title: Low cumulative manganese exposure affects striatal GABA but not dopamine.
abstract: The introduction of the anti-knock methylcyclopentadienyl manganese (Mn) tricarbonyl (MMT) in gasoline has raised concerns about the potential for manganese neurotoxicity. Because subpopulations such as the elderly in the early stages of neurodegenerative disease may be at increased risk for manganese toxicity, a pre-Parkinsonism rat model was used to evaluate whether sub-chronic manganese exposure can aggravate the neurochemical and behavioral dysfunctions characteristic of Parkinsonism. Sub-threshold levels of dopamine depletion of 3.5, 53 and 68% were generated via intrastriatal unilateral 6-hydroxydopamine (6-OHDA) doses. A sub-chronic dosing regimen of low cumulative manganese exposure (4.8 mg Mn/kg body weight, 3 i.p. injections per week x 5 weeks) was started 4 weeks after 6-OHDA treatments. Neurochemical and neuromotor (functional observational battery (FOB)) measures were evaluated. Manganese produced significant (P < 0.05) reductions of 30-60% in motor function. This effect was exacerbated in the presence of a pre-Parkinsonism condition [Neurotox. Teratol. 22 (2000) 851]. Manganese did not affect striatal dopamine, but resulted in significant increases in striatal y-aminobutyric acid (GABA) of 16 and 22% (P < 0.01) in both striati and a borderline non-significant 4% increase in frontal cortex (P = 0.076). Manganese treatment produced increased aspartate (P < 0.01) in the manganese and 6-OHDA treated striatum. In light of previous studies predominantly showing dopamine depletion with elevated manganese exposures, the significant effects of manganese on striatal GABA but not on striatal dopamine at the low cumulative exposure administered here suggest a progression in manganese toxicity with increasing cumulative dose, whereby GABA levels are adversely affected before striatal dopamine levels. Because these neurochemical disruptions were accompanied by motor dysfunction that was exacerbated in the presence of a pre-Parkinsonism condition, an increased environmental burden of manganese may have deleterious effects on populations with sub-threshold neurodegeneration in the basal ganglia (e.g. pre-Parkinsonism).
authors.affiliation: Environmental Toxicology, University of California, Santa Cruz 95064, USA. gwiazda@etox.ucsc.edu
authors.forename: R H
authors.initials: RH
authors.lastname: Gwiazda
authors.forename: D
authors.initials: D
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Sheridan
authors.forename: D R
authors.initials: DR
authors.lastname: Smith
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004781:Environmental Exposure / Q000009:adverse effects; D005260:Female; D007274:Injections, Intraperitoneal; D008345:Manganese / Q000008:administration & dosage*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D008345:Manganese; D005680:gamma-Aminobutyric Acid; D004298:Dopamine