A recent study in mice documented the first biochemical pathway involved in the physical symptoms of nicotine withdrawal. Nicotine disrupts dopamine release via striatal cholinergic interneurons, which maintain acetylcholine tone in the striatum and govern motor function. Now, research has shown that procyclidine, a muscarinic antagonist approved by the US Food and Drug Administration (FDA) for Parkinson’s disease, blocks the physical symptoms of nicotine withdrawal, apparently via cross talk between nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs).
“It is important to know that there is communication between the different types of acetylcholinergic receptors,” said Carolyn Dresler, MD, MPA, Former Associate Director for Medical and Health Sciences at the FDA Center for Tobacco Products. “It is a new way to look at interneuronal communications between acetylcholine receptors that are affecting both motor responses and behavioral responses [to nicotine withdrawal.]”
The study, Striatal Cholinergic Interneurons Control Physical Nicotine Withdrawal via Muscarinic Receptor Signaling, explored the activity of cholinergic interneurons in the striatum. Cholinergic interneurons function via activation of both nAChRs and mAChRs throughout the striatum. Nicotine is one of the nAChR agonists, and abrupt cessation of nicotine supply triggers withdrawal symptoms in both humans and rodents.
Abrupt nicotine withdrawal in humans induces characteristic physical and affective behaviors. The unpleasant symptoms of nicotine withdrawal provide negative reinforcement and increase the likelihood of returning to tobacco use.
Tobacco use in humans also has a strong habitual component, Dr. Dresler said. Smoking and other tobacco use typically begin in the early teen years, and attempts to quit can start at any time thereafter; however, most are unsuccessful. Because the physically and psychologically unpleasant aspects of nicotine withdrawal reinforce the habitual behaviors of tobacco use, reducing the physical and psychological discomfort of nicotine withdrawal can help break those learned habits.
Rodent models lack the learned behaviors of tobacco use, but nicotine-addicted rodents exhibit characteristic behaviors when nicotine is withdrawn. Marked paw tremor and locomotion depression as well as anxiety-like behaviors are common symptoms of nicotine withdrawal in rodents.
Cholinergic interneurons appear to play key roles in movement disorders, including Parkinson’s disease. In rodent models of Parkinson’s disease, depleting cholinergic interneuronal signaling in the dorsal striatum can rescue motor dysfunction. The rescue of motor dysfunction seen in Parkinson’s models suggests a similar approach to the Parkinson’s-like motor dysfunction seen in nicotine withdrawal.
Working with genetic knockout models of striatal cholinergic interneuronal signaling inhibition, researchers found that nicotine alters normal signaling to reduce dopamine release during withdrawal and induce motor dysfunction. Procyclidine, an antimuscarinic used to treat motor dysfunction in Parkinson’s disease in humans as well as rodent models, effectively counteracts nicotine withdrawal symptoms in mice. There do not appear to be reports of similar studies in humans.
Does it make sense to study procyclidine in humans to reduce nicotine withdrawal symptoms?
“Absolutely, starting tomorrow!” Dr. Dresler said. “But prescribing it for someone trying to quit smoking is not the next step. There needs to be a full development plan with dose-ranging studies to find out if, and at what doses, you can get these effects in humans. And there are questions of safety that this work does not answer.
“This is a fascinating paper that needs to be replicated and novel neurobiology that needs to be studied in more depth. In mice, procyclidine is clearly showing an effect, but we don’t know at this point if it might be clinically impactful in humans. Let us hope these studies can be done.”