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Mike Reed : Consequences of Levodopa Therapy for ParkinsonÂ?s Disease

ParkinsonÂ?s disease has been traditionally thought of as a dopaminergic (DA) disease in which cells of the substantia nigra pars compacta (SNc) die. However, accumulating evidence implies an important role for the serotonergic (5HT) system in ParkinsonÂ?s disease. We use a mathematical model to investigate the consequences of levodopa therapy on the serotonergic system and on the pulsatile release of DA from dopaminergic and serotonergic terminals in the striatum. We compute the time course of DA release in the striatum from both 5HT and DA neurons and show how the time course changes as more and more SNc cells die. This enables us to explain the shortening of the therapeutic time window for the efficacy of levodopa as ParkinsonÂ?s disease progresses. Finally, we study the effects 5HT1a and 5HT1b autoreceptor agonists and explain why they have a synergistic effect and why they lengthen the therapeutic time window for LD therapy. Our results are consistent with and help explain results in the experimental literature and provide new predictions that can be tested experimentally.

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