Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre-synaptic mechanism(s): implications to manganese-induced parkinsonism.
The long-term consequences of chronic manganese (Mn) exposure on neurological health is a topic of great concern to occupationally-exposed workers and in populations exposed to moderate levels of Mn. We have performed a comprehensive assessment of Mn effects on dopamine (DA) synapse markers using positron emission tomography (PET) in the non-human primate brain. Young male Cynomolgus macaques were given weekly i.v. injections of 3.3-5.0 mg Mn/kg (n = 4), 5.0-6.7 mg Mn/kg (n = 5), or 8.3-10.0 mg Mn/kg (n = 3) for 7-59 weeks and received PET studies of various DA synapse markers before (baseline) and at one or two time points during the course of Mn exposure. We report that amphetamine-induced DA release measured by PET is markedly impaired in the striatum of Mn-exposed animals. The effect of Mn on DA release was present in the absence of changes in markers of dopamine terminal integrity determined in post-mortem brain tissue from the same animals. These findings provide compelling evidence that the effects of Mn on DA synapses in the striatum are mediated by inhibition of DA neurotransmission and are responsible for the motor deficits documented in these animals.
Guilarte
Tomás R
TR
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. tguilart@jhsph.edu
Burton
Neal C
NC
McGlothan
Jennifer L
JL
Verina
Tatyana
T
Zhou
Yun
Y
Alexander
Mohab
M
Pham
Luu
L
Griswold
Michael
M
Wong
Dean F
DF
Syversen
Tore
T
Schneider
Jay S
JS
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D003511:Cyclohexanols / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008252:Macaca fascicularis; D008297:Male; D008345:Manganese; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D049268:Positron-Emission Tomography / Q000379:methods; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D003511:Cyclohexanols; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; C079213:RTI 121; C032811:dihydrotetrabenazine; D008345:Manganese; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D004298:Dopamine; D013747:Tetrabenazine