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Unilateral MPTP lesion in a rhesus monkey: effects on the striatal dopaminergic system measured in vivo with PET
K L Leenders1, S M Aquilonius, K Bergström
1MRC Cyclotron Unit, Hammersmith Hospital, London, U.K.
Abstract:
We have produced in one monkey a unilateral lesion of the dopaminergic nigrostriatal pathway by slowly infusing 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) into the right internal carotid artery, resulting in contralateral hemiparkinsonism. This procedure was combined with a series of positron emission tomography scans before and after the lesion, using several dopaminergic tracers in parallel. We show that specific binding of [11C]nomifensine in the lesioned striatum disappears to a large extent (80-90%) as a result of the lesion, indicating a corresponding loss of striatal dopamine re-uptake binding sites and thus of the dopamine nerve terminal pool. The uptake of radioactivity in the striatum contralateral to the lesion remained unchanged. In parallel, an early increase in ipsilateral [11C]raclopride binding, indicating upregulation of dopamine D2 receptors, was seen following the presynaptic lesion. [11C]Deprenyl uptake, indicating monoamine oxidase type B enzyme concentration, did not change after the lesion.
Insights
A unilateral lesion in a monkey model of Parkinson's disease caused an 80-90% loss of dopamine re-uptake sites. Dopamine D2 receptors were upregulated following the nigrostriatal pathway lesion.
Area of Science:
- Neuroscience
- Pharmacology
- Radiochemistry
Background:
- The dopaminergic nigrostriatal pathway is crucial for motor control.
- Degeneration of this pathway leads to Parkinson's disease.
- MPTP is a neurotoxin used to create animal models of Parkinson's disease.
Purpose of the Study:
- To investigate the effects of a unilateral nigrostriatal lesion on dopamine re-uptake sites and dopamine D2 receptors using PET imaging.
- To assess the utility of specific radiotracers in a Parkinson's disease model.
Main Methods:
- Unilateral nigrostriatal pathway lesion induced by MPTP infusion in a monkey.
- Positron emission tomography (PET) scans using [11C]nomifensine, [11C]raclopride, and [11C]deprenyl before and after lesioning.
- Quantification of radiotracer binding to assess dopamine re-uptake sites, dopamine D2 receptors, and monoamine oxidase B (MAO-B) activity.
Main Results:
- MPTP lesion resulted in an 80-90% reduction in [11C]nomifensine binding in the lesioned striatum, indicating loss of dopamine re-uptake sites.
- No significant change in radioactivity uptake in the contralateral striatum.
- Early ipsilateral increase in [11C]raclopride binding, suggesting dopamine D2 receptor upregulation.
- [11C]Deprenyl uptake remained unchanged, indicating stable MAO-B enzyme concentration.
Conclusions:
- Unilateral nigrostriatal lesions lead to a substantial loss of striatal dopamine re-uptake sites.
- Dopamine D2 receptors upregulate in response to presynaptic dopaminergic deficits.
- [11C]Nomifensine and [11C]raclopride are sensitive PET tracers for evaluating dopaminergic pathway integrity and receptor changes in Parkinson's disease models.