SEROTONIN 5-HT(1A) 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 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-HT1A receptor agonist, were moderately potent, receptor-mediated inhibitors of tyrosine hydroxylation in synaptosomes, with EC50 values of 8.4 and 7.0 muM, respectively. The inhibitory activity of 8-OH-DPAT was attenuated by 5-HT1A-selective antagonists [10 muM propranolol, 10 muM (-)-alprenolol, 10 muM NAN-190 {1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl] piperazine hydrobromide} and 10 muM pindolol] but not by a beta adrenoceptor antagonist devoid of activity at the 5-HT1A receptor (10 muM atenolol) or by a D2-dopamine-selective receptor antagonist [10 muM (-)-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. These results suggest that 5-HT1A heteroreceptors are located on dopamine nerve terminals in the rat striatum and regulate tyrosine hydroxylation in a tonic, inhibitory fashion.