Effect of kynurenine loading on quinolinic acid production in the rat: studies in vitro and in vivo.

In vitro and in vivo techniques were used to examine the production and subsequent fate of the endogenous excitotoxin quinolinic acid (QUIN) following administration of its bioprecursor L-kynurenine (KYN). Incubation of liver slices in the presence of 10-1000 microM KYN resulted in a dose- and time-dependent release of QUIN into the incubation medium. Less than 15% of total QUIN produced was recovered from the tissue. In vivo experiments, performed with a microdialysis probe inserted in the jugular vein of anesthetized rats, showed that injection of KYN (20-600 mg/kg, i.v.) causes rapid and dose-dependent increases in the serum level of QUIN. Peak QUIN concentrations in serum dialysates were reached 75 minutes following KYN administration. Longer lasting increases were detected following the administration of pyrazinamide (20 mg/kg, i.p.), an indirectly acting stimulator of QUIN biosynthesis in the periphery. The data demonstrate the feasibility of assessing the mechanisms of QUIN production and disposition in experimental paradigms which can be expected to allow insights into the function and possible dysfunction of QUIN in the brain.