Effect of L-tryptophan, L-5-hydroxytryptophan and L-tryptophan prodrugs on the extracellular levels of 5-HT and 5-HIAA in the hippocampus of the rat using microdialysis

The effect of the natural precursors and synthetic prodrugs of serotonin (5-HT) on the extracellular levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in vivo in the hippocampus of the freely moving rat using microdialysis. Under physiological conditions, brain tryptophan hydroxylase, the rate-limiting enzyme in 5-HT synthesis, is not fully saturated. Therefore, the physiological precursors, L-tryptophan (L-Trp) and L-5-hydroxytryptophan (L-5-HTP), and some synthetic prodrugs of L-Trp were administered in three different ways. Intraperitoneal injection, oral administration by means of a gastric cannula and intrahippocampal application through the microdialysis probe were used. L-Trp, administered i.p. and in situ in the hippocampus (50 mg/kg i.p. and 5 mu M, 60 min) and L-5-HTP (25 mg/kg p.o., 25 mg/kg i.p. and 5 mu M, 60 min) induced a significant increase of 5-HT and/or 5-HIAA, suggesting that the release/synthesis of 5-HT was increased. As administration of these precursors was clinically not always satisfying in human, because of their side-effects, some synthetic prodrugs of L-Trp were prepared. A significant increase of 5-HIAA was induced by [1,3-dipalmitoylamino-(2-L-tryptophanyloxy)propane] (185 mg/kg p.o.). However, the other orally administered L-Trp prodrugs (L-alpha-(n-pentylamino)-3-indolpropionic acid (70 mg/kg p.o.) and L-alpha-(D-gluco-2,3,4,5,6-pentahydroxyhexylamino)-3-indolpropionic acid (90 mg/kg p.o.)) had no effect on 5-HT nor on 5-HIAA. These results indicate that only the intracerebral application of natural 5-HT precursors leads to an increase in 5-HT release in the hippocampus.