L-DOPA is the most effective treatment for Parkinson's disease, but causes adverse motor effects that limit its utility. Such effects include, abnormal involuntary movements (dyskinesia) and fluctuations in motor function. The development of motor complications during L-DOPA treatment is believed to depend on an abnormal transduction of chemical signals into gene expression changes within striatal neurons. The Ras/extracellular signal regulated protein kinase 1/2 (ERK 1/2) signaling cascade becomes activated in striatal neurons in response to the stimulation of either dopamine or glutamate receptors, both of which have been implicated in the genesis of dyskinesia. In this project, the levels of activation of ERK1/2 will be assessed in dopamine-denervated mice treated chronically with L-DOPA. A battery of behavioural tests will allow for an allocation of the animals to different motor response categories based on the absence or presence of dyskinesia. Drugs that antagonize different types of dopamine and glutamate receptors will be used to try and block both the activation of ERK1/2 and the development of L-DOPA-induced dyskinesia and motor fluctuations. Finally, the causal role of ras-mediated ERK1/2 activation in the L-DOPA-induced motor complications will be established by studying mice that either lack or overexpress critical regulatory components of this signaling cascade. The project will lead to the identification of therapeutical targets for the treatment or prevention of L-DOPA-induced dyskinesia.