DESCRIPTION (Adapted from the applicant's abstract): The rationale for this project derives from a substantial literature showing functional deficits in locus coeruleus activity and norepinephrine-mediated behavior in aging animals. It is argued that the few studies of TH, the rate-limiting enzyme in catecholamine biosynthesis, that have been described in aging animals or human disease have been inconclusive since these studies have only assayed baseline TH activity under optimal conditions. The working hypothesis is that regulation of neurochemical adaptive responsiveness in locus coeruleus neurons is reduced in aging animals. This difference will be reflected in changes in the induction or activation of TH following neurotoxic insult or pharmacologic manipulation of this neural system. Three major aims are proposed to test this hypothesis. The first asks if there is an age-dependent alteration in the ability of these neurons to induce TH in response to partial damage by 6-hydroxydopamine. TH mRNA induction will be measured by in situ hybridization and TH protein by immunohistochemistry and comparisons will be made to the induction of group II beta tubulin as a marker for regenerating neurons. The second uses enzyme assays to study age-related alterations in TH activation (phosphorylation) in response to the same experimental treatment. The third aim has two parts. The first looks for age-related changes in TH activation in response to treatments with clonidine, oxotremorine, and reserpine, while the second aims to identify the protein kinase system(s) which may be responsible for altered TH regulation in aging.