Funded Studies
L-DOPA-induced dyskinesia (abnormal involuntary movements, AIMs) is a major complication of the pharmacotherapy of Parkinson's disease. Subjects suffering from L-DOPA-induced dyskinesia show complex cellular changes in the brain region that governs the selection of appropriate motor behaviors. Genetically modified mice may offer an opportunity to conclusively identify the prime determinants of such cellular changes. However, a valid model of L-DOPA-induced dyskinesia in the mouse has thus far not been available. In this project, we shall subject normal (wild-type) mice to parkinson-like lesions using dopamine-selective neurotoxins. The mice will then be treated chronically with either L-DOPA or other antiparkinsonian drugs that are known to induce very little dyskinesia in patients. The incidence and phenomenology of the AIMs that may occur during these treatments will then be compared. In order to verify that mouse AIMs provide a valid equivalent of L-DOPA-induced dyskinesia in patients. We shall then test the effects of medications with reported anti-dyskinetic efficacy in the clinic. This study will pave the way for the analysis of transgenic mice that carry different mutations of the gene encoding for DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa), a critical regulator of dopamine-dependent signaling, particularly enriched in a region of the brain (the caudate-putamen) that shows striking cellular alterations in dyskinesia.