Dopamine Terminal Loss and Onset of Motor Symptoms in MPTP-Treated Monkeys: A Positron Emission Tomography Study with 11C-CFT

Wüllner, Ullrich; Pakzaban, Peyman; Brownell, Anna Liisa; Hantraye, Philippe; Burns, Lindsay H.; Shoup, Timothy M.; Elmaleh, David R.; Petto, Andrew J.; Spealman, Roger D.; Brownell, G.L.; Isacson, Ole

doi:10.1006/exnr.1994.1069

Cited by 48 publications

(36 citation statements)

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“…Our study and previous reports are consistent with the changes seen in the MPTP-lesioned monkey where the nigro-striatal DAergic neurons demonstrated marked cell loss (Kish et al, 1988;Parent and Lavoie, 1993). Reductions in striatal DAT binding sites were also demonstrated in autoradiographic experiments on aged monkeys (Kaufman and Madras, 1993) or in patients with Parkinson's disease (Chinaglia et al, 1992;Janowsky et al, 1987;Kaufman and Madras, 1991;Murray et al, 1995), and in imaging studies (PET and SPECT) of monkeys treated with MPTP and parkinsonian patients (Fischman et al, 1997;Frost et al, 1993;Wullner et al, 1994). Estimates of DA innervation density are available for rat brain denervated by intramesencephalic administration of 6-hydroxydopamine and were compared to the binding to DAT (Doucet et al, 1986;Soucy et al, 1997).…”

Section: Discussionmentioning

confidence: 88%

Neurotensin receptors and dopamine transporters: Effects of MPTP lesioning and chronic dopaminergic treatments in monkeys

Goulet

Morissette

Grondin

et al. 1999

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The effect of denervation with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of the dopamine (DA) nigrostriatal pathway on neurotensin (NT) receptor and DA transporter (DAT) in basal ganglia of monkeys (Macaca fascicularis) was investigated. The MPTP lesion induced a marked depletion of DA (90% or more vs. control) in the caudate nucleus and putamen. The densities of NT agonist binding sites labeled with [125I]NT and the NT antagonist binding sites labeled with [3H]SR142948A decreased by half in the caudate-putamen of MPTP-monkeys. In addition, the densities of [125I]NT and [3H]SR142948A binding sites markedly decreased (-77 and -63%, respectively) in the substantia nigra of MPTP-monkeys. Levocabastine did not compete with high affinity for [125I]NT binding in the monkey cingulate cortex, suggesting that only one class of NT receptors was labelled in the monkey brain. An extensive decrease of [3H]GBR12935 DAT binding sites (-92% vs. Control) was observed in the striatum of MPTP-monkeys and an important loss of DAT mRNA(-86% vs. Control) was observed in substantia nigra. Treatments for 1 month with either the D1 agonist SKF-82958 (3 mg/kg/day) or the D2 agonist cabergoline (0.25 mg/kg/day) had no effect on the lesion-induced decrease in NT and DAT binding sites or DAT mRNA levels. The decrease of striatal NT binding sites was less than expected from the decrease of DA content in this nucleus, suggesting only partial localization of NT receptors on nigrostriatal DAergic projections. These data also suggest that under severe DA denervation, treatment with D1 or D2 DA agonists does not modulate NT receptors and DAT density.

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Section: Discussionmentioning

confidence: 88%

Neurotensin receptors and dopamine transporters: Effects of MPTP lesioning and chronic dopaminergic treatments in monkeys

Goulet

Morissette

Grondin

et al. 1999

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“…Some label presynaptic dopamine transporters, like [ 11 C]CFT (Wullner et al 1994) or the SPECT tracer beta-CIT, whereas others reflect vesicular monoamine transporter type 2 (VMAT2) sites that occur on presynaptic vesicles that store dopamine for subsequent release. (Marek et al 2001) VMAT2 sites on presynaptic vesicles are less likely to be regulated than either decarboxylase or DAT (DaSilva et al 1993;Chan et al 1999;Lee et al 2000;Frey et al 2001).…”

Section: Discussionmentioning

confidence: 99%

[¹⁸F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

Racette

Good

Antenor

et al. 2006

American J of Med Genetics Pt B

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Parkinson Disease (PD) is a late onset disorder with age-dependent penetrance that may confound genetic studies since affected individuals may not demonstrate clinical manifestations at the time of evaluation. The use of endophenotypes, biologic surrogates for clinical disease diagnoses, may permit more accurate classification of at-risk subjects. Positron emission tomography (PET) measurements of 6-[ 18 F]fluorodopa ([ 18 F]FDOPA) uptake indicate nigrostriatal neuronal integrity and may provide a useful endophenotype for PD linkage studies. We performed [ 18 F]FDOPA PET in 11 members of a large, multi-incident Amish family with PD, 24 normals and 48 people with clinically definite idiopathic PD (PD controls). Clinical diagnoses in the Amish were clinically definite PD in four, clinically probable in one, clinically possible in five, and normal in one. Abnormal [ 18 F]FDOPA posterior putamen uptake was defined as less than three standard deviations below the normal mean. The criteria were applied to the Amish sample to determine a PET endophenotype for each. We performed genetic simulations using SLINK to model the effect phenoconversion with the PET endophenotype had on logarithm of odds (LOD) scores. PET endophenotype confirmed the status of two clinically definite subjects. Two clinically definite Amish PD subjects had normal PETs. Two possible PD were converted to "PET definite PD". The remainder had normal PETs. The average maximum LOD score with the pre-PET was 6.14±0.84. Simulating phenoconversion of subjects with unknown phenotypes increased the LOD score to 7.36±1.23. The [ 18 F]FDOPA PET endophenotype permits phenoconversion in multi-incident PD families and may increase LOD score accuracy and power of an informative pedigree.

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“…The effects of MPTP treatment on dopamine metabolism were not significant in the midbrain in the a-synuclein mice compared to non-transgenic mice most likely due to the reduced impact of MPTP on the cell bodies that are highly represented in this region compared to the terminals in the caudate region [35]. MANOVA analysis however showed a significant difference between the saline-injected transgenic and non-transgenic mice, suggesting that expression of mutant human a-synuclein does result in an alteration of neurotransmitter homeostasis of the nigrostriatal dopaminergic system but this effect was not exacerbated to a significant degree by MPTP treatment in this region.…”

Section: Dopamine Metabolismmentioning

confidence: 71%

Increased Dopaminergic Neuron Sensitivity to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) in Transgenic Mice Expressing Mutant A53T α-Synuclein

Matsuoka

Sziráki³

et al. 2007

Neurochem Res

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Familial Parkinson's disease (PD) has been linked to point mutations and duplication of the alpha-synuclein gene and mutant alpha-synuclein expression increases the vulnerability of neurons to exogenous insults. In this study, we analyzed the levels of dopamine and its metabolites in the olfactory bulb (OB), and nigrostriatal regions of transgenic mice expressing human, mutant A53T alpha-synuclein (alpha-syn tg) and their non-transgenic (ntg) littermates using a sub-toxic, moderate dose of MPTP to determine if mutant human alpha-synuclein sensitizes the central dopaminergic systems to oxidative stress. We observed that after a single, sub-lethal MPTP injection, dopamine levels were reduced in striatum and SN in both the alpha-syn tg and ntg mice. In the olfactory bulb, a region usually resistant to MPTP toxicity, levels were reduced only in the alpha-syn tg mice. In addition, we identified a significant increase in dopamine metabolism in the alpha-syn transgenic, but not ntg mice. Finally, MPTP treatment of alpha-syn tg mice was associated with a marked elevation in the oxidative product, 3-nitrotyrosine that co-migrated with alpha-synuclein. Cumulatively, the data support the hypothesis that mutant alpha-synuclein sensitizes dopaminergic neurons to neurotoxic insults and is associated with greater oxidative stress. The alpha-syn tg line is therefore useful to study the genetic and environmental inter-relationship in PD.

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Dopamine Terminal Loss and Onset of Motor Symptoms in MPTP-Treated Monkeys: A Positron Emission Tomography Study with 11C-CFT

Cited by 48 publications

References 0 publications

Neurotensin receptors and dopamine transporters: Effects of MPTP lesioning and chronic dopaminergic treatments in monkeys

Neurotensin receptors and dopamine transporters: Effects of MPTP lesioning and chronic dopaminergic treatments in monkeys

[¹⁸F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

Increased Dopaminergic Neuron Sensitivity to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) in Transgenic Mice Expressing Mutant A53T α-Synuclein

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Dopamine Terminal Loss and Onset of Motor Symptoms in MPTP-Treated Monkeys: A Positron Emission Tomography Study with 11C-CFT

Cited by 48 publications

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Neurotensin receptors and dopamine transporters: Effects of MPTP lesioning and chronic dopaminergic treatments in monkeys

Neurotensin receptors and dopamine transporters: Effects of MPTP lesioning and chronic dopaminergic treatments in monkeys

[18F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

Increased Dopaminergic Neuron Sensitivity to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) in Transgenic Mice Expressing Mutant A53T α-Synuclein

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[¹⁸F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies