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Kynurenic Acid And Schizophrenia

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Developments in Tryptophan and Serotonin Metabolism

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 527))

Abstract

In recent years the “dopamine (DA) hypothesis of schizophrenia”, has been modified into a more diversified view where an attenuated glutamatergic neurotransmission is believed to participate in the pathogenesis of the disease. Thus, schizophrenia may be regarded as a glutamate deficiency disorder. Kynurenic acid (KYNA) is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl D-aspartate (NMDA) -receptor. Mounting evidence indicates that the compound is significantly involved in basal neurophysiological processes in the brain. Thus, in anaesthetized rats, pharmacologically elevated KYNA concentration (by means of PNU 156561A) was associated with increased firing rate and burst firing activity of midbrain DA neurons. Similar alterations in basal firing characteristics are also observed following systemic administration of PCP or ketamine, indicating per se that elevated levels of brain KYNA is associated with psychotomimetic effects. Indeed, cerebrospinal fluid (CSF) level of kynurenic acid was elevated in 28 male first episode schizophrenic patients (1.67 ¡À0.27 nM) as compared to 17 male healthy controls (0.97 ¡À0.07 nM. Elevated brain KYNA concentration was also found to dramatically affect the responsivity of rat midbrain DA neurons to the atypical antipsychotic drug clozapine. Thus, whereas clozapine produced increased firing rate and burst firing activity of these neurons in untreated rats, elevation of brain KYNA levels was found to reverse the action of clozapine into a pure inhibitory response. The present study suggests a contribution of KYNA in the pathogenesis of schizophrenia and link the dopamine hypothesis of schizophrenia together with the idea of a deficiency of glutamate function in this disease.

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Author information

Authors and Affiliations

  1. Sophie Erhardt, Dept. of Physiology and Pharmacology, Karolinska Institutet, SE 171 77, Stockholm, Sweden

    Sophie Erhardt, Lilly Schwieler & Göran Engberg

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  1. Sophie Erhardt
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  2. Lilly Schwieler
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Editors and Affiliations

  1. University of Padova, Padova, Italy

    Graziella Allegri , Carlo V. L. Costa  & Eugenio Ragazzi ,  & 

  2. University of Hamburg, Hamburg, Germany

    Hans Steinhart

  3. Istituto G. Gaslini, Genova Quarto, Italy

    Luigi Varesio

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Erhardt, S., Schwieler, L., Engberg, G. (2003). Kynurenic Acid And Schizophrenia. In: Allegri, G., Costa, C.V.L., Ragazzi, E., Steinhart, H., Varesio, L. (eds) Developments in Tryptophan and Serotonin Metabolism. Advances in Experimental Medicine and Biology, vol 527. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0135-0_18

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  • DOI: https://doi.org/10.1007/978-1-4615-0135-0_18

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-4939-6

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