Dopamine Transmission Impaired by Manganese

Tomás R. Guilarte, Ph.D., Neal C. Burton
Johns Hopkins Bloomberg School of Public Health
NIEHS Grants R01ES010975 and T32ES007141

NIEHS grantees at Johns Hopkins University report that manganese exposure inhibits dopamine neurotransmission from the substantia nigra region of the brain leading to motor activity impairments. These results follow on previous studies from this laboratory using cynomologus macaques, also known as crab-eating macaques or long-tailed macaques. Previous research has shown that these monkeys have slight cognitive and fine motor deficits in response to manganese exposure.

The debilitating neurological condition manganism results from chronic high-dose exposure to the essential trace mineral manganese. Movement abnormalities associated with manganism resemble the same condition in Parkinson’s disease. Manganese-induced parkinsonism most often results from high exposure in industrial settings related to steel production; however other sources include the impairment of manganese excretion in some liver diseases, patients receiving high doses of manganese from parenteral nutrition, the injection of illicit psychostimulant drugs containing manganese, and possibly exposure to ambient concentrations of manganese generated from gasoline containing the additive methylcyclopentadienyl manganese tricarbonyl.

The monkeys were treated weekly with manganese doses ranging from 3.3-10 milligrams per kilogram body weight from seven up to 59 weeks. They received PET scans prior to the beginning of dosing and at one or two times points during the exposure. The researchers found that amphetamine-induced dopamine release was markedly reduced in the manganese-exposed animals. They conclude that the manganese exposure is responsible for the motor deficits documented in the monkeys. These findings may have implications for the prevention and treatment of symptoms of parkinsonism.

Citation: Guilarte TR, Burton NC, McGlothan JL, Verina T, Zhou Y, Alexander M, Pham L, Griswold M, Wong DF, Syversen T, Schneider JS. Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre-synaptic mechanism(s): implications to manganese-induced parkinsonism. J Neurochem. 2008 Dec;107(5):1236-47.

Note: Neal Burton is a Ph.D. student and was honored at the Society of Toxicology’s Annual Meeting in March 2006. Burton brought home first prize in the Neurotoxicology Specialty Section competition for his poster titled "In Vivo Attenuation of the Parkinsonian Phenotype by Induction of the Keap1-Nrf2 Pathway."