Serotonin 5-HT1A receptors mediate inhibition of tyrosine hydroxylation in rat striatum.
The role of serotonin (5-HT)1A heteroreceptors as modulators of dopamine synthesis was investigated by using in vitro and in vivo methods. In vitro studies were conducted utilizing either synaptosome-rich preparations of rat striatal tyrosine hydroxylase or soluble preparations of rat striatal tyrosine hydroxylase enzyme. 5-HT1A receptor modulation of tyrosine hydroxylation in vitro was estimated by using a radiometric, coupled enzyme assay. For in vivo investigations of the modulation of tyrosine hydroxylation, striatal dopa accumulation was measured (high-performance liquid chromatography-electrochemical detection) after administration of the aromatic amino acid decarboxylase inhibitor NSD-1015 (3-hydroxybenzylhydrazine). Both serotonin and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist, were moderately potent, receptor-mediated inhibitors of tyrosine hydroxylation in synaptosomes, with EC50 values of 8.4 and 7.0 microM, respectively. The inhibitory activity of 8-OH-DPAT was attenuated by 5-HT1A-selective antagonists [10 microM propranolol, 10 microM (-)-alprenolol, 10 microM NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl] piperazine hydrobromide) and 10 microM pindolol] but not by a beta adrenoceptor antagonist devoid of activity at the 5-HT1A receptor (10 microM atenolol) or by a D2-dopamine-selective receptor antagonist [10 microM (-)-sulpiride]. In vivo 8-OH-DPAT exhibited a biphasic dose-response curve for inhibition of tyrosine hydroxylation, significant inhibition (30%, P < .05) occurred at a dose of 0.3 mg/kg s.c. In vivo, the 5-HT1A-selective antagonist NAN-190 (1 or 3 mg/kg s.c.) caused dramatic 2- to 2.5-fold elevations of dopa accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Johnson
E A
EA
Department of Behavioral Medicine, West Virginia University, Health Sciences Center Morgantown.
Tsai
C E
CE
Shahan
Y H
YH
Azzaro
A J
AJ
D015107:4-Butyrolactone / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D004298:Dopamine / Q000096:biosynthesis*; D065127:Dopamine D2 Receptor Antagonists; D006900:Hydroxylation / Q000187:drug effects; D008297:Male; D009411:Nerve Endings / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors*
D065127:Dopamine D2 Receptor Antagonists; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D014446:Tyrosine 3-Monooxygenase; D015107:4-Butyrolactone; D004298:Dopamine