cessation. The proven preclinical efficacy of metformin in alleviating withdrawal symptoms along with its well-established safety profile for diabetes treatment should encourage investigators to translate these findings into future clinical trials for higher continuous abstinence rates in smokers, with the added benefit of normalizing glycemic control.”

This research was supported by the National Institutes of Health and a National Center for Advancing Translational Sciences Award.

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