Increased sensitivity of striatal dopamine release to H2O2 upon chronic rotenone treatment.
It is believed that both mitochondrial dysfunction and oxidative stress play important roles in the pathogenesis of Parkinson's disease (PD). We studied the effect of chronic systemic exposure to the mitochondrial inhibitor rotenone on the uptake, content, and release of striatal neurotransmitters upon neuronal activity and oxidative stress, the latter simulated by H(2)O(2) perfusion. The dopamine content in the rat striatum is decreased simultaneously with the progressive loss of tyrosine hydroxylase (TH) immunoreactivity in response to chronic intravenous rotenone infusion. However, surviving dopaminergic neurons take up and release only a slightly lower amount of dopamine (DA) in response to electrical stimulation. Striatal dopaminergic neurons showed increased susceptibility to oxidative stress by H(2)O(2), responding with enhanced release of DA and with formation of an unidentified metabolite, which is most likely the toxic dopamine quinone (DAQ). In contrast, the uptake of [(3)H]choline and the electrically induced release of acetylcholine increased, in coincidence with a decline in its D(2) receptor-mediated dopaminergic control. Thus, oxidative stress-induced dysregulation of DA release/uptake based on a mitochondrial deficit might underlie the selective vulnerability of dopaminergic transmission in PD, causing a self-amplifying production of reactive oxygen species, and thereby contributing to the progressive degeneration of dopaminergic neurons.
Milusheva
Elisaveta
E
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest.
Baranyi
Mária
M
Kittel
Agnes
A
Sperlágh
Beáta
B
Vizi
E Sylvester
ES
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000494:pharmacology*; D013469:Sulpiride / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D012402:Rotenone; D013469:Sulpiride; D006861:Hydrogen Peroxide; D014446:Tyrosine 3-Monooxygenase; D000109:Acetylcholine; D004298:Dopamine