AGING AND VULNERABILITY TO 6HYDROXYDOPAMINE

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This application is from a new investigator and is aimed at research topic 16 - sensory and motor processing. The nigrostriatal dopamine (DA) system of the brain has been shown to play a major role in the control of movement. A gradual loss of nigrostriatal dopamine neurons occurs during normal aging in humans, and many elderly persons display one or more of the signs of Parkinson's disease without having the disease. This may indicate that older people that have parkinsonian signs may have a greater than normal loss of nigrostriatal DA. Although the cause for the normally occurring loss of midbrain DA cells in the elderly is not known, animal studies have indicated that the DA neurons of older animals may be more vulnerable to the effects of various neurotoxins. The purpose of the experiments in the present application is too determine if the nigrostriatal DA system of older animals is more sensitive to the neurotoxic effects of the dopaminergic toxin 6- hydroxydopamine (6-OHDA), and to begin to develop a model of the aging brain that is partially depleted of DA. It is hypothesized that the nigrostriatal DA system in older rats will be more sensitive to the neurotoxic effects of 6-OHDA than the nigrostriatal DA system of younger rats. The initial set of experiments will be to generate a dose- response curve in young adult animals for the DA-depleting effects of 6-OHDA. Male Fischer-344 rats (4 months old) will be given a single, unilateral injection of 6-OHDA into the right lateral ventricle. The doses examined will be 0, 50, 100, 150, and 200 mug of 6-OHDA per injection. Three weeks later, DA and metabolite levels will be measured in the striatum, nucleus accumbens, substantia nigra, and medial prefrontal cortex. Based on the results of these experiments, a dose of 6-OHDA that reduces striatal DA levels by approximately 50 percent in young adult rats will given to rats of three ages; 4 months, 18 months, and 24 months old. Three weeks later the rats will be anesthetized and in vivo electrochemistry experiments will be carried out on both sides of the brain to map out potassium-evoked overflow of DA, and subsequent clearance of DA, in the striatum. Following the experiments, post-mortem levels of DA and metabolites will be measured to determine the extent of whole tissue depletion by the 6-OHDA. The results of these experiments will help determine if the nigrostriatal DA system of the aging rat brain is more susceptible to the neurotoxic effects of 6-OHDA, and will begin to determine possible differences in presynaptic dopaminergic functioning in the aging versus younger brain in response to a neurotoxic insult.