Paraquat induces long-lasting dopamine overflow through the excitotoxic pathway in the striatum of freely moving rats.
The herbicide paraquat is an environmental factor that could be involved in the etiology of Parkinson's disease. We have previously shown that paraquat penetrates through the blood-brain barrier and is taken up by neural cells. In this study, we examined the in vivo toxic mechanism of paraquat to dopamine neurons. GBR-12909, a selective dopamine transporter inhibitor, reduced paraquat uptake into the striatal tissue including dopaminergic terminals. The subchronic treatment with systemic paraquat significantly decreased brain dopamine content in the striatum and slightly in the midbrain and cortex, and was accompanied by the diminished level of its acidic metabolites in rats. When paraquat was administered through a microdialysis probe, a transitory increase in the extracellular levels of glutamate, followed by long-lasting elevations of the extracellular levels of NO(x)(-) (NO(2)(-) plus NO(3)(-)) and dopamine were detected in the striatum of freely moving rats. This dopamine overflow lasted for more than 24 h after the paraquat treatment. Dopamine overflow was inhibited by N(G)-nitro-L-arginine methyl ester, dizocilpine, 6,7-dinitroquinoxaline-2,3-dione and L-deprenyl. The toxic mechanism of paraquat involves glutamate induced activation of non-NMDA receptors, resulting in activation of NMDA receptor-channels. The influx of Ca(2+) into cells stimulates nitric oxide synthase. Released NO would diffuse to dopaminergic terminals and further induce mitochondrial dysfunction by the formation of peroxynitrite, resulting in continuous and long-lasting dopamine overflow. The constant exposure to low levels of paraquat may lead to the vulnerability of dopaminergic terminals in humans, and might potentiate neurodegeneration caused by the exposure of other substances, such as endogenous dopaminergic toxins.
Shimizu
K
K
Department of Legal Medicine, Asahikawa Medical College, 078-8510, Asahikawa, Japan. kmatsuba@asahikawa-med.ac.jp
Matsubara
K
K
Ohtaki
K
K
Fujimaru
S
S
Saito
O
O
Shiono
H
H
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006540:Herbicides / Q000493:pharmacokinetics*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism; D009043:Motor Activity; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010269:Paraquat / Q000493:pharmacokinetics*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012642:Selegiline / Q000494:pharmacology
D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D006540:Herbicides; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011810:Quinoxalines; D015102:3,4-Dihydroxyphenylacetic Acid; D012642:Selegiline; D009569:Nitric Oxide; D018698:Glutamic Acid; C056723:FG 9041; D016291:Dizocilpine Maleate; D010269:Paraquat; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine; D006719:Homovanillic Acid