Long-term effect of MPTP in the mouse brain in relation to aging: neurochemical and immunocytochemical analysis.
The long-term effect of the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central monoaminergic neurons in young (2-3 months) and aging (12 months) C57BL/6 mice has been studied using neurochemical and immunocytochemical techniques. MPTP treatment (4 x 20 mg/kg i.p. given 12 h apart) resulted in significant depletion of dopamine (DA) concentration in the striatum, substantia nigra, nucleus accumbens, and olfactory tubercle 1 week after treatment in both young and aging mice. Although a decreased DA concentration in the ventral tegmental area was not seen in young mice, aging mice did show a significant decrease. The extent of decrease of DA concentration was greater in aging mice than in young mice in all areas investigated except in dorsal striatum. The long-term effect of MPTP on DA neurons in young mice included considerable recovery of DA concentration in both nigrostriatal and mesolimbic DA systems following the initial profound depletion; such recovery was minimal in aging mice, even 3 months after MPTP treatment. In young mice treated with MPTP, no significant change of norepinephrine (NE) or serotonin (5-HT) concentration was observed in any area investigated while a significant decrease of NE and 5-HT concentration was seen in several brain areas investigated in aging mice. Immunocytochemical analysis revealed that the MPTP injection resulted in marked disappearance of tyrosine hydroxylase (TH)-immunoreactive (IR) fibers in striatum of both young and aging mice 1 week following treatment. Partial recovery of TH-IR fibers was seen 5 weeks or 3 months after MPTP treatment in young mice, while no such apparent recovery was seen in aging mice. Aging mice also showed significant decrease in the number of TH-positive cell bodies in the substantia nigra and ventral tegmental area through all periods investigated, while such a significant decrease was only seen in the substantia nigra of young mice 1 week after treatment. We conclude that aging mice are more sensitive to MPTP and show more widespread damage to the monoaminergic systems than young mice, suggesting that MPTP-treated aging mice provide a more useful model for studying anatomical and neurochemical characteristics of Parkinson's disease than young mice.
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Department of Neurobiology and Anatomy, University of Rochester School of Medicine, NY 14642.
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D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000375:Aging; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D006651:Histocytochemistry; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000378:metabolism; D010300:Parkinson Disease / Q000503:physiopathology; D012016:Reference Values; D012701:Serotonin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid