Tryptophan Availability Modulates Serotonin Release from Rat Hypothalamic Slices

Abstract

Application of a novel in vitro experimental system has allowed us to describe the relationship between tryptophan availability and serotonin release from rat hypothalamic slices. Superfusing hypothalamic slices with a physiologic medium containing /-tryptophan ( 1, 2, 5 , or 10 p M ) caused dose-dependent elevations in tissue tryptophan levels; the magnitude of the elevations produced by supplementing the medium with <5 pM tryptophan was within the physiologic range for rat brain tryptophan levels. Slice serotonin levels rose biphasically as the tryptophan concentration in the medium was increased. Superfusing the slices with medium supplemented with a low tryptophan concentration (1 or 2 p M ) caused proportionally greater incremental changes in serotonin levels than the increases caused by further elevating the tryptophan concentration ( 5 or 10 p M ) . The spontaneous release of serotonin from the slices exhibited a dose-dependent relationship with the tryptophan concentration of the superfusion medium, Electrically evoked serotonin release, which was calcium-dependent and tetrodotoxin-sensitive, also increased in proportion to the medium tryptophan concentration. These data suggest that the rate at which serotonin is released from hypothalamic nerve terminals is coupled to brain tryptophan levels. Accelerations in hypothalamic serotonin synthesis, caused by elevating brain tryptophan levels, result in proportionate increases in the rates of serotonin release during rest and with membrane depolarization. Key Words: Serotonin release-Tryptophan availability-Hypothalamus-Superfused brain slices. Schaechter J. D. and Wurtman R. J. Tryptophan availability modulates serotonin release from rat hypothalamic slices. J. Neurochem. 53, 1925-1933 (1989).The rate at which the brain synthesizes serotonin (5-HT) in vivo varies with its tryptophan concentration (Eccleston et al., 1965; Weber and Horita, 1965;Moir and Eccleston, 1968). This relationship exists because the rate-limiting enzyme in 5-HT biosynthesis, tryptophan hydroxylase, is unsaturated with tryptophan. The concentration of tryptophan normally present in the brain (approximately 10-40 p M ) (Curzon, 1986) is less than the estimated K,,, of tryptophan hydroxylase for its amino acid substrate (50 p M ) (Friedman et al., 1972), and thus much less than that needed for full saturation of the enzyme. Hence, treatments which raise brain tryptophan levels within their physiologic range (e.g

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Augmentatie van antidepressiva: mogelijkheden voor verbeterde werkzaamheid?

“…Uit zowel dierexperimenteel als klinisch onderzoek blijkt dat voldoende tryptofaan, de bouwsteen voor serotonine, noodzakelijk is voor de biochemische (Schaechter & Wurtman, 1989;Westerink & Devries, 1991) en therapeutische respons van SSRI's. Als er onvoldoende tryptofaan beschikbaar is zal de door SSRI's geı¨nduceerde serotoninestijging sterk verminderen (ongepubliceerde eigen resultaten) en het therapeutisch effect uitblijven (Delgado et al, 1990) (voor een review zie Bell et al, 2001;Reilly et al, 1997).…”

Alteration of 5-Hiaa Levels in Frontal Cortex and Dorsal Raphe Nucleus in Rats Treated With Combined Administration of Tryptophan and Ethanol

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