Experiments outlined in this proposal focus on mechanisms regulating the catecholamine biosynthetic enzymes, especially dopamine-p-hydroxylase (DBH), and their relevence to adaptation and behavioral function. DBH activity and concentration are responsive to diverse stimuli; changes in enzyme activity reflect the organism's attempt to adapt to a stimulus, and are mediated by biochemical regulatory mechanisms. We have evidence that changes in DBH are governed by a rich array of variables; stimulus- and genetically-determined variables are considered in this proposal. In a given inbred rat strain, different stimuli cause quite different changes in DBH activity. The same stimulus can produce opposite responses in different strains. Interactions between 3 stimuli (cold exposure, immobilization, footshock) and several inbred rat strains will be studied in 4 phases. First, responses will be analyzed descriptively between stimuli and strains. We will assess DBH activity (in vivo and in vitro procedures to be used) as well as enzyme protein concentration (using immunologic procedures) in brain and adrenal tissue to define the nature and direction of change. Second, mechanisms responsible for DBH changes will be determined. Potential changes in physicochemical properties of the enzymes, "endogenous inhibitor" concentration, axoplasmic transport, enzyme protein synthesis and degradation will be assessed. These studies will include formal genetic analyses, and a comparison of sex differences. Third, model systems for study of regulatory processes in adrenal organ or cell culture will be developed to facilitate study of the molecular events involved. Fourth, the behavioral relevance of these responses will be explored using inbred and hybrid rats.
NIH ExPorter
NIH ExPorter