DOPAMINE SYNAPTIC MECHANISMS IN TOURETTE'S SYNDROME

$0P01FY2002NSNIH

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Tourette syndrome (TS) is a common neuropsychiatric disorder with onset in childhood. Some data suggests that TS is part of a spectrum ranging from tics to Obsessive-Compulsive Disorder. The clinical pharmacology of TS implicates abnormalities of dopaminergic neurotransmission, possibly involving the nigrostriatal dopaminergic projection, in the pathophysiology of TS. Our prior data indicates normal density of dorsal striatal dopaminergic innervation. We hypothesize that TS is marked by abnormal regulation of striatal dopamine neurotransmission. We will use PET methods to study striatal dopaminergic function in TS and control subjects to determine the existence of functional abnormalities in TS striatal dopaminergic synapses. We will compare binding of one striatal dopamine terminal marker, [[11C]dihydrotetrabenazine, that is not regulated by alterations in synaptic dopamine flux, with another dopamine terminal marker that is regulated by synaptic dopamine flux, [11C]methylphenidate. We will search for specific alterations in striatal dopamine synaptic physiology by direct measurement of the stimulant releasable pool of striatal dopamine with amphetamine challenge- [11C]raclopride PET and estimates of synaptic striatal dopamine concentrations with [11C]raclopride PET after alpha-methyl-tyrosine depletion of dopamine. Discovery of an alteration in striatal dopamine synaptic physiology would lead to more mechanistic hypotheses regarding the nature of the abnormality in TS. The major alternative hypotheses is a subregional difference in dopaminergic innervation of the ventral striatum. We have preliminary data suggesting the presence of a focal abnormality of ventral striatal dopaminergic innervation in TS. We will collect additional imaging data evaluate the validity of this finding. Failure to uncover abnormalities in striatal dopamine synapse function or subregional difference sin innervation will direct attention away from the striatal dopaminergic synapse.

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