Some metabotropic glutamate receptor ligands reduce kynurenate synthesis in rats by intracellular inhibition of kynurenine aminotransferase II

Some metabotropic glutamate receptor (mGluR) ligands, such as quisqualate, L-(+)-2-amino-4-phosphonobutyric acid (L-AP4), 4-carboxy-3-hydroxyphenylgly cine (4C3HPG), and L-serine-O-phosphate (L-SOP), reduced the formation of t he endogenous excitatory amino acid receptor antagonist kynurenate in brain and liver slices. The use of novel, subtype-selective mGluR agonists and a ntagonists excluded a role for any known mGluR subtype in this effect. The reduction of kynurenate formation was no longer observed when slices were i ncubated with the active mGluR ligands in the absence of extracellular Na+. trans-Pyrrolidine-2,4-dicarboxylate (trans-PDC), a broad-spectrum ligand o f Na+-dependent glutamate transporters, was also able to reduce kynurenate formation. Quisqualate, 4C3HPG, L-AP4, and L-SOP did not further reduce kyn urenate formation in the presence of trans-PDC, suggesting that the two cla sses of drugs may share the same mechanism of action. Hence, we hypothesize d that the active mGluR ligands are transported inside the cell and act int racellularly to reduce kynurenate synthesis. We examined this possibility b y assessing the direct effect of mGluR ligands on the activity of kynurenin e aminotransferases (KATs) I and II, the enzymes that transaminate kynureni ne to kynurenate. In brain tissue homogenates, KAT II (but not KAT I) activ ity was inhibited by quisqualate, 4C3HPG, L-AP4, L-SOP, and trans-PDC. Drug s that were unable to reduce kynurenate formation in tissue slices were ina ctive. We conclude that some mGluR ligands act intracellularly, inhibiting KAT II activity and therefore reducing kynurenate formation. This effect sh ould be taken into consideration when novel mGluR ligands are developed for the treatment of neurological and psychiatric diseases.