Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates
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Published on: January 15, 2010
Tomás R Guilarte1, Ming-Kai Chen, Jennifer L McGlothan
1Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. tguilart@jhsph.edu
Abstract:
We tested the hypothesis that movement abnormalities induced by chronic manganese (Mn) exposure are mediated by dysfunction of the nigrostriatal dopamine system in the non-human primate striatum. Motor function and general activity of animals was monitored in parallel with chronic exposure to Mn and Positron Emission Tomography (PET) studies of in vivo dopamine release, dopamine transporters and dopamine receptors in the striatum. Analysis of metal concentrations in whole blood and brain was obtained and post-mortem analysis of brain tissue was used to confirm the in vivo PET findings. Chronic Mn exposure resulted in subtle motor function deficits that were associated with a marked decrease of in vivo dopamine release in the absence of a change in markers of dopamine (DA) terminal integrity or dopamine receptors in the striatum. These alterations in nigrostriatal DA system function were observed at blood Mn concentrations within the upper range of environmental, medical and occupational exposures in humans. These findings show that Mn-exposed non-human primates that exhibit subtle motor function deficits have an apparently intact but dysfunctional nigrostriatal DA system and provide a novel mechanism of Mn effects on the dopaminergic system.
Insights
Chronic manganese (Mn) exposure causes subtle motor deficits by disrupting dopamine release in the nigrostriatal pathway, even when dopamine transporters and receptors remain intact.
Area of Science:
- Neuroscience
- Toxicology
- Neuroimaging
Background:
- Chronic manganese (Mn) exposure is linked to neurological effects.
- The nigrostriatal dopamine system is crucial for motor control.
- Understanding Mn's impact on this system is vital for public health.
Purpose of the Study:
- To investigate if movement abnormalities from chronic Mn exposure involve nigrostriatal dopamine system dysfunction.
- To correlate motor deficits with changes in dopamine release, transporters, and receptors in non-human primates.
Main Methods:
- Non-human primates underwent chronic Mn exposure.
- Motor function and general activity were monitored.
- Positron Emission Tomography (PET) was used to study in vivo dopamine release, transporters, and receptors.
- Blood and brain Mn concentrations were analyzed.
Main Results:
- Chronic Mn exposure induced subtle motor deficits.
- A significant decrease in in vivo dopamine release was observed.
- Dopamine terminal integrity and dopamine receptors in the striatum showed no significant changes.
- Observed alterations occurred at Mn blood concentrations relevant to human exposures.
Conclusions:
- Mn-exposed non-human primates exhibit motor deficits despite an apparently intact nigrostriatal dopamine system.
- Mn causes dysfunction in dopamine release, offering a novel mechanism for its neurotoxic effects.
- Findings highlight potential risks of Mn exposure within environmental, medical, and occupational ranges.
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