Novel D3 Receptor Compunds for the Treatment of Tourette Syndrome: A combined In Vivo and In Vitro Approach

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of California
Investigators Name
Weber, Martin, PhD

Current medications for Tourette Syndrome (TS) successfully treat some symptoms of TS, yet often they have high discontinuation rates because unwanted symptoms are not reduced or because of significant side-effects. Thus, there is a clear need for new, more effective medications. We propose to study a potentially novel class of medications for the treatment of TS. A functional excess of dopamine activity appears to be one mechanism underlying some TS symptoms, and many medications currently used to treat TS act by blocking the D2 and D3 dopamine receptors. The combined blocking of these receptors reduces tic severity but can also lead to troublesome side effects. Studies suggest that drugs that selectively block the D3 receptor only may reduce tics without causing major side effects. However until now, highly selective D3 medications have not been available. Our collaborators, Drs. Mach and Luedtke, have recently succeeded in synthesizing a panel of selective D3 receptor antagonists and partial agonists, and have made these medications available for testing in this project. We plan to test the effects of D3 stimulation on signaling pathways within mice brain cells, and then determine whether such effects are opposed by D3 antagonists. The D3 receptor antagonists will be tested in mice using the Prepulse Inhibition (PPI) model, which has been used to successfully predict the ability of drugs to suppress tics in patients. PPI is disrupted in patients with TS, but is restored by TS medications. If the D3 receptor antagonists can restore PPI, these compounds would be good candidates for both further development, and possibly for clinical trials in TS. Behavioral studies will be complemented by biochemical studies designed to understand how D3 receptors work in the basal ganglia brain cells. In the future, we plan to translate these experiments into measures of D3 function in humans, and ultimately, into clinical trials based on the mechanisms that we identify in our laboratory studies. Martin Weber, Ph.D. University of California School of Medicine at San Diego, La Jolla, CA Award: $30,890 (Fellowship) Tourette Association of America Inc. – Research Grant Award 2008-2009