Serotonin 5-HT1A receptors mediate inhibition of tyrosine hydroxylation in rat striatum
Johnson, E.A.; Tsai, C.E.; Shahan, Y.H.; Azzaro, A.J.
Journal of Pharmacology and Experimental Therapeutics 266(1): 133-141
1993
ISSN/ISBN: 0022-3565 PMID: 8101215 Document Number: 408240
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-HT-1A 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 (highperformance liquid chromatrography-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-HT-1A receptor agonist, were moderately potent, receptor-mediated inhibitors of tyrosine hydroxylation in synaptosomes, with EC-50 values of 8.4 and 7.0 mu-M, respectively. The inhibitory activity of 8-OH-DPAT was attenuated by 5-HT-1A selective antagonists (10 mu-M propranolol, 10 mu-M (-)-alprenolol, 10 mu-M NAN-190 (1-(2-methoxyphenyl)-4-(4-(2-pthalimido)butyl) piperazine hydrobromide) and 10 mu-M pindolol) but not by a beta adrenoceptor antagonist devoid of activity at the 5-HT-1A receptor (10 mu-M atenolol) or by a D-2-dopamine-selective receptor antagonist (10 mu-M (-)sulpiride). In vivo 8-OH-DPAT exhibited a biphasic dose-response curve for inhibition of tyrosine hydroxylation, significant inhibition (30%, P lt .05) occurred at a dose of 0.3 mg/kg s.c. In vivo, the 5-HT-1A-selective antagonist NAN-190 (1 or 3 mg/kg s.c.) caused dramatic 2- to 2.5-fold elevations of dopa accumulation. These results suggest that 5-HT-1A heteroreceptors are located on dopamine nerve terminals in the rat striatum and regulate tyrosine hydroxylation in a tonic, inhibitory fashion.