Although the etiological and pathophysiological processes of Tourette Syndrome (TS) are not well understood, several lines of evidence have implicated dysfunction of dopaminergic systems within the brain, and in particular the dopamine-containing fibers that project from the substantia nigra to cells within the striatum, as underlying this debilitating disorder. Such inferences are based on the involuntary motor symptoms which characterize TS, the relationship between dysfunction of the dopaminergic input to the striatum and other movement disorders (e.g., Parkinson’s disease), as well as the therapeutic efficacy of haloperidol, a dopamine receptor antagonist, which is known to affect the nigrostriatal dopaminergic pathway. Despite this information, a basic understanding of the mechanisms by which dopaminergic input influences the activity of striatal neurons, and how this activity subsequently impinges on motor behavior are not known. Therefore, an investigation into the influences of dopamine on the activity of striatal neurons would provide valuable information concerning the precise actions of that neurotransmitter, which could in turn be used to evaluate the mechanisms of action of drugs known to affect TS symptomatology. Before these experiments are undertaken, however, it is imperative that the identities of the striatal neurons under investigation are determined. Recently, we have shown that two functionally distinct subclasses of striatal cells can be identified on the basis of differences in their responses to stimulation of motor-related fibers from the cerebral cortex. Moreover, the activity of these two subpopulations of cells has been found to correlate with different aspects of motor dysfunction within the context of an animal model of Parkinson’s disease. Therefore, the proposed experiments will first attempt to establish the morphological (shape) identity of these separate subclasses of striatal cells using intracellular dye injections. In addition, their sites of projection (if any) to other brain structures will be investigated. This analysis will provide new information concerning the intrinsic structural organization of the striatum, as well as a firm foundation for the subsequent investigations into the actions of dopamine on these separate neuronal subtypes, and their responses to drugs known to influence TS. An understanding of the mechanisms by which dopamine affects striatal cells could suggest alternative approaches for therapeutic intervention, and may provide further insights into the pathophysiology of TS. Finally, knowledge of their projection sites may indicate how alterations in the output of these striatal cell classes influence other brain structures, and ultimately motor behavior. Eric S. Nisenbaum, Ph.D. University of Pittsburgh Pittsburgh, PA Award $20,000 Tourette Association of America Inc. – Research Grant Award 1990