Gradual slowing of movement in Parkinson's disease (PD) is due to the steady decline in brain levels of dopamine, a chemical signal that facilitates normal movement. Our most effective medications for the treatment of PD (namely, L-dopa and dopamine agonists) work by replacing the lost dopamine. However they can produce side effects of involuntary jerking and twisting movements known as dyskinesias, which in some patients are as disabling as the disease itself. In the search for improved therapeutic strategies, blockers of the adenosine A2A receptor (A2A blockers) have emerged as attractive candidates with the potential to treat the symptoms of PD without exacerbating dyskinesias. Although initial clinical trials have indeed demonstrated the benefit of A2A blockade in advanced PD patients who had already developed dyskinesias, the effect of of A2A blockers on the development of dyskinesias is unknown. This project will explore the role of the adenosine A2A receptor in a pre-clinical model of dyskinesia development in PD. Earlier studies directed by Drs. Jiang-Fan Chen and Michael Schwarzschild showed that excessive motor responses to L-dopa in parkinsonian mice do not develop in the absence of the A2A receptor, and raised the possibility that the early use of A2A blockers in PD may help prevent the development of dyskinesias. Drs. Elena Bastia, Chen and Schwarzschild now propose to characterize this A2A receptor-dependence further using a combination of brain-specific A2A receptor knockout mice together with specific A2A blockers. They seek to determine whether brain A2A receptors play a crucial role in the induction (versus the maintenance versus the expression) of excessive responses to L-dopa and dopamine agonists in this pre-clinical model of dyskinesia. In addition to providing insights into the neurobiology of dopamine brain signaling, the proposed experiments may facilitate the rational development of A2A antagonists as a promising therapeutic strategy for dyskinesias in PD.