Dopamine D2 synthesis-modulating receptors are present in the striatum of the guinea pig.
Dopamine and selective agonists of D1 [(1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride, SKF 38393] and D2 [(3-[2-[N-(3-hydroxyphenylethyl)-N-propylamino]ethyl] phenol, RU 24926] receptors were examined as inhibitors of the activity of tyrosine hydroxylase in the striatum of the guinea pig. In soluble enzyme preparations, the agonists were weak inhibitors of the activity of tyrosine hydroxylase. However, the catechol-containing agonists dopamine (EC50 = 44.7 microM) and SKF 38393 (EC50 = 35.5 microM) were more potent than the non-catechol agonist RU 24926 (EC50 = 447 microM). All of the agonists were much more potent in synaptosome-rich preparations of guinea pig striatum, where stimulation of autoreceptors mediated inhibition of the enzyme (SKF 38393, D1, EC50 = 27 nM; RU 24926, D2, EC50 = 30 nM; dopamine, non-selective, EC50 = 1.5 microM). The D1 antagonist, SCH 23390 [(R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine hydrochloride], did not significantly reduce the action of SKF 38393 or dopamine. Furthermore, the D2 antagonist, (-)-sulpiride, significantly antagonized the inhibitory activity of both RU 24926 and dopamine. Studies in synaptosome-rich preparations from the striatum of the rat showed that both SKF 38393 (EC50 = 398 nM) and RU 24926 (EC50 = 58 nM) were also effective autoreceptor-mediated inhibitors of the activity of tyrosine hydroxylase in the rat. However, in the rat, SCH 23390 and (-)-sulpiride were equally effective in attenuating the inhibitory actions of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Johnson
E A
EA
Department of Behavioral Medicine, West Virginia University, Morgantown 26506.
Tsai
C E
CE
Lucci
J
J
Harrison-Shahan
Y
Y
Azzaro
A J
AJ
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D011954:Receptors, Dopamine / Q000096:biosynthesis* / Q000187:drug effects; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013469:Sulpiride / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism
D001552:Benzazepines; D010627:Phenethylamines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C025254:RU 24926; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D013469:Sulpiride; D014446:Tyrosine 3-Monooxygenase