Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates.
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.
Guilarte
Tomás R
TR
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. tguilart@jhsph.edu
Chen
Ming-Kai
MK
McGlothan
Jennifer L
JL
Verina
Tatyana
T
Wong
Dean F
DF
Zhou
Yun
Y
Alexander
Mohab
M
Rohde
Charles A
CA
Syversen
Tore
T
Decamp
Emmanuel
E
Koser
Amy Jo
AJ
Fritz
Stephanie
S
Gonczi
Heather
H
Anderson
David W
DW
Schneider
Jay S
JS
D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008252:Macaca fascicularis; D008297:Male; D008345:Manganese / Q000378:metabolism / Q000633:toxicity*; D008774:Methylphenidate / Q000493:pharmacokinetics; D008959:Models, Neurological; D009048:Motor Skills / Q000187:drug effects*; D049268:Positron-Emission Tomography / Q000379:methods; D020891:Raclopride / Q000493:pharmacokinetics; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002247:Carbon Isotopes; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D011954:Receptors, Dopamine; D008774:Methylphenidate; D008345:Manganese; D020891:Raclopride; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid