Parkinson's disease (PD) is a common disorder, occuring in 1-2 percent of people over the age of 55. The efficacy of levodopa, our best symptomatic therapy, is limited by the development of motor fluctuations and dyskinesia. Understanding the mechanisms underlying emergence of these motor complications is essential to developing methods to prevent or treat them. The goal of this proposal is to assess the contribution of the remaining striatal monoaminergic terminals to the clinical response to levodopa and its evolution during long-term levodopa therapy. There are three aims. 1) Determine the importance of reuptake of dopamine into residual dompamine terminals by examining the effects of inhibition of the dopamine transporter (DAT) using the DAT inhibitor, methylphenidate. The effects of methylphenidate alone and in combination with levodopa will be examined to determine if dopamine reuptake influences the off drug severity of PD and whether it alters the response to a 2 hour levodopa infusion, specifically, makes it appear more like that observed in advanced PD patients. 2) Determine if serotonin terminals and the serotonin transporter (SERT) assume a role in reuptake and storage of dopamine in advanced PD when the serotonergic terminals become a large portion of the residual stiatal monoaminergic terminals. The effects of paroxetine, a selective SERT inhibitor, on response to a 2 hour levodopa infusions will be examined. 3) Determine if autoreceptors on residual dopamine terminals influence PD severity by examining the response to a step wise infusion with apomorphine, a D-1, D-2 receptor agonist capable of inhibiting motor behavior at low doses in animals. These studies assess the importance of the remaining monoaminergic terminals on the response to levodopa, determine how loss of reuptake contributes to the development of motor complications and suggest whether the remaining terminals might be pharmacologically manipulated to therapeutic advantage.
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