DOPAMINE D1, D2, AND D3 RECEPTORS AS BIOMARKERS FOR IMAGING NIGROSTRIATAL NEURONS

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DESCRIPTION (provided by applicant): Parkinson Disease (PD), the second most common neurodegenerative disease, affects more than one million people in North America, and no treatment has been proven to slow progression. Neuroimaging biomarkers have the potential to provide unbiased measurements of PD progression. Changes in dopamine receptors related to loss of nigrostriatal neurons may lead to "dysregulation" of dopamine D2 and D3 receptors with a change in the D2:D3 ratio. A change in the D2:D3 ratio may play a key role in the behavioral consequences of CNS syndromes characterized by altered D2-like receptor function. However, the precise role of D3 in the pathophysiology and treatment remains to be determined. We previously developed a novel procedure to measure the density of D2 and D3 receptors in vitro and found that D3 receptors in striatum and substantia nigra change differently from D1 and D2 receptors in PD brains. We previously evaluated three different presynaptic PET tracers, [11C]DTBZ, [11C]CFT and [18F]fluoroDOPA for nigrostriatal neurons in monkeys given a wide range of doses of the selective dopaminergic neurotoxin MPTP. These PET studies demonstrated that striatal uptake of each of these linearly correlates with the number of nigrostriatal neurons (using unbiased stereologic counts of tyrosine hydroxylase [TH] immunostained neurons in nigra) but only when the loss of nigrostriatal neurons does not exceed 50%. In contrast, each of these tracers linearly correlates with in vitro measures of striatal dopamine. The in vivo PET measures correlated well with each other and with quantitative autoradiography of VMAT2 and DAT in striatum. Interestingly, motor ratings correlated fully with nigral cell counts and not with striatal dopamine or other terminal field measures, suggesting that factors other than just loss of striatal terminal fields influence motor parkinsonism. We hypothesize that changes in postsynaptic dopamine receptors may account for this discrepancy. In this project, we propose to conduct quantitative autoradiography measures of the postsynaptic dopamine receptors (D1, D2 and D3) in the striatum from brain tissues from 41 monkeys, 16 of them are treated with a wide range of single internal carotid MPTP doses (0 to 0.31 mg/kg); 10 of them will be studied at different times after a MPTP (5 at 10 days and 5 at 3 weeks); 3 groups of 5 will have a single dose of MPTP then treated for 2 months with chronic levodopa, a dopamine receptor agonist pramipexole or placebo. These additional measures are expected to provide a more complete reflection of the state of nigrostriatal neurons than presynaptic measures alone. The overall goal of this 2-year project is to determine how postsynaptic markers change after dopamine denervation to determine the most effective neuroimaging measures for accurate measurement of the severity of nigrostriatal injury. We also will investigate the effects chronic treatment with levodopa or pramipexole (a dopamine D3 receptor agonist) on these markers. The studies proposed in this grant have great potential for extending our understanding of the functional roles of dopamine receptor subtypes in PD progression.