These studies are designed to further our understanding of the role of protein phosphorylation in regulating catecholamine synthesis in the central nervous system. We will be testing the hypothesis that specific treatments that alter catecholamine formation in situ do so by altering tyrosine hydroxylase phosphorylation. Experiments will be carried out to distinguish between the different protein kinases that can activate tyrosine hydroxylase so that the kinase(s) responsible for tyrosine hydroxylase activation in situ can be identified. Initial studies on soluble enzyme preparations will be followed by phosphorylation studies on synaptosomal preparations in order to determine if treatment with cyclic nucleotides, depolarizing agents, calcium ionophores, phorbol esters or stimulant drugs produces an alteration in catecholamine formation via an alteration in tyrosine hydroxylase phosphorylation. A final set of experiments will be carried out to determine if the activation of rat striatal tyrosine hydroxylase produced by in vivo stimulation of the nigrostriatal pathway is mediated by phosphorylation and, if so, by which kinase system(s). In light of the evidence linking abnormalities in catecholamine regulation to psychiatric disorders, it is anticipated that these studies will increase our understanding of the mechanism of action of psychoactive drugs on a biochemical level, and will also aid in the elucidation of the biochemistry of mental health and psychiatric disorders.
