Mechanisms of Graft-Induced Dyskinesias in an Animal Model of Parkinson's Disease

Embryonic dopamine neurons can be transplanted to the region of the brain that becomes depleted of dopamine in Parkinson's disease (PD). Studies performed in both patients and animal models of PD have shown that dopamine transplants in the striatum can restore dopaminergic neurotransmission and improve some of the symptoms of the disease. An unexpected finding has however emerged from two NIH-sponsored clinical trials, where a considerable proportion of the transplanted patients developed postoperative, graft-induced dyskinesias (GID). Our project has four aims:

1. To develop a model of GID in the rat, which will provide a cost-effective tool for studying the mechanisms of this complication;
2. To test the hypothesis that the development of GID is conditioned by such factors as graft size and graft location within the striatum;
3. To examine whether GID are dependent on graft-derived dopamine and whether preoperative L-DOPA-induced dyskinesias predispose to GID;
4. To test the hypothesis that an inflammatory reaction in the striatum, as occurs in chronic immune rejection, can evoke GID.

The project will thus clarify the conditions that predispose to dyskinesia after intrastriatal transplantation of dopamine neurons, and provide important indications for the design of future clinical trials.