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Acute manganese administration alters dopamine transporter levels in the non-human primate striatum

Cited 65 time in Web of Science Cited 70 time in Scopus
Authors
Chen, Ming-Kai; Lee, Jae-Sung; McGlothan, Jennifer L; Furukawa, Eri; Adams, Robert J; Alexander, Mohab; Wong, Dean F; Guilarte, Tomas R
Issue Date
2005-12-06
Publisher
Elsevier
Citation
Neurotoxicology. 2006 Mar;27(2):229-36. Epub 2005 Dec 2.
Keywords
AnimalsCocaine/analogs & derivatives/pharmacologyDopamine Plasma Membrane Transport Proteins/*metabolismDopamine Uptake Inhibitors/pharmacologyKineticsMaleManganese/*pharmacologyManganese Compounds/pharmacologyMembranes/drug effects/metabolismPapioNeostriatum/drug effects/*metabolism/radionuclide imagingPositron-Emission TomographyPresynaptic Terminals/drug effects/metabolismRatsRats, Long-EvansSulfates/pharmacology
Abstract
We used positron emission tomography (PET) to measure non-invasively the effect of acute systemic administration to manganese sulfate (MnSO4) on dopamine transporter (DAT) levels in the living non-human primate brain. Baboons received [11C]-WIN 35,428 PET scans to measure DAT levels before and after acute MnSO4 administration. In one animal, we observed a 46% increase in DAT binding potential (BP), a measure of DAT binding site availability, 1 week after Mn administration. DAT levels returned to baseline values at 4 months and remained constant at 10 months after treatment. A subsequent single MnSO4 injection to the same animal also resulted in a 57% increase in DAT-BP, 2 days after administration. In a second animal, a 76% increase in DAT-BP relative to baseline was observed at 3 days after Mn injection. In this animal, the DAT-BP returned to baseline levels after 1 month. Using in vitro receptor binding assays, we found that Mn inhibits [3H]-WIN 35,428 binding to rat striatal DAT with an inhibitory constant (Ki) of 2.0+/-0.3mM (n=4). Saturation isotherms and Scatchard analysis of [3H]-WIN 35,428 binding to rat striatal DAT showed a significant decrease (30%, p<0.001) in the maximal number of binding sites (Bmax) in the presence of 2mM MnSO4. No significant effect of Mn was found on binding affinity (Kd). We also found that Mn inhibits [3H]-dopamine uptake with an IC50 of 11.4+/-1.5mM (n=4). Kinetic studies and Lineweaver-Burk analysis showed a significant decrease (40%, p<0.001) in the maximal velocity of uptake (Vmax) with 5mM MnSO4. No significant effect of Mn was found on Michaelis-Menten constant (Km). These in vitro findings suggest that the increase in DAT levels in vivo following acute Mn administration may be a compensatory response to its inhibitory action on DAT. These findings provide helpful insights on potential mechanisms of Mn-induced neurotoxicity and indicate that the DAT in the striatum is a target for Mn in the brain.
ISSN
0161-813X (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16325911

http://hdl.handle.net/10371/27756
DOI
https://doi.org/10.1016/j.neuro.2005.10.008
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College of Medicine/School of Medicine (의과대학/대학원)Nuclear Medicine (핵의학전공)Journal Papers (저널논문_핵의학전공)
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