Striatal Dopaminergic Neurotransmission in Tourette Syndrome

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Michigan
Investigators Name
Kume, Akito, MD, PhD

Successful pallidative therapy of tics in Tourette Syndrome (TS) can markedly improve the functional status of people with TS. Unfortunately, the most useful drugs for treatment of tics are dopamine receptor antagonists whose utility is limited by the side effects. Efforts to develop an improved pharmacotherapy for TS have been hampered by lack of knowledge of the pathophysiology of TS. No abnormalities have been found in the sparse number of TS brains that have been examined. Some evidence implicates the striatum as the locus of a pathology in TS. Perhaps the best clue regarding the cause of tics is based on the fact that dopamine receptor antagonists ameliorate these symptoms. This fact implicates dopaminergic neurotransmission in the pathophysiology of tics. Increased dopamine release, hypersensitive dopamine receptors, or alterations of striatal dopamine metabolism have been proposed as possible mechanisms that are involved. Efforts to follow up on this clue have produced conflicting results, due partly to the very limited number of brain specimens available for postmortem analysis. Limited studies indicate that brain dopamine and dopamine metabolite levels are normal. However, these results are based on a very small number of samples. Using a small number of postmortem samples, a recent binding study reported no changes in striatal dopamine receptors, but did show a substantial increase in the density of striatal dopamine transporter binding sites. This suggests dopaminergic hyperinnervation of the striatum as the underlying cause of tics. Based on prior studies, we hypothesize that there is excessive striatal dopaminergic innervation in TS, and predict increased density of striatal dopaminergic terminals. We will test this prediction using PET with [11C] methoxytetrabenazine (MTBZ), an improved PET ligand for the dopaminergic terminal. Verification of this hypothesis would enhance our understanding of the pathophysiology of tics and would also suggest new avenues for TS treatment. Akito Kume, M.D., Ph.D. University of Michigan, Ann Arbor, MI Award $20,000 Tourette Association of America Inc. – Research Grant Award 1994