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 (K_i) of 2.0 ± 0.3 mM (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 (B_max) in the presence of 2 mM MnSO₄. No significant effect of Mn was found on binding affinity (K_d). We also found that Mn inhibits [³H]-dopamine uptake with an IC₅₀ of 11.4 ± 1.5 mM (n = 4). Kinetic studies and Lineweaver-Burk analysis showed a significant decrease (40%, p < 0.001) in the maximal velocity of uptake (V_max) with 5 mM MnSO₄. No significant effect of Mn was found on Michaelis-Menton constant (K_m). 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.