Kynurenic acid in psychiatric disorders : studies on the mechanisms of action

Kynurenic acid, a metabolite of tryptophan along the kynurenine pathway, is an endogenous antagonist at NMDA- and α7* nicotinic acetylcholine- (α7*nACh) receptors. Previous studies have shown that elevated levels of endogenous kynurenic acid are associated with an increased firing of midbrain dopamine neurons as well as a reduced prepulse inhibition (PPI), a behavioral model for sensorimotor gating. Furthermore, kynurenic acid is elevated in the CSF and in the postmortem prefrontal cortex of patients with schizophrenia. The aim of this thesis was to investigate the mechanisms of action of kynurenic acid with regard to its action on midbrain dopamine firing and PPI; to analyze the interaction between the antipsychotic drug clozapine and kynurenic acid, and finally; to further study the involvement of kynurenic acid in psychiatric disorders.

The excitation of ventral tegmental area (VTA) dopamine neurons observed in rats with elevated levels of kynurenic acid were mimicked by pretreatment with 4-chlorokynurenine (4- Cl-KYN). Administration of SDZ 220-581 was also found to increase firing of VTA dopamine neurons. However, administration of methyllycaconitine (MLA) decreased firing of these neurons. These results demonstrate that the increased firing of VTA dopamine neurons following elevation of brain kynurenic acid is primarily mediated through glutamatergic rather than by cholinergic mechanisms.

Administration of SDZ 220–581 or CGS 19755 was associated with a robust reduction in PPI, whereas L-701,324, 4-Cl-KYN or MLA failed to alter PPI. Kynurenine increased brain kynurenic acid levels 5-fold and tended to decrease PPI. These results suggest that neither antagonism of the glycine site of the NMDA receptor nor antagonism of the α7*nACh receptor disrupts PPI. Rather, blockade of the glutamate recognition site is necessary to reduce PPI.

Clozapine increased firing of VTA dopamine neurons in control rats. Pretreatment with indomethacin was found to elevate brain kynurenic acid levels and to reverse the excitatory action of clozapine into an inhibitory response. In contrast, pretreatment with parecoxib decreased brain kynurenic acid formation and clearly potentiated the excitatory effect of clozapine. These results show that endogenous levels of brain kynurenic acid are of importance for the response of clozapine on VTA dopamine neurons and we propose that clozapine is able to interact as a partial agonist with the glycine site of the NMDA receptor.

CSF kynurenic acid and kynurenine was found to be elevated in patients with schizophrenia compared to controls. Violent male suicide attempters and male suicide attempters with a diagnosis of major depression had higher CSF kynurenic acid than controls. Furthermore, CSF levels of kynurenic acid correlated with CSF MIP-1β in all subjects, with CSF eotaxin-3 in controls and tended to correlate with IL-6 in all subjects.

An up-regulated kynurenine pathway may be a consequence of an activated immune system as studies have shown that immunological agents induce the first and rate-limiting enzymes in the production of kynurenic acid, thus indicating that kynurenic acid is a marker of immune-activation. Elevation of endogenous kynurenic acid may be a potential mechanism by which the immune system initiate psychiatric symptoms. This theory is supported by the close correlation between cytokines/chemokines and kynurenic acid in the CSF of suicide attempters observed in the present thesis. Altogether the present results suggest that kynurenic acid, with its unique receptor profile, may be the link between an activated immune system and the alterations in glutamatergic, cholinergic and dopaminergic neurotransmission proposed to occur in psychiatric disorders.

List of scientific papers

I. LINDERHOLM KR, Andersson A, Olsson S, Olsson E, Snodgrass R, Engberg G, Erhardt S (2006). "Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis" Neuropharmacology 53: 918-924
https://pubmed.ncbi.nlm.nih.gov/17959203

II. LINDERHOLM KR, Powell S, Olsson E, Holtze M, Snodgrass R, Erhardt S. (2010). "Role of the NMDA-receptor in prepulse inhibition in the rat." International Journal of Tryptophan Research 3: 1-12

III. Schwieler L, LINDERHOLM KR, Nilsson-Todd LK, Erhardt S, Engberg G. (2008). "Clozapine interacts with the glycine site of the NMDA receptor: Electrophysiological studies of dopamine neurons in the rat ventral tegmental area. " Life Sciences 83: 170-175
https://pubmed.ncbi.nlm.nih.gov/18590745

IV. LINDERHOLM KR, Skogh E, Olsson S, Dahl M-L, Holtze M, Samuelsson M, Lundberg KM, Erhardt S. (1970). "Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia." (Submitted)

V. LINDERHOLM KR, Lindqvist D, Janelidze S, Olsson SK, Jönsson EG, Hagell P, Samuelsson M, Träskman-Bendz L, Erhardt S, Brundin L. (1970). "Kynurenic Acid in the CSF of Male Suicide Attempters Increased Levels in Patients with Major Depression and Correlation to Inflammatory Parameters." (Manuscript)