Reduction of Serotonergic Function in Rat Brain by Tryptophan Depletion: Effects in Control and Fluvoxamine-Treated Rats

Abstract: The administration of tryptophan (Trp)-free amino acid mixtures to depressed patients responding to serotonin 5-hydroxytryptamine (5-HT)] uptake inhibitors (SSRIs) worsens their clinical state. This procedure reduces Trp availability to brain and thus impairs 5-HT synthesis. We have examined the influence of Trp depletion on extracellular 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the rat brain using in vivo microdialysis. The treatment with the SSRI fluvoxamine significantly increased 5-HT content in dialysates from frontal cortex, as compared with control rats (10.2 ± 2.7 vs. 3.1 ± 0.4 fmol per fraction), whereas 5-HIAA was unaffected. Food deprivation for 20 h reduced dialysate 5-HT content to almost control values in fluvoxamine-treated rats (10.2 ± 2.7 vs. 4.3 ± 0.6 fmol per fraction) but did not alter dialysate 5-HIAA content (7.8 ± 0.4 vs. 7.2 ± 0.5 pmol per fraction). The administration of Trp-free amino acid mixtures to fluvoxamine-treated rats significantly attenuated the release of 5-HT in frontal cortex (～50%) and, to a lesser extent, in the midbrain raphe nuclei. This effect was more marked in rats not deprived from food before the experiments (67% reduction of dialysate 5-HT content in frontal cortex) and was absent in control rats (treated with saline). In contrast, dialysate 5-HIAA was markedly affected by Trp depletion in all groups, including controls (65–75% reductions). These data show that the administration of an amino acid mixture with the same composition and dose (in milligrams per kilogram of body weight) as those inducing a severe mood impairment in depressed patients reduces 5-HT and 5-HIAA concentrations in brain dialysates. The reduction of 5-HT release, however, occurs only in animals previously treated with the antidepressant fluvoxamine for 2 weeks, which would be consistent with a marked reduction of 5-HT-mediated transmission in treated depressed patients but not in healthy controls.