title: Effect of (+/-)-methyl 3-ethyl-2,3,3a,4-tetrahydro-1H-indolo-[3,2,1-de] [1,5] naphthyridine-6-carboxylate hydrochloride (OM-853), a new vincamine analogue, on the metabolism and function of cerebral serotonergic neurons.
abstract: Effect of (+/-)-methyl 3-ethyl-2,3,3a,4-tetrahydro-1H-indolo[3,2,1-de] [1,5] naphthyridine-6-carboxylate hydrochloride (OM-853), a new vincamine analogue, on the metabolism and function of cerebral 5-hydroxytryptamine (5-HT) neurons was investigated using male Wistar rats. The single administration of OM-853 (200 mg/kg, p.o.) induced the facilitation of metabolic turnover of 5-HT in various brain areas except the cerebral cortex, pons-medulla and cerebellum. In vitro addition of OM-853 inhibited the uptake of [14C]5-HT in striatal slices only at a high concentration (10(-4) M). On the other hand, a low concentration of OM-853 (10(-8)-10(-6) M) induced the increase of the spontaneous and high K+ (30 mM)-evoked releases of [14C]5-HT from striatal slices. OM-853 had more potent inhibitory effect on the binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin (8-hydroxy DPAT) to 5-HT1A receptors and/or 5-HT autoreceptors than that of [3H]-ketanserin to 5-HT2 receptors. The stimulatory effect of OM-853 (10(-7) M) on [14C]5-HT release was antagonized by 10(-7) M 8-hydroxy DPAT, which is known to act at presynaptic 5-HT autoreceptors as an agonist. These results suggest that OM-853 may induce facilitation of 5-HT turnover by enhancing 5-HT release, probably via the inhibition of presynaptic 5-HT autoreceptor.
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Koda
authors.forename: T
authors.initials: T
authors.lastname: Hashimoto
authors.forename: M
authors.initials: M
authors.lastname: Katsura
authors.forename: K
authors.initials: K
authors.lastname: Kuriyama
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014748:Vinca Alkaloids / Q000494:pharmacology*; D014749:Vincamine / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D013764:Tetrahydronaphthalenes; D014748:Vinca Alkaloids; D012701:Serotonin; D011189:Potassium Chloride; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C038627:vinconate; D007650:Ketanserin; D014749:Vincamine