Indolic and Kynurenine Pathway Metabolites of Tryptophan in Rat Brain: Effect of Precursor Availability on in Vivo Release

Abstract

Changes in tryptophan metabolism which influence central nervous system function are generally considered to be mediated through changes in serotonin (5HT) neurotransmission. It has been known for nearly 30 years that tryptophan loading or other interventions which increase brain tryptophan availability increase brain tissue levels of 5HT (Green et al., 1962; Wang et al., 1962) and that such an increase appears secondary to increased synthesis by increasing substrate availability as tryptophan hydroxylase is unsaturated in vivo (Carlsson and Lindquist, 1978). Over the last decade, there has been increasing interest in another route of tryptophan metabolism — the kynur-enine pathway. Several indoleamine-2, 3 dioxygenase metabolites are neuro-active and have been implicated in the pathogenesis of a number of neurological disorders. The kynurenine pathway metabolites which are perhaps of most interest are the excitatory amino acid (EAA) receptor ligands, quinolinic acid (QUIN) and kynurenic acid (KYNA). QUIN is an agonist at the N-methyl-D-aspartate (NMDA) receptor (Stone and Perkins, 1981) and a potent neurotoxin (Schwarcz et al., 1983). The enzymes leading to its synthesis from tryptophan have all been identified in the mammalian brain, and it is therefore likely it is formed de novo in the brain. However, the presence of QUIN in brain was not determined until sensitive gas chromatography/mass spectrometry (GCMS) assays were developed (Wolfensberger et al., 1983; Heyes and Markey, 1988). KYNA is a broad spectrum glutamate receptor antagonist and protects against QUIN (and other excitotoxin)-induced neurotoxicity. KYNA has also recently been shown to exist within the brain (Moroni et al., 1988). Both QUIN and KYNA tissue levels are increased following tryptophan loading, how-ever such a change in tissue levels does not necessarily reflect a change in their concentrations in the active compartment, the extracellular fluid (ECF). Within the ECF, QUIN and KYNA have access to EAA receptors and may therefore modulate glutamate (and aspartate) neurotransmission. We were therefore interested in determining whether QUIN and KYNA existed within the ECF and whether their concentrations would be influenced by alterations in precursor availability.