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National Institute of Environmental Health Sciences

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Publication Detail

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

Authors: Chen, Ming-Kai; Lee, Jae-Sung; McGlothan, Jennifer L; Furukawa, Eri; Adams, Robert J; Alexander, Mohab; Wong, Dean F; Guilarte, Tomás R

Published In Neurotoxicology, (2006 Mar)

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.

PubMed ID: 16325911 Exiting the NIEHS site

MeSH Terms: Animals; Cocaine/analogs & derivatives; Cocaine/pharmacology; Dopamine Plasma Membrane Transport Proteins/metabolism*; Dopamine Uptake Inhibitors/pharmacology; Kinetics; Male; Manganese Compounds/pharmacology; Manganese/pharmacology*; Membranes/drug effects; Membranes/metabolism; Neostriatum/diagnostic imaging; Neostriatum/drug effects; Neostriatum/metabolism*; Papio; Positron-Emission Tomography; Presynaptic Terminals/drug effects; Presynaptic Terminals/metabolism; Rats; Rats, Long-Evans; Sulfates/pharmacology

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