Metabolism of [5‐3H]Kynurenine in the Rat Brain In Vivo: Evidence for the Existence of a Functional Kynurenine Pathway

: The incorporation of tritium label into quinolinic acid (QUIN), kynurenic acid (KYNA), and other kynurenine (KYN) pathway metabolites was studied in normal and QUIN‐lesioned rat striata after a focal injection of [5‐3H]KYN in vivo. The time course of metabolite accumulation was examined 15 min to 4 h after injection of [5‐3H]KYN, and the concentration dependence of KYN metabolism was studied in rats killed 2 h after injection of 1.5–1,500 µM [5‐3H]KYN. Labeled QUIN, KYNA, 3‐hydroxykynurenine (3‐HK), 3‐hydroxyanthranilic acid, and xanthurenic acid (XA) were recovered from the striatum in every experiment. Following injection of 15 µM [5‐3H]KYN, a lesion‐induced increase in KYN metabolism was noted. Thus, the proportional recoveries of [3H]KYNA (5.0 vs. 1.8%), [3H]3‐HK (20.9 vs. 4.5%), [3H]XA (1.5 vs. 0.4%), and [3H]QUIN (3.6 vs. 0.6%) were markedly elevated in the lesioned striatum. Increases in KYN metabolism in lesioned tissue were evident at all time points and KYN concentrations used. Lesion‐induced increases of the activities of kynurenine‐3‐hydroxylase (3.6‐fold), kynureninase (7.6‐fold), kynurenine aminotransferase (1.8‐fold), and 3‐hydroxyanthranilic acid oxygenase (4.2‐fold) likely contributed to the enhanced flux through the pathway in the lesioned striatum. These data provide evidence for the existence of a functional KYN pathway in the normal rat brain and for a substantial increase in flux after neuronal ablation. This method should be of value for in vivo studies of cerebral KYN pathway function and dysfunction.