Journal Article

Chronic Exposure to Manganese Alters Brain Responses to Amphetamine: A Pharmacological Magnetic Resonance Imaging Study

Jason M. Williams, Dejan Milatovic, John C. Gore, Michael Aschner and Malcolm J. Avison

in Toxicological Sciences

Volume 114, issue 2, pages 310-322
Published in print April 2010 | ISSN: 1096-6080
Published online January 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq002
Chronic Exposure to Manganese Alters Brain Responses to Amphetamine: A Pharmacological Magnetic Resonance Imaging Study

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The parkinsonian symptoms and increased Mn accumulation in dopaminergic (DAergic) neurons of the basal ganglia implicate impaired dopamine signaling in the neurotoxic effects of chronic manganese overexposure. Using blood oxygenation level–dependent (BOLD) pharmacological magnetic resonance imaging (phMRI), we mapped brain responses to acute amphetamine (AMPH; 3 mg/kg, ip), which stimulates midbrain DAergic systems, in male Sprague-Dawley rats following 6 weeks of chronic MnCl2 (5 mg Mn/kg, one per week, iv) or saline treatment. Plasma Mn content, measured immediately following phMRI, was elevated twofold in Mn-treated animals (p < 0.05), but the twofold increase in mean striatal Mn content did not reach significance. In saline-treated animals, AMPH stimulated robust positive BOLD responses throughout the basal ganglia and their reciprocally innervated connections. In contrast, acute AMPH stimulated a negative BOLD response in many of these structures in the Mn-treated group, resulting in significant differences between saline- and Mn-treated AMPH-evoked BOLD responses within caudate putamen, globus pallidus, substantia nigra, mediodorsal thalamic nucleus, and somatosensory cortex. These results demonstrate the utility of AMPH-evoked phMRI as readout of the DAergic signaling in vivo and confirm the vulnerability of DAergic systems to Mn.

Keywords: manganese; Parkinson’s disease; dopamine; basal ganglia; neurodegeneration; magnetic resonance imaging

Journal Article.  8263 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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