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Role of the level of expression of striatal dopamine transporter relative to striatal dopaminergic terminals in the pathogenesis of levodopa induced motor fluctuations in Parkinson’s disease Koochesfahani, Kaveh M.

Abstract

Motor complications in response to levodopa therapy are major problems in the treatment of Parkinson's disease (PD). In this study we investigated the possible relationship between the level of dopamine transporter expressed on surviving striatal dopaminergic terminals and variations in extracellular dopamine levels in PD patients with stable response to levodopa and those with motor fluctuations. We assessed the changes of endogenous and exogenous dopamine levels over time in response to oral methylphenidate and levodopa respectively. 3D PET was performed with the D2 receptor antagonist [¹¹C]raclopride (RAG) at baseline, 1 and 4 hours following the administration of oral methylphenidate (0.8 mg/kg) or oral levodopa (250/25 mg) to two groups of PD patients consisting of fluctuators and stable responders to levodopa. In parallel, we measured the ratio of dopamine transporters to the number of dopaminergic terminals in the striatum. For this purpose we used [¹¹C]MP and [¹¹C]DTBZ PET scans to estimate the levels of dopamine transporter expression and the vesicular monoamine transporter 2 (VMAT2) respectively. At the dose used, oral methylphenidate produced no significant change in extracellular dopamine levels, as estimated by comparing changes in putaminal RAC binding at baseline and one and four hours following its administration. This could be the result of severe degeneration of dopaminergic terminals with subsequent reductions in the levels of endogenous dopamine and DAT. Although the putaminal RAC binding significantly changed after administration of levodopa, the regression of RAC binding potentials at the three times to log (MP/DTBZ) was not significant implying that the ratio of dopamine transporters to dopaminergic terminals did not affect exogenous dopamine release and clearance.

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