DOPAMINE NEUROTOXICITY: AGE-DEPENDENT BEHAVIORAL AND HISTOLOGICAL EFFECTS

Authors: CANTUTI-CASTELVET, IPPOLITA - MASS GENERAL HOSPITAL; Shukitt-Hale, Barbara; Joseph, James

Submitted to: Neurobiology of Aging
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/5/2002
Publication Date: 9/24/2003
Citation: Cantuti-Castelvetri, I., Shukitt-Hale, B., and Joseph, J.A. Dopamine neurotoxicity: Age-dependent behavioral and histological effects. Neurobio. Aging 2003, 24: 697-706.

Interpretive Summary: A great deal of information suggests that aging may be the result of our increasing inability to counteract the effect of very reactive molecules called free radicals. This appears to be especially true in the brain, and the ultimate expression of this may be through deficits in motor function. One system in the brain is called the dopaminergic system and unfortunately the neurotransmitter in this system, dopamine, can make free radicals. Therefore, we wanted to examine whether young and middle-aged would show sensitivity to this neurotransmitter, if we surgically placed it into an area of the brain known to show changes with age (the substantia nigra) and then examined motor behavior and cell loss in the substantia nigra. The results showed that the middle-aged animals were more impaired than the young animals and showed more cell loss in the substantia nigra, suggesting that there is increased oxidative stress sensitivity in the middle-aged animals that is reflected in their behavior

Technical Abstract: The oxidative stress 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 mo) and middle-aged (15 mo) rats were chronically treated with DA in the substantia nigra (SN, 1umol/2ul 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.