The most dramatic tic-suppressing drugs in the clinical treatment of Tourette Syndrome (TS) are the neuroleptic agents. These drugs interact with the dopamine neuron system. Many insights into the biological basis of TS have resulted from attempts to understand neuroleptic effects on the dopamine system in dopamine-rich areas of the brain such as the basal ganglia. Despite this, no clear picture of the underlying pathophysiology of TS exists which hampers uncovering improved therapeutic interventions. What is becoming clear is that many dopamine mediated effects of neuroleptics may result from a functional interaction between the dopamine and the glutamate neuron system in complex circuits involving the basal ganglia and cerebral cortex. There is now substantial evidence for specific effects of neuroleptic agents on glutamate systems that may be an important component of their pharmacological profile. The best studied glutamate receptor (cell surface protein) the N-methyl-D-aspartate (NMDA) receptor, can be modulated through a number of distinct sites on the receptor complex. Therefore, the objective of my research is to examine the NMDA receptor following chronic administration of three pharmacologically distinct neuroleptic drugs in rats. Two of the drugs (pimozide and haldol) have proven effective in the clinical treatment of TS while the third (clozapine) is thought to be less effective. Each drug has specific effects on the dopamine system, but their differential effects on the glutamate system are largely unknown. I will examine how each of these drugs affect the regional binding and functional modulation of NMDA receptors. Specifically, a high affinity radioactive ligand will be used to measure the in vitro response of the receptor to a series of agents known to activate the receptor in vivo. Previously we have shown that these receptor agonist agents such as glycine, glutamate and spermidine are regionally specific, and receptor stimula stimulation by these agents may measure receptor function. Also studied will be the (intracellular) molecular expression of NMDA receptor subunits in the same regions of the cerebral cortex and basal ganglia. The different neuroleptic agents may have a similar effect on NMDA receptor function as measured by receptor binding, but a different effect on the subcellular machinery that manufactures the receptor. These studies will provide further understanding of the molecular mechanism of neuroleptic drugs and their effects on the glutamate neuron system. This data may aid in the formation of new theories, hypotheses and potential new drug treatment strategies for TS. Lance McCoy, M.D. University of Rochester Medical Center, Rochester, NY Award $20,000 Tourette Association of America Inc. – Research Grant Award 1995