Prominent among current hypotheses which attempt to account for-the neurochemical basis of Tourette Syndrome is the concept of excessive dopamine activity in discrete areas of the brain, especially those areas that regulate movement, thought and affect. However, the causes and exact sites of dopaminergic hyperactivity, and the functional changes which underlie the expressed behaviors of TS have not yet been clearly defined. In our studies–aimed at understanding the mechanisms by which dopamine modulates neuronal function in the brain, we have observed that dopamine stimulates the formation of phosphoinositide second messengers by acting at a probably novel subtype of dopamine receptor. A high correlation exists between the regional brain distribution of this dopaminergic action and various dopamine-associated functions and behaviors. Therefore, it is possible that this new action of dopamine is involved in disorders, such as TS, that are thought to result from aberrations in dopamine neurotransmission. Using the rat striatum as a preliminary experimental model, the present project will attempt to define the relationship between this newfound action of dopamine and the previously uncovered biochemical effects of the transmitter. Another goal of the present investigation will be to determine the types and functions of striatal neurons that bear the new subtype of dopamine receptor. Furthermore, knowing that TS is a childhood disorder with variable age of onset, the pattern of development of the phosphoinositide linked dopamine system will be assessed in newborn through adult rats, and compared with the development of various dopamine-mediated behaviors. Future projects will address sex differences and examine other brain areas, such as the cortex, that have been implicated in TS. Postmortem human tissue will eventually be studied to confirm that observations in the rodent can be meaningfully extrapolated to humans. Information from these various approaches will be integrated to give a clearer picture of the role of dopamine in striatal function or dysfunction, and in formulating novel strategies for the treatment of Tourette’s disorder. Ashiwel S. Undie, Ph.D., Neurochemistry Division Medical College of Pennsylvania, Philadelphia, PA Award $25,000 Tourette Association of America Inc. – Research Grant Award 1991