No Differential Regulation of Dopamine Transporter (DAT) and Vesicular Monoamine Transporter 2 (VMAT2) Binding in a Primate Model of Parkinson Disease

Linlin Tian,Morvarid Karimi,Jinbin Xu,Chris A Brown,Huchuan Xia,Robert H Mach,Susan K Loftin,Joel S Perlmutter,Henning Ulrich

doi:10.1371/journal.pone.0031439

Linlin Tian, Morvarid Karimi + Show 7 more

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https://doi.org/10.1371/journal.pone.0031439

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Abstract

Radioligands for DAT and VMAT2 are widely used presynaptic markers for assessing dopamine (DA) nerve terminals in Parkinson disease (PD). Previous in vivo imaging and postmortem studies suggest that these transporter sites may be regulated as the numbers of nigrostriatal neurons change in pathologic conditions. To investigate this issue, we used in vitro quantitative autoradioradiography to measure striatal DAT and VMAT2 specific binding in postmortem brain from 14 monkeys after unilateral internal carotid artery infusion of 1-Methyl-4-Phenyl-1,2,3,6-tetrahydropyridine (MPTP) with doses varying from 0 to 0.31 mg/kg. Quantitative estimates of the number of tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in substantia nigra (SN) were determined with unbiased stereology, and quantitative autoradiography was used to measure DAT and VMAT2 striatal specific binding. Striatal VMAT2 and DAT binding correlated with striatal DA (rs = 0.83, rs = 0.80, respectively, both with n = 14, p<0.001) but only with nigra TH-ir cells when nigral cell loss was 50% or less (r = 0.93, n = 8, p = 0.001 and r = 0.91, n = 8, p = 0.002 respectively). Reduction of VMAT2 and DAT striatal specific binding sites strongly correlated with each other (r = 0.93, n = 14, p<0.0005). These similar changes in DAT and VMAT2 binding sites in the striatal terminal fields of the surviving nigrostriatal neurons demonstrate that there is no differential regulation of these two sites at 2 months after MPTP infusion.

Highlights

Selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) combined with striatal DA deficiency produces the major motor manifestations of idiopathic Parkinson disease (PD) [1,2]
Treatment The loss of striatal Dopamine Transporter (DAT) and Vesicular Monoamine Transporter 2 (VMAT2) binding sites was similar following a wide range of MPTP doses and was not statistically different from each other (Wilcoxon signed ranks test z(14) = 20.089, p = 0.93)
The present study demonstrates that DAT and VMAT2 striatal binding sites do not have differential regulation across a wide range of nigral cell loss

Summary

Introduction

Selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) combined with striatal DA deficiency produces the major motor manifestations of idiopathic PD [1,2]. Reduction of dopaminergic neurons in PD patients and animal models of parkinsonism leads to substantial loss of the presynaptic markers DAT, TH and VMAT2. Previous studies have used in vitro or in vivo methods to measure the effects of nigrostriatal deficiency on loss of striatal DAT and VMAT2. One in vitro autoradiographic study from PD patients revealed greater striatal loss of DAT than VMAT2 specific binding sites [3]. Studies with MPTP-treated rodents have produced conflicting data on the extent of reduction of striatal

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