title: The role of the intracellular and extracellular serotonin in the regulation of melatonin production in rat pinealocytes.
abstract: This study investigated whether the activation of pinealocyte beta-adrenergic receptors is involved in the regulation of serotonin (5-HT) synthesis and release, as it is for melatonin production. In addition, the role of the intra- and extra-cellular 5-HT in modulating the synthesis of melatonin induced by the beta-adrenergic agonist isoproterenol (ISO) was also studied. The incubation of dissociated pinealocytes with 0.1-10 microM ISO resulted in a concentration-dependent increase of melatonin synthesis. 5-HT release and intracellular 5-HT content were increased by 0.1 and 1 microM ISO but they were reduced after ISO 10 microM. Moreover, when incubated with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA), the secretion of 5-HT as well as the intracellular 5-HT levels were markedly reduced in both ISO-stimulated and unstimulated conditions. Melatonin release was also inhibited by PCPA, although it responded in the expected manner to increasing concentrations of ISO. These data indicate that the release of 5-HT from pinealocytes depends on the availability of cytoplasmic 5-HT, which in turn is highly dependent on the tryptophan hydroxylase activity. In cells stimulated with moderate ISO concentrations, 5-HT release may be an important regulatory process of pineal 5-HT. After a large stimulation of N-acetyltransferase (NAT) activity by ISO, the synthesis of melatonin prevails on 5-HT release, whose decrease is associated to a deficit of intracellular 5-HT. On the other hand, the present study shows that the incubation of pineal cells with high concentrations of 5-HT or with a selective 5-HT2 receptor agonist, alpha-methyl-5-hydroxytryptamine, reverses partially the inhibitory effect of PCPA on the ISO-stimulated melatonin synthesis. In contrast the 5-HT2 antagonist, ketanserin, results in an inhibiton of the release of melatonin following ISO stimulation. These results suggest that released 5-HT may have a role in the full expression of the beta-adrenergically induced NAT activity and, thus, may contribute to the optimal melatonin synthesis at night.
authors.affiliation: Neurobiologie des Fonctions Rythmiques et Saisonnières, CNRS-URA 1332, Université Louis Pasteur, Strasbourg, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Miguez
authors.forename: V
authors.initials: V
authors.lastname: Simonneaux
authors.forename: P
authors.initials: P
authors.lastname: Pevet
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D010134:Fenclonine / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008550:Melatonin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010870:Pineal Gland / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D018490:Serotonin Agents / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D012701:Serotonin; D007650:Ketanserin; D001191:Arylamine N-Acetyltransferase; D008550:Melatonin; D007545:Isoproterenol; D010134:Fenclonine