Repurposing Procyclidine New Hope for Smokers: Existing Drug Could Boost Smoking Cessation Success

Could a Parkinson’s drug help smokers quit for good? Researchers at Kist have discovered a novel brain mechanism behind nicotine withdrawal and found that Procyclidine, an existing FDA-approved drug, can significantly reduce withdrawal symptoms.

According to the World Health Organization (WHO), over 22 % of the global population smokes, with more than 9 million smoking-related deaths reported annually. Effective treatments to alleviate nicotine withdrawal symptoms caused by smoking cessation are essential for successful smoking cessation. Currently, approved treatments for nicotine withdrawal include Bupropion and Varenicline, but there is a pressing need for new therapeutic options to improve smoking cessation success rates.

The research team led by Dr. Heh-In Im at the Center for Brain Disorders of the Korea Institute of Science and Technology (Kist) has identified a novel brain region and neural mechanism involved in regulating nicotine withdrawal symptoms. Building on this discovery, the team found that an existing Parkinson’s disease drug can effectively alleviate nicotine withdrawal symptoms, thus increasing its potential for therapeutic use.

When smoking is stopped, specific areas of the brain become hyperactive, causing physical withdrawal symptoms such as tremors and reduced activity. These symptoms significantly disrupt daily life and are major factors leading smokers to relapse. Therefore, understanding the internal processes triggered by nicotine withdrawal is crucial for achieving smoking cessation.

The research team pinpointed the role of striatal cholinergic interneurons in nicotine withdrawal symptoms. Through experiments on mice, they selectively inhibited sodium channel expression in the striatal cholinergic interneurons to reduce neural activity. This intervention significantly alleviated tremors caused by nicotine withdrawal. Using advanced multi-electrode array technology, the team confirmed that suppressing cholinergic interneurons completely blocked abnormal neural activity changes.

Additionally, microdialysis experiments showed that suppressing cholinergic interneurons restored dopamine levels in the striatum, which had decreased by over 20 % during nicotine withdrawal, to normal levels. Based on these findings, the team explored the potential use of Procyclidine, an FDA-approved drug for Parkinson’s disease, for nicotine withdrawal treatment. Procyclidine mimics the inhibition effect on the neural activity of cholinergic interneurons, making it a promising candidate for alleviating physical symptoms of nicotine withdrawal.

Notably, administering a single low dose of Procyclidine to mice prior to inducing nicotine withdrawal reduced tremors — a primary physical withdrawal symptom — by over 50 %. This study demonstrates the potential of repurposing a safe and established drug for nicotine withdrawal treatment, significantly shortening the clinical trial process. This approach could improve access to smoking cessation therapies and effectively reduce health issues caused by smoking.

Dr. Im stated, “This study presents new possibilities for smoking cessation treatment by mitigating the disruptions caused by withdrawal symptoms. It provides an additional treatment option alongside Bupropion and Varenicline. Moving forward, we aim to deepen our understanding of addiction mechanisms, including nicotine, and develop effective therapies.”

Original Article: Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling; Advanced Science; DOI:10.1002/advs.2024022741

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