Dopamine neurotoxicity: age-dependent behavioral and histological effects.
The oxidative stress (OS) theory has implicated the involvement of reactive oxygen species (ROS) in both aging and age-dependent neurodegenerative diseases. The dopaminergic system is particularly vulnerable to ROS, and dopamine (DA) itself can be an endogenous source of ROS. The present study evaluated the hypothesis that DA-induced toxicity is age-dependent, and tested the behavioral and histological correlates of DA neurotoxicity in aging. Young (6 months) and middle-aged (15 months) rats were chronically treated with DA in the substantia nigra (SN, 1 micromol/2 microl vehicle per side/day/5 days) and were subsequently examined for changes in motor function and histology. The neurotoxic effect of DA treatment was an age-dependent effect, as middle-aged animals that received DA infusions in the SN were more impaired than their age-matched controls, especially on tasks that involved greater sensory-motor coordination, whereas young animals that received DA behaved similarly to their age-matched controls. The behavioral effects noted were accompanied by a loss of the tyrosine hydroxylase phenotype in substantia nigra. However, selective neurodegeneration was not noted in the SN of the treated animals, nor was a selective iron deposition noted at the site of injection. These results suggest that a neurochemical deficit and not cell loss per se within the nigrostriatal system underlies the motor behavioral deficits observed in the middle-aged rats.
Cantuti-Castelvetri
Ippolita
I
USDA Human Nutrition Research Center on Aging at Tufts University, Room 919, 711 Washington Street, Boston, MA 02111, USA.
Shukitt-Hale
Barbara
B
Joseph
James A
JA
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000633:toxicity*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011597:Psychomotor Performance; D051381:Rats; D011916:Rats, Inbred F344; D011930:Reaction Time; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013194:Staining and Labeling; D013378:Substantia Nigra / Q000187:drug effects* / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism
D017382:Reactive Oxygen Species; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine