Endogenous kynurenic acid and schizophrenia : Physiological and pharmacological aspects

Kynurenic acid is a glutamate receptor antagonist with a preferential action at the glycine/D-serine site of the N-methyl-D-aspartic acid (NMDA) receptor. The compound is a metabolite of tryptophan and is synthesized in astrocytes. Previous studies have shown increased levels of kynurenic acid in the CSF and post mortem in the prefrontal cortex of patients with schizophrenia. The aim of the present thesis was to further investigate in the rat the physiological significance of kynurenic acid as well as its importance for the pathophysiology of schizophrenia. Studies include a disclosure of a prostaglandin-mediated regulation of kynurenic acid synthesis and analysis of the role of the compound in the regulation of firing activity of dopamine neurons in ventral tegmental area (VTA). Furthermore, an interaction of the antipsychotic drug clozapine with endogenous kynurenic acid is analyzed and the significance of kynurenic acid for behavior is studied using prepulse inhibition (PPI) methodology. Systemic administration of diclofenac and indomethacin, inhibitors with a preferential selectivity for cyclooxygenase (COX)-1, was associated with an increased formation of kynurenic acid in brain, whereas meloxicam and parecoxib, selective COX-2 inhibitors, decreased brain kynurenic acid formation. Both the elevation and the lowering in brain kynurenic acid levels following administration of the COX inhibitors were effectively prevented by the prostaglandin E1/E2 analog misoprostol. Pharmacological manipulation of kynurenic acid synthesis with COX inhibitors thus enabled us to study a role of the compound in the control of firing of midbrain dopamine neurons. An increase in brain kynurenic acid concentration (by 150-300%), induced by indomethacin, increased firing rate and burst firing activity of VTA dopamine neurons whereas a reduction in brain kynurenic acid concentration (by 39-44%) elicited by parecoxib, was associated with a clear-cut reduction in firing activity of these neurons. Thus, endogenous brain concentrations of kynurenic acid appear to be of critical physiological importance for maintaining neuronal activity of VTA dopamine neurons. In the next series of experiments we investigated the effects of clozapine and haloperidol on VTA dopamine neurons in rats with attenuated NMDA receptor function induced by increased levels of endogenous brain kynurenic acid. Here, clozapine, in contrast to haloperidol, was found to interact with the NMDA receptor complex. We propose a novel mechanism of action of the atypical antipsychotic drug clozapine, i.e. stimulation of the glycine/D-serine site of the NMDA receptor. Elevated levels of endogenous kynurenic acid induced by systemic administration of kynurenine or PNU 156561A were associated with a disruption in PPI, an effect that could be reversed by antipsychotic drugs. It is proposed that kynurenic acid acts as an endogenous modulator of the PPI response. Taken together, the results of the present thesis suggest that endogenous kynurenic acid in the brain is involved in the physiological regulation of glutamate neurotransmission. Hereby, this endogenous NMDA receptor antagonist may participate in the pathophysiology of schizophrenia. LIST OF PUBLICATIONS I. Schwieler L, Erhardt S, Erhardt C, Engberg G (2005). Prostaglandin-mediated control of rat brain kynurenic acid synthesis – opposite action by COX-1 and COX-2 isoforms. Journal of Neural Transmission 112;863-872. II. Schwieler L, Erhardt S, Nilsson L, Linderholm K, Engberg G (2006). Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons -possible involvement of endogenous kynurenic acid. Synapse 5;290-298. III. Schwieler L, Erhardt S. (2003). Inhibitory action of clozapine on rat ventral tegmental area dopamine neurons following increased levels of endogenous kynurenic acid. Neuropsychopharmacology 28;1770-1777. IV. Schwieler L, Engberg G, Erhardt S (2004) Clozapine modulates midbrain dopamine neuron firing via interaction with the NMDA receptor complex. Synapse 52;114-122. V. Erhardt S, Schwieler L, Emanuelsson C, Geyer M (2004). Endogenous kynurenic acid disrupts prepulse inhibition. Biological Psychiatry 56;255-260.