Dopamine transporter binding is unaffected by L-DOPA administration in normal and MPTP-treated monkeys

Pierre-Olivier Fernagut, Qin Li, Sandra Dovero, Piu Chan, Tao Wu, Paula Ravenscroft, Michael Hill, Zhenwen Chen, Erwan Bezard, Pierre-Olivier Fernagut, Qin Li, Sandra Dovero, Piu Chan, Tao Wu, Paula Ravenscroft, Michael Hill, Zhenwen Chen, Erwan Bezard

Abstract

Background: Radiotracer imaging of the presynaptic nigrostriatal dopaminergic system is used to assess disease progression in Parkinson's disease (PD) and may provide a useful adjunct to clinical assessment during therapeutic trials of potential neuroprotective agents. Several clinical trials comparing dopamine agonists to L-DOPA or early vs. late L-DOPA have revealed differences between clinical assessment and imaging of the presynaptic dopaminergic system, hence questioning the comparability of these measures as neuroprotection outcome variables. Thus, results of these studies may have been affected by factors other than the primary biological process investigated.

Methodology/principal findings: We tested the possibility that L-DOPA might interfere with DAT binding. Post-mortem DAT binding was conducted in normal and MPTP-treated macaque monkeys that were administered L-DOPA, acutely or chronically. In parallel, DAT SPECT was conducted in MPTP-treated animals that were administered chronic L-DOPA. [99mTc]TRODAT-1 SPECT binding was similarly reduced in all MPTP monkeys regardless of L-DOPA treatment. L-DOPA had no significant effect on post-mortem DAT binding either in saline or in MPTP-lesioned animals.

Conclusions/significance: These data indicate that L-DOPA does not induce modifications of DAT expression detectable by SPECT of by DAT binding autoradiography, suggesting that differences between clinical assessment and radiotracer imaging in clinical trials may not be specifically related to L-DOPA treatment.

Conflict of interest statement

Competing Interests: MH and PR are employees of Motac Neuroscience Ltd. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Experimental flowchart illustrating study design,…
Figure 1. Experimental flowchart illustrating study design, treatments and group assignments.
Figure 2. In vivo assessment of DAT…
Figure 2. In vivo assessment of DAT density using [99mTc]TRODAT-1 SPECT in control, MPTP and MPTP-monkeys treated chronically with L-Dopa.
** indicates significant difference compared with control group (p

Figure 3. DAT binding autoradiography in the…

Figure 3. DAT binding autoradiography in the posterior striatum (AC −4 mm).

A. Representative DAT…
Figure 3. DAT binding autoradiography in the posterior striatum (AC −4 mm).
A. Representative DAT binding autoradiogram from a control animal illustrating the position of striatal subregions. B. Representative autoradiogram from a MPTP-treated monkey. Cd: caudate nucleus, Put: putamen DL: dorsolateral, DM: dorsomedial, VL: ventrolateral, VM: ventromedial. ** indicates significant difference compared with corresponding control group (p<0.001 using Bonferonni test following two-way ANOVA).
Figure 3. DAT binding autoradiography in the…
Figure 3. DAT binding autoradiography in the posterior striatum (AC −4 mm).
A. Representative DAT binding autoradiogram from a control animal illustrating the position of striatal subregions. B. Representative autoradiogram from a MPTP-treated monkey. Cd: caudate nucleus, Put: putamen DL: dorsolateral, DM: dorsomedial, VL: ventrolateral, VM: ventromedial. ** indicates significant difference compared with corresponding control group (p<0.001 using Bonferonni test following two-way ANOVA).

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