ToxSci Advance Access published online on June 10, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp124
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Effects of Chronic Manganese Exposure on Glutamatergic and GABAergic Neurotransmitter Markers in the Non-Human Primate Brain
* Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
Department of Pharmacy, University of Wisconsin, Madison, WI
Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia. PA
Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
¶ Corresponding author: Tomás R. Guilarte, Ph.D., Neurotoxicology & Molecular Imaging Laboratory, Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, 615 North Wolfe Street, Room E6622, Baltimore, Maryland 21205, Phone: (410) 955-2485, FAX: (410) 502-2470, E-mail: tguilart{at}jhsph.edu
Received March 10, 2009; revision received May 14, 2009; accepted May 30, 2009
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Abstract |
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The neurological sequelae of chronic Mn exposure include psychiatric, cognitive and motor deficits, suggesting the potential involvement of multiple neurotransmitter systems and brain regions. Available evidence in rodents suggests that Mn causes dysregulation of glutamatergic and GABAergic neurotransmitter systems. However, this has never been studied comprehensively in the non-human primate brain. Cynomolgus macaques were given weekly i.v. injections of 3.3-5.0mg Mn/kg, 5.0-6.7mg Mn/kg, or 8.3-10.0mg Mn/kg for 7-59 weeks. Total glutamate, glycine, and GABA concentrations were measured by HPLC with fluorescence detection in 13 brain areas in Mn-treated and control monkeys. Neurotransmitter concentrations did not change with chronic Mn exposure. Quantitative autoradiography of the N-methyl-D-aspartate receptor, the GABAa receptor, and glutamate transporters was used to assess their regional distribution. Each of these neurotransmitter receptors remained almost universally unchanged with Mn treatment. Immunohistochemical analysis of glutamine synthetase (GS) demonstrated a selective Mn-induced decrease in the globus pallidus, which could potentially alter synaptic and/or astrocytic levels of glutamate. This study shows that in non-human primates with previous documentation of Mn-induced brain pathology, the glutamatergic and GABAergic systems appear to be mostly unaffected by chronic Mn exposure with the exception of reduced GS expression in the globus pallidus.
Key Words: manganese; neurotoxicity; non-human primates; glutamate; GABA; brain.