Effects of Chronic Manganese Exposure on Glutamatergic and GABAergic Neurotransmitter Markers in the Nonhuman Primate Brain

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 gamma-aminobutyric acidergic (GABAergic) neurotransmitter systems. However, this has never been studied comprehensively in the nonhuman primate brain. Cynomolgus macaques were given weekly i.v. injections of 3.3-5.0 mg Mn/kg, 5.0-6.7 mg Mn/kg, or 8.3-10.0 mg Mn/kg for 7-59 weeks. Total glutamate, glycine, and GABA concentrations were measured by high performance liquid chromatography (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 nonhuman 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.