Abstract
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Objectives Pharmacological therapy using levodopa is the mostly used drug in Parkinson disease (PD). However, during long-term use of L-dopa 40% of the patients will develop another movement disorder, dyskinesia. We have previously shown in primate models of PD that mGluR5 expression is enhanced in basal ganglia and several other brain areas when dopamine transporter function declines.
Methods Four young adult male primates (macaca fascicularis) were included to the study. Animals were treated with MPTP (0.1 mg/kg weekly) and after stable parkinsonian symptoms with L-dopa for 3 months to develop dyskinesia. PET imaging were conducted before and after MPTP and after appearance of behavioral symptoms of dyskinesia. PET imaging was performed under propofol anesthesia (0.3mg/kg/min iv) on mGluR5 expression by using [18F]FPEB and dopamine transporters by using [11C]CFT. Starting from the administration of [11C]CFT (8-10 mCi i.v., specific activity 1400 mCi/µmol) or [18F]FPEB (1-3 mCi, specific activity 1900 mCi/µmol) dynamic volumetric data were acquired for 90 min.
Results Dopamine transporter binding did not decrease further after development of dyskinesia. Binding potential values in the putamen were 3.32+/-.68, 1.47+/-.14 and 1.44+/-.04 before and after MPTP and after dyskinesia, correspondingly. mGluR5 expression enhanced significantly (50-90%) in several brain areas after MPTP and further enhanced in supplementary motor area, insulate and primary motor cortex >30% and putamen 14% after development of dyskinesia.
Conclusions These studies provide profound evidence of the interplay of dopaminergic and glutamatergic transmitter and receptor systems. Antagonism for mGluR5 might be a new target for drug development of PD and especially for inhibition of development of dyskinesia.
Research Support NIBIB R01EB012864 and NIMH R01MH91684 to ALB and NINDS P50NS39793 to OI