SEROTONIN 5-HT(1A) RECEPTORS MEDIATE INHIBITION OF TYROSINE HYDROXYLATION IN RAT STRIATUM

The role of serotonin (5-HT)1A heteroreceptors as modulators of dopami ne synthesis was investigated by using in vitro and in vivo methods. i n vitro studies were conducted utilizing either synaptosome-rich prepa rations of rat striatal tyrosine hydroxylase or soluble preparations o f rat striatal tyrosine hydroxylase enzyme. 5-HT1A receptor modulation of tyrosine hydroxylation in vitro was estimated by using a radiometr ic, coupled enzyme assay. For in vivo investigations of the modulation of tyrosine hydroxylation, striatal dopa accumulation was measured (h igh-performance liquid chromatrography-electrochemical detection) afte r administration of the aromatic amino acid decarboxylase inhibitor NS D-1015 (3-hydroxybenzylhydrazine). Both serotonin and 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonis t, were moderately potent, receptor-mediated inhibitors of tyrosine hy droxylation in synaptosomes, with EC50 values of 8.4 and 7.0 muM, resp ectively. The inhibitory activity of 8-OH-DPAT was attenuated by 5-HT1 A-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 ant agonist 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 inhib ition 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 an tagonist NAN-190 (1 or 3 mg/kg s.c.) caused dramatic 2- to 2.5-fold el evations of dopa accumulation. These results suggest that 5-HT1A heter oreceptors are located on dopamine nerve terminals in the rat striatum and regulate tyrosine hydroxylation in a tonic, inhibitory fashion.