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Absence of spare autoreceptors regulating dopamine agonist inhibition of tyrosine hydroxylation in slices of rat striatum

K Bohmaker, T Puza, M Goldstein and E Meller

Millhauser Laboratories, Department of Psychiatry, University School of Medicine, New York, New York.

Incubation of rat striatal slices with forskolin (0.05-10 microM) elicited a dose-dependent increase in the activity of tyrosine hydroxylase (TH) assayed in subsequently solubilized extracts of the enzyme. At low concentrations (33 microM) of the cofactor (6R)-5,6,7,8- tetrahydro-L-biopterin dihydrochloride TH activity was increased 2.5 to 3-fold. Kinetic analysis of TH activity as a function of (6R)-5,6,7,8- tetrahydro-L-biopterin dihydrochloride concentration indicated that the enzyme isolated from control slices was composed of multiple species with different Km's for cofactor. Treatment with forskolin (1.5-15 microM) converted the enzyme into a single species with a low Km (28 microM) for (6R)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride. The dopamine (DA) agonist R-(-)-N-n-propylnorapomorphine (0.1 microM) reversed forskolin-induced activation of TH. Concentration-response curves were obtained for inhibition of forskolin-stimulated TH by R-(-)- N-n-propylnorapomorphine and the DA autoreceptor-selective agonists (+)- and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine and 3-[4-(4-phenyl- 1,2,3,6-tetrahydropyridyl-1)-butyl]indole. R-(-)-N-n- propylnorapomorphine maximally inhibited forskolin-stimulated activity 85%, as indicated by ALLFIT computer analysis of concentration-response curves. (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine and 3-[4-(4-phenyl- 1,2,3,6-tetrahydropyridyl-1)-butyl]indole produced a lower degree of maximal inhibition (54 and 63%, respectively), whereas (-)-3-(3- hydroxyphenyl)-N-n-propylpiperidine was inactive. The D2 DA receptor blocker sulpiride (1 microM) competitively antagonised the effects of all the agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 248, Issue 1, pp. 97-103, 01/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics




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