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Molecular Pharmacology, Vol 18, 91-99, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Presynaptic Regulation of Tyrosine Hydroxylase Activity in Rat Striatal Synaptosomes by Dopamine Analogs

W. G. WAGGONER 1, JOHN MCDERMED 1, and H. J. LEIGHTON 1

1 Departments of Pharmacology and Organic Chemistry, Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709

Tyrosine hydroxylase activity in rat striatal synaptosomes was inhibited by four different dopamine agonists: dopamine (DA) (IC50 0.2 µM), apomorphine (APO) (IC50 = 0.1 µM), 6,7-dihydroxy-2-aminotetralin (ADTN) (IC50 0.2 µM), and 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7HDPT) (IC50 = 1.3 µM). The inhibitory activities of DA and ADTN were antagonized by the addition of the dopamine uptake inhibitor benztropine but not by the addition of the dopamine receptor antagonist fluphenazine. The inhibitory activity of APO was marginally antagonized by the addition of either benztropine or fluphenazine. The inhibitory activity of 7HDPT was antagonized by fluphenazine and other neuroleptics but not by benztropine. In contrast to the other agonists, 7HDPT did not inhibit soluble tyrosine hydroxylase assayed in the presence of the synthetic cofactor, 6,7-dimethyl-5,6,7,8-tetrahydropterine (DMPH4). The inhibition of synaptosomal tyrosine hydroxylase by 7HDPT was also antagonized by DMPH4, dibutyryl cAMP, and FeSO4 in the presence of beta-mercaptoethanol but not by ATP, GTP, cAMP, or dibutyryl cGMP or by high concentrations (11 mM) of calcium. Incubation of synaptosomes with concentrations of 7HDPT which inhibited synaptosomal tyrosine hydroxylation by greater than 50% did not cause a significant change in the Vmax of tyrosine hydroxylase or the Km of tyrosine hydroxylase for the synthetic cofactor DMPH4. It is concluded that 7HDPT is a valuable agent for studying presynaptic mechanisms of tyrosine hydroxylase regulation in the rat striatum since its activity appears to be mediated primarily through presynaptic plasma membrane dopamine receptors. The mechanism by which presynaptic dopamine receptors may regulate tyrosine hydroxylase activity is discussed.

Note:
ACKNOWLEDGMENT The authors greatly appreciate the graphic assistance of Mrs. Beverly Nobles.

Submitted on July 25, 1979
Accepted on February 25, 1980




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