Ea. Johnson et al., SEROTONIN 5-HT(1A) RECEPTORS MEDIATE INHIBITION OF TYROSINE HYDROXYLATION IN RAT STRIATUM, The Journal of pharmacology and experimental therapeutics, 266(1), 1993, pp. 133-141
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.