Potential Mechanisms Underlying Nicotine’s therapeutic effects in Tourette Syndrome

Grant Type
Clinical
Grant Year
1999-2000
Institution Location
Foreign
Institution Organization Name
McGill University Canada
Investigators Name
Clarke, Paul B. S., PhD

Tourette Syndrome (TS) is a familial neuropsychiatric disorder characterized by persistent motor movements (tics) and vocalizations. Its cause is not yet known. However, it is thought that the symptoms are due, at least in part, to abnormally high levels of activity of a brain neurotransmitter (i.e. chemical signal) called dopamine. Indeed, drugs that block the effects of dopamine have beneficial therapeutic effects and are widely used. Since these dopamine-blocking drugs (i.e. antagonists) are only partially effective and are associated with significant side effects, there is a need for better drug treatments. Short-term treatment is often associated with sedation and difficulty in moving. Worse still, in a few cases long-term treatment with dopamine antagonists can lead to tardive dyskinesia, which is a movement disorder that might not go away when the patient stops taking the drug. Therefore, it would be very useful to reduce exposure to dopamine antagonist drugs by adding a second drug. Recent clinical studies suggest that nicotine can greatly decrease the dose of dopamine antagonist needed in the treatment of TS movements. This is a welcome finding, but from a scientific point of view it is puzzling because other evidence suggests that nicotine increases levels of dopamine in the brain, and should therefore counteract the effect of a dopamine antagonist. The aim of our project is to better understand how nicotine administration enhances the effects of a dopamine blocker. To do this, we will use laboratory rats. When these animals are given increasing doses of a dopamine antagonist, they tend to become less and less mobile; nicotine (administered as a pure drug) enhances this effect. This enhancement by nicotine comes on rather slowly after injection, and lasts for several hours. This is strange, because nicotine reaches the brain very rapidly, and then is broken down quite rapidly. Therefore, we doubt that nicotine is working in its normal manner, which would be by stimulating its receptors in the brain. Instead, we propose two possible theories: either nicotine is converted into a pharmacologically active breakdown product, or else nicotine is turning off (“desensitizing”) rather than stimulating some of its own receptors. If we find that either of our proposed mechanisms is true, this will serve as an incentive for companies to develop more effective drug therapies for Tourette Syndrome based on nicotine-like compounds. Paul B.S. Clarke, Ph.D. McGill University Montreal, Quebec, Canada Award $16,083 Tourette Association of America Inc. – Research Grant Award 1999-2000