METABOLISM OF [5-H-3]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), kynure nic acid (KYNA), and other kynurenine (KYN) pathway metabolites was st udied in normal and QUIN-lesioned rat striata after a focal injection of [5-H-3]KYN in vivo. The time course of metabolite accumulation was examined 15 min to 4 h after injection of [5-H-3]KYN, and the concentr ation dependence of KYN metabolism was studied in rats killed 2 h afte r injection of 1.5-1,500 mu M [5-H-3]KYN. Labeled QUIN, KYNA, 3-hydrox ykynurenine (3-HK), 9-hydroxyanthranilic acid, and xanthurenic acid (X A) were recovered from the striatum in every experiment, Following inj ection of 15 mu M [5-H-3]KYN, a lesion-induced increase in KYN metabol ism was noted. Thus, the proportional recoveries of [H-3]KYNA (5.0 vs. 1.8%), [H-3]3-HK (20.9 vs, 4.5%), [H-3]XA (1.5 vs. 0.4%), and [H-3]QU IN (3.6 vs. 0.6%) were markedly elevated in the lesioned striatum. Inc reases in KYN metabolism in lesioned tissue were evident at all time p oints and KYN concentrations used. Lesion-induced increases of the act ivities of kynurenine-3-hydroxylase (3.6-fold), kynureninase (7.6-fold ), kynurenine aminotransferase (1.8-fold), and 3-hydroxyanthranilic ac id oxygenase (4.2-fold) likely contributed to the enhanced flux throug h the pathway in the lesioned striatum. These data provide evidence fo r the existence of a functional KYN pathway in the normal rat brain an d for a substantial increase in flux after neuronal ablation. This met hod should be of value for in vivo studies of cerebral KYN pathway fun ction and dysfunction.