Acute manganese administration alters dopamine transporter levels in the non-human primate striatum.
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.
Chen
Ming-Kai
MK
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Lee
Jae-Sung
JS
McGlothan
Jennifer L
JL
Furukawa
Eri
E
Adams
Robert J
RJ
Alexander
Mohab
M
Wong
Dean F
DF
Guilarte
Tomás R
TR
D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008345:Manganese / Q000494:pharmacology*; D017895:Manganese Compounds / Q000494:pharmacology; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D010215:Papio; D049268:Positron-Emission Tomography; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D013431:Sulfates / Q000494:pharmacology
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D017895:Manganese Compounds; D013431:Sulfates; D008345:Manganese; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; C039798:manganese sulfate