The nigrostriatal dopamine (DA) system of the brain plays a major role in the control of movement. A gradual loss of nigrostriatal DA neurons occurs during normal aging in humans, and many elderly persons display one or more of the signs of Parkingson's disease without having the disease. This may indicate that these people have a greater than normal loss of nigrostriatal DA. An animal model of aging with a partial loss of DA neurons (ICV injection of 6-hydroxydopamine, 6-OHDA) is currently being developed by the applicant. The experiments in the present proposal will use this model to determine the extent of spontaneous recovery of presynaptic dopaminergic functioning in young, middle-aged and aged rats. In addition, the effects of the potent dopaminergic factor glial cell line-derived neurotrophic factor (GDNF) will also be examined in this model. It is hypothesized that the nigrostriatal DA system in aged rats will have a reduced capacity to recover from the neurotoxic effects of 6-OHDA compared to young rats. It is further hypothesized that GDNF will be less effective in aged animals compared to young animals both in its ability to protect against 6-OHDA and to promote recovery after the lesion. The first specific aim will examine spontaneous recovery in young (4 months old) middle-aged (14 months old), and aged (24 months old) male and female Fischer-344 rats following partial bilateral lesions with 6-OHDA. Locomotor activity, basal levels and evoked overflow of DA and its metabolites in the striata (as measured with microdialysis), and tyrosine hydroxylase immunohistochemistry studies will be carried out at several time points after the lesion to determine extent of recovery. Post-mortem measurements of tissue monoamines will be analyzed as well. The second specific aim will evaluate the ability of GDNF to prevent or reduce 6-OHDA-induced changes in locomotor activity and presynaptic dopaminergic function in the three age groups, while the third specific aim will examine the ability of GDNF to promote behavioral and neurochemical recovery from the lesion in the three age groups. The results of these experiments will help determine if the nigrostriatal DA system of the aging brain has the same capacity to recover from a neurotoxic insult as that of younger animals, and will begin to evaluate age-related differences in response of nigrostriatal DA neurons to neurotrophic factors.
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