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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH031706-07
Application #
3375253
Study Section
(BPNA)
Project Start
1986-04-01
Project End
1989-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Brown University
Department
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Patrick, S L; Walker, J M; Perkel, J M et al. (1993) Increases in rat striatal extracellular dopamine and vacuous chewing produced by two sigma receptor ligands. Eur J Pharmacol 231:243-9
Patrick, S L; Thompson, T L; Walker, J M et al. (1991) Concomitant sensitization of amphetamine-induced behavioral stimulation and in vivo dopamine release from rat caudate nucleus. Brain Res 538:343-6
Davis, M E; Patrick, R L (1990) Diacylglycerol-induced stimulation of neurotransmitter release from rat brain striatal synaptosomes. J Neurochem 54:662-8
Thompson, T L; Colby, K A; Patrick, R L (1990) Activation of striatal tyrosine hydroxylase by in vivo electrical stimulation: comparison with cyclic AMP-mediated activation. Neurochem Res 15:1159-66
Goldstein, S R; Matsumoto, R R; Thompson, T L et al. (1989) Motor effects of two sigma ligands mediated by nigrostriatal dopamine neurons. Synapse 4:254-8
Colby, K A; Thompson, T L; Patrick, R L (1989) Tyrosine hydroxylase phosphorylation in rat brain striatal synaptosomes. Brain Res 478:103-11
Matsumoto, R R; Brinsfield, K H; Patrick, R L et al. (1988) Rotational behavior mediated by dopaminergic and nondopaminergic mechanisms after intranigral microinjection of specific mu, delta and kappa opioid agonists. J Pharmacol Exp Ther 246:196-203