Inhibition of tyrosine hydroxylase activity by serotonin in explants of newborn rat locus ceruleus.

The long-term regulation of tyrosine hydroxylase (TH) by serotonin has been studied with cultures of newborn rat locus ceruleus explants. The presence of serotonin in the culture medium for a 24-h period was followed by an inhibition of TH activity in the explants. This effect lasted several days, with a maximal effect 2 days after treatment. Moreover, the decrease was reversible and dependent on the concentration of serotonin used (from 1 microM to 1 mM). The mechanisms of this regulation have been studied using drugs such as those known to act specifically on serotoninergic receptors and those known to interfere with protein synthesis. Thus, the action of serotonin (10(-5) M) on TH activity was suppressed with equimolar concentrations of serotoninergic antagonists such as metergoline or methiothepin. It was reproduced by quipazine, a drug capable of acting as a serotoninergic agonist. Inhibitors of protein synthesis acting either at the transcriptional or the translational levels can reproduce the inhibition of TH activity by serotonin alone. Furthermore, the effects of one or the other of these compounds and that of serotonin were not additive. This study confirms the hypothesis of an inhibitory control by serotonin on TH activity in the noradrenergic neurons of the locus ceruleus. Serotonin could regulate the synthesis of the enzyme through specific serotoninergic receptors.