Aging of neuronal systems is a complex process that likely involves functional changes in neuronal elements that determine cell death. Data from numerous studies support the hypothesis that the dopamine (DA) neuronal system appears be a key player that is altered in movement disorders, such as Parkinson's disease, and changes in DA function may, impart, relate to movement abnormalities seen in aged animals and humans. This competing renewal plans to examine the dynamics of dopamine transporter (DAT) function during aging, which may be involved with some of the functional changes that occur with DA neurons in senescence. In addition, in an attempt to recover or rescue DA neurons and restore movement functions through the DA system, the principal investigator plans to assess the potential regenerative/protective effects of two putative dopaminotrophic factors, glial cell-derived neurotrophic factor (GDNF) and Neurturin, on dopamine neurons in young and aged Fischer 344 rats. Previous studies from the principal investigator's lab have demonstrated that a consistent alteration in aging processes appears to involve a change in the functional properties of the dopamine transporter (DAT) located on cell soma, axons and dendrites of dopaminergic neurons. Since it is well established that dopamine in the substantia nigra plays a major role in movement behavior, and alterations in DA function in the substantia nigra may play a major role in age-related alterations in motor performance in man and animals, they hypothesize that GDNF, and possibly a close peptide relative, Neurturin, will restore function to aged neurons that reside in the substantia nigra of aged rats. In addition, GDNF and Neurturin may be capable of minimizing age-induced degeneration of dopamine neurons. The principal investigator hypothesizes that these trophic factors will increase dopamine content, dopamine release and uptake. He will employ in vivo electrochemistry recordings to evaluate the DAT, and microdialysis to assess changes in extracellular dopamine and dopamine metabolites following treatments with GDNF and Neurturin. These studies should lead to a better understanding of the functional properties of aged DA neurons and the effects on DA neuronal function seen following treatments with the trophic factors, GDNF and Neurturin. In addition to the symptomatic effects of trophic factor treatment, the principal investigator plans to establish whether age related changes in dopamine can be prevented by treatment with GDNF and Neurturin. All changes in DAT and dopaminergic parameters as a function of aging and trophic factor treatment will be correlated with the behavioral status of the animals.
