Dopamine Transporter Binding Is Unaffected by L-DOPA Administration in Normal and MPTP-Treated Monkeys

Abstract

BackgroundRadiotracer 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 FindingsWe 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/SignificanceThese 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.

PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking

“…The MPTP intoxication protocol, chronic l-DOPA treatment, clinical assessments, terminal procedure, and characterization of the extent of nigrostriatal denervation in the animals terminated before viral transfection were conducted as previously published (18,22,25,37,82). DAT binding autoradiography using [ 125 I]-(E)-N-(3-iodoprop-2-enyl)-2β-carboxymethyl-3β-(4′-methylphenyl)-nortropane (Chelatec) showed a dramatic and similar reduction (>95%) in all MPTP-treated groups compared with control animals, as published elsewhere (84).…”

Modeling Parkinson's Disease in Primates: The MPTP Model

“…Moreover, within the regions of diminished dopaminergic markers, there is substantial preservation in striosomes relative to the surrounding matrix (Moratalla et al 1992). Higher doses or stronger regimens of intoxication, although generating more comprehensive behavioral phenotypes, abolish these differences with more homogenous pattern of denervation in putamen and caudate while the ventral striatum remains less affected (Bezard et al 2001c;Meissner et al 2003;Guigoni et al 2005;Fernagut et al 2010).…”

PET imaging of dopamine transporters with [ 18 F]FE-PE2I: Effects of anti-Parkinsonian drugs

“…For animal studies, the results might be affected by the methodologies such as dose of L-DOPA, administration route, administration period and DAT expression status. Whereas, in nonhuman primates and human studies, L-DOPA does not affect the DAT binding (17)(18)(19). In conclusion, L-DOPA effect on DAT binding are unpredictable.…”