The neurotoxin MPTP does not reproduce in the rhesus monkey the interregional pattern of striatal dopamine loss typical of human idiopathic Parkinson's disease

doi:10.1016/0304-3940(88)90066-3

Neuroscience Letters

Volume 92, Issue 2, 5 October 1988, Pages 228-233

https://doi.org/10.1016/0304-3940(88)90066-3 Get rights and content

Abstract

Using high-pressure liquid chromatography with electrochemical detection, we measured dopamine (DA) and homovanillic acid (HVA) in caudate nucleus, putamen and substantia nigra in 4 untreated rhesus monkeys and 4 monkeys with permanent parkinsonism produced by repeated injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; total dose: 2.1–6.45 mg/kg, i.m.). MPTP consistently produced a severe striatal and nigral loss of DA and HVA and an increase in the ratio ‘HVA/DA’. In this respect, MPTP mimicked the changes found in human Parkinson's disease (PD). However, MPTP lowered the DA in caudaute (−99.6%) to the same degree as in putamen (−99.5%). This is in contrast to idiopathic PD where the caudate is significantly less affected by DA loss (−84%) than the putamen (−98%). Thus, in our rhesus monkies MPTP failed to reproduce the interregional caudate-putamen gradient characteristic of idiopathic PD. The DA pattern produced by MPTP was similar to the DA loss in caudate (−98%) and putamen (−99%) observed in patients with postencephalitic parkinsonism.

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Cited by (71)

Correlation between decreased motor activity and dopaminergic degeneration in the ventrolateral putamen in monkeys receiving repeated MPTP administrations: A positron emission tomography study
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Citation Excerpt :
Therefore, the identified subregion (i.e., the ventral striatum) can be distinguished from the lateral striatum, which has higher correlation coefficient values (cf. Fig. 3). As in previous studies (Pifl et al., 1988; Snow et al., 2000), changes in DAT binding demonstrated that repeated MPTP treatments reduced presynaptic dopaminergic terminals in the dorsal striatum as a whole, but these effects were most evident in the dorsomedial putamen (cf. Fig. 5). However, dopaminergic degeneration generally occurs in the caudal putamen prior to the rostral putamen in PD patients.
Parkinson's disease (PD) patients have remarkably reduced levels of dopaminergic biomarkers in the caudal putamen. However, the relationship between motor impairments and the localization of intrastriatal dopaminergic degeneration in monkey PD models remains unclear. To identify the striatal areas with dopaminergic dysfunction responsible for motor impairments, we measured changes in both general motor activity and in vivo dopaminergic biomarkers in three cynomolgus monkeys that repeatedly received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), starting in the normal state and continuing until after tremor appearance. Binding of dopamine transporters (DAT) and D₂ receptors were measured by positron emission tomography (PET) using [¹¹C]PE2I and [¹¹C]raclopride, respectively. Region-of-interest-based regression analysis demonstrated the degree of general motor activity reduction to be explained by striatal DAT binding but not by D₂ receptor binding. Furthermore, voxel-based analysis revealed a significant correlation between reduced general motor activity and decreased DAT binding, specifically in the ventrolateral putamen, which corresponds to the area receiving upper body motor inputs from the primary motor cortex. These results suggest that specific functional deficits in PD models are closely related to the degeneration of dopaminergic terminals in the striatal subregion responsible for these functions and that the level of deficit is dependent on the degree of degeneration.
Progression of dopaminergic depletion in a model of MPTP-induced Parkinsonism in non-human primates. An <sup>18</sup>F-DOPA and <sup>11</sup>C-DTBZ PET study
2010, Neurobiology of Disease
Citation Excerpt :
PET studies in PD patients have shown a caudo-rostral gradient of dopaminergic depletion, corresponding to neurochemical findings in post-mortem material (Kish et al., 1988). However, humans with parkinsonism secondary to MPTP intoxication have failed to replicate such pattern (Snow et al., 2000), as have most studies of MPTP-induced parkinsonism in monkeys (Pifl et al., 1988). The exact explanation for this difference between distribution of DA striatal innervation in PD and MPTP-induced parkinsonism patterns remains elusive.
Dopaminergic depletion in the nigrostriatal system is the neurochemical hallmark of Parkinson's disease (PD). Although numerous efforts have been made to determine the evolution of dopaminergic depletion in PD, “in vivo” data concerning the stages of this process are still scarce. We evaluated 6-[18F]-fluoro-l-DOPA (¹⁸F-DOPA) and 11C-(+)-α-dihydrotetrabenazine (¹¹C-DTBZ) using PET in a model of chronically MPTP-induced parkinsonism in non-human primates. Methods: Sixty-seven cynomolgus monkeys (Macaca fascicularis) were included in the study. Progressive parkinsonism was induced by repeated administration of small doses of MPTP (iv) over several months. Animals were classified as controls, asymptomatic, recovered (having exhibited parkinsonian features transiently) and stable parkinsonian, according to their motor status. Analysis of striatal dopaminergic activity was conducted by regions of interest (ROI) and statistical parametric mapping (SPM) over normalized parametric images. Results: A progressive loss of striatal uptake was evident among groups for both radiotracers, which correlated significantly with the clinical motor status. Changes occurred earlier, i.e. in the less affected stages, with ¹¹C-DTBZ. Similar results were achieved by ROI and SPM analysis. Uptake was similar with both radiotracers for the asymptomatic and recovered groups. Conclusions: Serial assessment with ¹⁸F-DOPA and ¹¹C-DTBZ PETs provides an effective approach to evaluate evolution of dopaminergic depletion in monkeys with MPTP-induced parkinsonism. This approach could be useful to perform studies aiming to test the effect of early therapeutic intervention and putative neuroprotective treatments.
Effects of dopamine depletion on reward-seeking behavior. Evidence from human and non-human primates
2009, Handbook of Reward and Decision Making
A large body of neuroscientific literature has implicated dopamine in reward processing. This chapter focuses on reward processing dysfunction in situations of dopamine depletion, namely parkinsonism, in both human and nonhuman primates. Clinical accounts of patients suffering from dopamine depletion, such as in Parkinson's disease, usually report motor symptoms. The chapter reviews the evidence that dopamine depletion can impair reward-seeking behavior, in both human patients and primate models with Parkinson's disease. Different reward-related processes (energization, decision-making, and learning) are considered with intent to make a conceptual link between consistent deficits and theoretical functions of dopamine (decoupling, disinhibition, and reinforcement) in fronto-striatal circuitry. It is suggested that a primary deficit may concern positive reinforcement of circuits leading to reward, which would fail to facilitate action selection in subsequent choice situations.
Zonisamide increases dopamine turnover in the striatum of mice and common marmosets treated with MPTP
2009, Journal of Pharmacological Sciences
The effect of zonisamide, an antiepileptic agent with anti-parkinsonian effects, was studied on dopamine neurons of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 mice and common marmosets. Groups of mice (n = 8 – 9) were treated with: MPTP (15 mg/kg every 2 h ×4); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/kg administered 1 h before the first MPTP dose); zonisamide (40 mg/kg ×4); and saline controls. Groups of common marmosets (n = 4 – 6) were treated with: MPTP (2.5 mg/kg every 24 h ×3); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/kg administered 1 h before the first MPTP dose); and saline controls. Brain dopamine and its metabolites were determined by HPLC. Dopamine content decreased in the striatum of MPTP-treated mice and monkeys. Co-administration of selegiline inhibited the effect of MPTP and dopamine contents were similar to those of the controls. Co-administration of zonisamide did not inhibit the effect of MPTP on dopamine content, but increased striatal dopamine turnover of animals treated with MPTP plus zonisamide more than in those treated with MPTP alone. MPTP treatment caused a compensatory increase of dopamine turnover in the striatum by remaining neurons. Zonisamide may help dopaminergic neurons by increasing striatal dopamine turnover following MPTP treatment.
Development of a stable, early stage unilateral model of Parkinson's disease in middle-aged rhesus monkeys
2008, Experimental Neurology
An important issue raised in testing new neuroprotective/restorative treatments for Parkinson's disease (PD) is the optimal stage in the disease process to initiate therapy. Current palliative treatments are effective in the early disease stages raising ethical concerns about substituting an experimental treatment for a proven therapy. Thus, we have endeavored to create a stable 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) nonhuman primate model of early PD. The new model was created by controlling for dose and route administration of MPTP (unilateral intracarotid infusion), and age of the animals (middleaged, 16–19 years old) in 27 female rhesus monkeys. All animals showed stable parkinsonian features lasting for up to 12-month as per behavioral evaluation. Compared with late-stage PD animals, postmortem analysis demonstrated that more dopaminergic neurons remained in the substantia nigra pars compacta, and more fibers were found in the striatum. In addition, tissue levels of striatal dopamine and its metabolites were also higher. Our results support that a milder but stable PD model can be produced in middle-aged rhesus monkeys.
Pathophysiology of the basal ganglia and movement disorders: From animal models to human clinical applications
2008, Neuroscience and Biobehavioral Reviews
Electrophysiological studies in control and MPTP treated primates have played a major role in our understanding of the physiology of the basal ganglia and the pathophysiology of Parkinson's disease (PD). Early models emphasized discharge rate and viewed the basal ganglia as a network of boxes (nuclei) connected by excitatory or inhibitory connections. More recent studies view the basal ganglia as neural networks with weak and non-linear interactions in and between the different nuclei.
Microelectrode electrophysiological recording enables the high resolution—both in the temporal domain (spike) and the spatial domain (neuron)—required for the in vivo investigation of neuronal networks of the basal ganglia. MPTP treated primates exhibit the full pathological and clinical spectrum of human Parkinsonism and therefore their electrophysiological study has promoted better understanding of the normal state, the dopamine-depleted state, and finally the testing of potential therapeutic interventions for PD. Here, we review the main insights learned from microelectrode physiological studies of MPTP monkeys over the last 20 years since the introduction of this animal model.

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The neurotoxin MPTP does not reproduce in the rhesus monkey the interregional pattern of striatal dopamine loss typical of human idiopathic Parkinson's disease

Abstract

Brain Res.

J. Neurol. Sci.

Brain Res.

Lancet

Eur. J. Pharmacol.

Psychiatry Res.

Neurosci. Lett.

Brain Res.

Life Sci.

Eur. J. Pharmacol.

Neurosci. Lett.

Neurosci. Lett.

Neurosci. Lett.

Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases

Neurology