When researchers noticed the similarities between symptoms from Parkinson’s disease and nicotine withdrawal, they narrowed in on the brain region involved. This led to the discovery that an existing Parkinson’s treatment could help alleviate withdrawal symptoms.
Quitting nicotine is notoriously difficult. The smoking cessation industry, a roughly $25 billion USD, offers various aids to help people kick their nicotine habits, often targeting cravings and behavioural symptoms such as irritability. However, there are physical symptoms that are frequently overlooked that drive people back to using nicotine if not adequately addressed.
“The physical symptoms of nicotine withdrawal are characterized by tremor or involuntary shaking, and immobility, such as slowed movement or freezing,” said Heh-In Im who leads a group in the Centre for Brain Function at the Korea Institute of Science and Technology. “Interestingly, tremor and immobility are also observed in Parkinson’s disease, and previous studies have demonstrated that inhibition of the cholinergic interneurons reduces these motor symptoms of Parkinson’s disease.”
Cholinergic interneurons are a small but important group of neurons located in the brain region called the striatum. “They are involved in motor control and movement disorders, including Parkinson’s disease,” said Baeksun Kim who, along with Im, published their findings in Advanced Science.
The similarity in symptoms plus the fact that nicotine strongly binds to receptors on the cholinergic interneurons led the team to hypothesize that inhibiting them could logically also alleviate nicotine withdrawal symptoms in the same way it did the tremors and immobility caused by Parkinson’s.
Repurposing medications
To test this hypothesis, the team genetically modified a rodent model for nicotine withdrawal in which the cholinergic interneurons were inhibited.
“These mice showed a significant reduction in hand tremor induced by nicotine withdrawal,” said Im. While the mechanism behind this effect is still unclear, the team found that dampening the activity of these neurons alleviates a dopamine shortage which occurs during withdrawal.
Having confirmed the role of these neurons in nicotine withdrawal, the team then tested an already approved drug to treat Parkinson’s symptoms called procyclidine. It too reduced the hand tremor from nicotine withdrawal, but unlike the previous experiment where the interneurons were inhibited by genetic modifications, procyclidine also alleviated the immobility symptoms.
“The unexpected but interesting result was that procyclidine prevented the reduced locomotor activity induced by nicotine withdrawal, but this effect was not observed after inhibition of the cholinergic interneurons,” said Kim. While they do not yet know why this happened, “this unexpected but positive side-effect raised the clinical value of procyclidine,” Kim said.
“The two most important components of smoking cessation are craving and withdrawal,” according to Im. Several pharmaceutical aides exist that reduce cravings, and the team believes that treatments targeting withdrawal symptoms could complement these and improve the chances a patient successfully quits.
Repurposing drugs like procyclidine also gives the researchers a head start as it is already approved in several countries including the US, South Korea, and the European Union.
The next steps will be to show that procyclidine doesn’t adversely interact with drug treatments for cravings and that combinations of the two improve rates of quitting.
Reference: Baeksun Ki, et al. Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling, Advanced Science (2024). DOI: 10.1002/advs.202402274
Feature image credit: Julia Engel on Unsplash
