Identifying the neural systems underlying Tourette Syndrome (TS) has proven difficult; due in part to the fact that the limited number of available therapeutic drugs appear to work through different mechanisms. In .addition, the symptoms of TS are often exacerbated by stressful or behaviorally activating environmental stimuli, suggesting that complex regulatory mechanisms may be involved in this disorder. Stimulation of the sciatic nerve (one model of environmental-stimuli) inhibits the activity of midbrain dopamine (DA) neurons. Based on theoretical models of basal ganglia function, this inhibition might enhance responsiveness to peripheral sensory information and could, therefore, be related to stress- or stimulus-induced symptoms of TS. The dorsal raphe; the primary source of serotonin projections to DA neurons, appears essential for this sciatic nerve-induced inhibition. Thus, we are examining in detail the nature of control exerted by the sciatic nerve and the dorsal raphe on DA neurons. In contrast, the pedunculopontine tegmental nucleus (PPN) exerts a primarily excitatory influence on DA neurons. Since the therapeutic effectiveness of DA blocking agents suggests that DA systems may be hyperactive in TS (as well as in other neurological and/or neuropsychiatric disorders), we will examine the influence of PPN inputs on DA neuronal activity. A better understanding of proximal and distal afferent regulation of DA neurons may provide clues to both the cause and the manifestation of TS. Mark D. Kelland, Ph.D. Sinai Hospital of Detroit, Detroit, MI Award: $20,000 Tourette Association of America, Inc. – Research Grant Award 1988