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-HT
1A receptors and/or 5-HT autoreceptors than that of [
3H]-ketanserin to 5-HT
2 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.
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