Although it appears that Tourette Syndrome (TS) does not involve a mutation of the D2 receptor gene (13), an understanding of the molecular events underlying the actions of D2-class antagonists should: 1) foster the development of more effective therapies for TS and 2) help identify those signaling elements that are defective in TS. Our central hypotheses are that 1) D2-class receptors in NAc neurons enhance the evoked release of arachidonic acid (AA) and its metabolites and 2) these metabolites reduce cellular excitability by modulating voltage-dependent calcium conductances and glutamate receptors. If our hypotheses are correct, then defects in AA metabolism or the linkage between D2-class receptor activation and AA metabolism become etiological candidates in TS. Establishing such a connection would open several therapeutic avenues for TS patients employing an already well-developed collection of agents for manipulating eicosanoid metabolism. Genetic studies of TS and associated gene therapies could also be helped immediately by linking D2-class receptors and eicosanoids. Base sequences for PLA2 isoforms and 5-, 12- and 15-lipoxygenases isoforms are available, making genetic mapping studies feasible. D. James Surmeier, Ph.D. University of Tennessee Health Science Center, Memphis, TN Award $10,000 Tourette Association of America Inc. – Research Grant Award 1992