Absence of spare autoreceptors regulating dopamine agonist inhibition of tyrosine hydroxylation in slices of rat striatum.
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)
Bohmaker
K
K
Millhauser Laboratories, Department of Psychiatry, University School of Medicine, New York, New York.
Puza
T
T
Goldstein
M
M
Meller
E
E
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D003342:Corpus Striatum / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000037:antagonists & inhibitors*
D015259:Dopamine Agents; D007211:Indoles; D011804:Quinolines; D011954:Receptors, Dopamine; D005576:Colforsin; C000470:EEDQ; C037307:3-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl-1)-butyl)indole; D014446:Tyrosine 3-Monooxygenase