Samina Bano

Mechanism of enhancement of rat brain serotonin synthesis by acute fluoxetine administration

Tsuiki et a!. (1995) reported in this Journal that nacute intraperitoneal administration of a 30 mg/kg of nbody weight dose of the specific serotonin [5-hydroxytryptamine n(5-HT)11 reuptake inhibitory (SSRI) antidepressant nfluoxetine enhances rat brain 5-HT synthesis, nas measured by the a-methyl-L-tryptophan autoradiographic nmethod, and suggested that this is in part ndue to an increase in tryptophan (Trp) availability to nthe brain. This process is determined by at least three nperipheral factors: binding to albumin, competition between nTrp and five other amino acids (valine, leucine, nisoleucine, phenylalanine, and tyrosine) for the same ncerebral uptake mechanism, and activity of the major nTrp-degrading enzyme, hepatic Trp pyrrolase (tryptophan n2,3-dioxygenase; EC 1.13.11.11) (for references, nsee Badawy and Morgan, 1991). Tsuiki et al. (1995) nshowed that fluoxetine does not influence the concentrations nof the Trp competitors, but increases that of nTrp itself (by 18% for the total content and 30% for nthe free fraction). Whether Trp binding to albumin nwas significantly altered by fluoxetine could not be nascertained from the data given.

Tryptophan Metabolism in Rat Liver After Administration of Tryptophan, Kynurenine Metabolites, and Kynureninase Inhibitors

Rat liver tryptophan (Trp), kynurenine pathway metabolites, and enzymes deduced from product/substrate ratios were assessed following acute and/or chronic administration of kynurenic acid (KA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), Trp, and the kynureninase inhibitors benserazide (BSZ) and carbidopa (CBD). KA activated Trp 2,3-dioxygenase (TDO), possibly by increasing liver 3-HAA, but inhibited kynurenine aminotransferase (KAT) and kynureninase activities with 3-HK as substrate. 3-HK inhibited kynureninase activity from 3-HK. 3-HAA stimulated TDO, but inhibited kynureninase activity from K and 3-HK. Trp (50 mg/kg) increased kynurenine metabolite concentrations and KAT from K, and exerted a temporary stimulation of TDO. The kynureninase inhibitors BSZ and CBD also inhibited KAT, but stimulated TDO. BSZ abolished or strongly inhibited the Trp-induced increases in liver Trp and kynurenine metabolites. The potential effects of these changes in conditions of immune activation, schizophrenia, and other disease states are discussed.