Glutamatergic mechanisms in schizophrenia : role of endogenous kynurenic acid

Kynurenic acid, a tryptohan metabolite synthesised in astrocytes, is an endogenous antagonist at glutamate receptors, in particular it blocks the glycine site of the (NMDA)-receptor, and at the a7* nicotinic receptor. The compound has been found to be elevated in the cerebrospinal fluid (CSF) as well as in the postmortem prefrontal cortex of patients with schizophrenia. Experimental data have shown that acute elevation of brain kynurenic acid is associated with an increased neuronal activity of ventral tegmental area (VTA) dopamine neurons as well as disrupted prepulse inhibition (PPI). The aim of the present thesis was to study the involvement of endogenous kynurenic acid in the pathophysiology of schizophrenia. Thus, the impact of subchronically elevated levels of kynurenic acid on PPI and on the spontaneous firing of VTA dopamine neurons was investigated. Furthermore, a putative interaction between endogenous kynurenic acid and the antipsychotic drugs clozapine and haloperidol on noradrenergic locus coeruleus (LC) neurons was analysed. Finally, kynurenic acid concentration in CSF from healthy controls and male patients with schizophrenia was analysed and CSF kynurenic acid concentration was correlated to the CSF concentrations of monoamine metabolites.

To subchronically elevate endogenous brain kynurenic acid, rats were exposed to kynurenine (the precursor of kynurenic acid; 20 mg/kg/day) and probenecid (a compound that prevents the efflux of kynurenic acid from the brain; 10 mg/kg/day) via subcutaneously implanted osmotic pumps, for 14 days. This treatment increased neuronal firing of VTA dopamine neurons, changed the response of these neurons to systemically administered nicotine (3-400 µg/kg, i.v.) and tended to disrupt PPI.

Clozapine (1.25-10 mg/kg, i.v.) and haloperidol (0.05-0. 8 mg/kg, i.v.) was found to increase the firing rate of LC noradrenergic neurons in control rats. A 2-fold increase in rat brain kynurenic acid levels, by pretreatment with the kynurenine 3-hydroxylase inhibitor PNU 156561A (40 mg/kg, i.v., 3 h), prevented the increase in firing rate of LC noradrenaline neurons induced by haloperidol and clozapine in high doses (2.5-10 mg/kg, i.v.). However, the excitatory action of the lowest dose of clozapine (1.25 mg/kg, i.v.) was not affected by elevated levels of brain kynurenic acid. Furthermore, pretreatment with L-701,324 (4 mg/kg, i.v.) a selective antagonist at the glycine site of the NMDA receptor, prevented the excitatory effects of both clozapine and haloperidol. Our results suggest that the excitation of LC noradrenaline neurons by haloperidol and clozapine involves a glutamatergic component.

Analysis of CSF confirmed that kynurenic acid concentration is elevated in male patients with schizophrenia. Positive correlations were found between kynurenic acid concentration and concentrations of the monoamine metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), which suggest that increased kynurenic acid formation is associated with an increased dopamine and serotonin turnover.

The results of the present thesis suggest that endogenous kynurenic acid acts a biologically important modulator of glutamatergic neurotransmission within the brain, and lend further support to the hypothesis that endogenous kynurenic acid participates in the pathophysiology of schizophrenia.

List of scientific papers

I. Nilsson LK, Schwieler L, Engberg G, Linderholm KR, Erhardt S (2005). "Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms. " Int J Neuropsychopharmacol 8(3): 329-39.
https://doi.org/10.1017/S1461145705005080

II. Nilsson LK, Linderholm KR, Erhardt S (2005). "Subchronic treatment with kynurenine and probenecid: effects on prepulse inhibition and firing of midbrain dopamine neurons." J Neural Transm Aug 5: Epub ahead of print.
https://doi.org/10.1007/s00702-005-0343-z

III. Nilsson LK, Linderholm KR, Engberg G, Paulson L, Blennow K, Lindstrom LH, Nordin C, Karanti A, Persson P, Erhardt S (2005). "Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. " Schizophr Res Aug 24: Epub ahead of print.
https://doi.org/10.1016/j.schres.2005.07.013

IV. Nilsson LK, Nordin C, Jonsson EG, Engberg G, Linderholm KR, Erhardt S (2005). "Cerebrospinal fluid kynurenic acid in male and female healthy controls - correlation with monomine metabolites and influence of confounding factors." [Submitted]

V. Nilsson LK, Nordin C, Jonsson EG, Skogh E, Erhardt S (2005). "Cerebrospinal fluid kynurenic acid in male patients with schizophrenia - correlation with monomine metabolites." [Submitted]