Skip to main content

Advertisement

SpringerLink
Log in

The Astrocyte-Derived α7 Nicotinic Receptor Antagonist Kynurenic Acid Controls Extracellular Glutamate Levels in the Prefrontal Cortex

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

The cognitive deficits seen in schizophrenia patients are likely related to abnormal glutamatergic and cholinergic neurotransmission in the prefrontal cortex. We hypothesized that these impairments may be secondary to increased levels of the astrocyte-derived metabolite kynurenic acid (KYNA), which inhibits α7 nicotinic acetylcholine receptors (α7AChR) and may thereby reduce glutamate release. Using in vivo microdialysis in unanesthetized rats, we show here that nanomolar concentrations of KYNA, infused directly or produced in situ from its bioprecursor kynurenine, significantly decrease extracellular glutamate levels in the prefrontal cortex. This effect was prevented by the systemic administration of galantamine (3 mg/kg) but not by donepezil (2 mg/kg), indicating that KYNA blocks the allosteric potentiating site of the α7AChR, which recognizes galantamine but not donepezil as an agonist. In separate rats, reduction of prefrontal KYNA formation by (S)-4-ethylsulfonyl benzoylalanine, a specific inhibitor of KYNA synthesis, caused a significant elevation in extracellular glutamate levels. Jointly, our results demonstrate that fluctuations in endogenous KYNA formation bidirectionally influence cortical glutamate concentrations. These findings suggest that selective attenuation of cerebral KYNA production, by increasing glutamatergic tone, might improve cognitive function in individuals with schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Albuquerque, E. X., Pereira, E. F., Alkondon, M., & Rogers, S. W. (2009). Mammalian nicotinic acetylcholine receptors: From structure to function. Physiological Reviews, 89, 73–120.

    Article  CAS  PubMed  Google Scholar 

  • Alkondon, M., Pereira, E. F., Eisenberg, H. M., & Albuquerque, E. X. (2000). Nicotinic receptor activation in human cerebral cortical interneurons: A mechanism for inhibition and disinhibition of neuronal networks. Journal of Neuroscience, 20, 66–75.

    CAS  PubMed  Google Scholar 

  • Amori, L., Wu, H.-Q., Marinozzi, M., Pellicciari, R., Guidetti, P., & Schwarcz, R. (2009). Specific inhibition of kynurenate synthesis enhances extracellular dopamine levels in the rodent striatum. Neuroscience, 159, 196–203.

    Article  CAS  PubMed  Google Scholar 

  • Biton, B., Bergis, O. E., Galli, F., et al. (2007). SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile. Neuropsychopharmacology, 32, 1–16.

    Article  CAS  PubMed  Google Scholar 

  • Buchanan, R. W., Conley, R. R., Dickinson, D., et al. (2008). Galantamine for the treatment of cognitive impairments in people with schizophrenia. American Journal of Psychiatry, 165, 82–89.

    Article  PubMed  Google Scholar 

  • Buchanan, R. W., Freedman, R., Javitt, D. C., Abi-Dargham, A., & Lieberman, J. A. (2007). Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia. Schizophrenia Bulletin, 33, 1120–1130.

    Article  PubMed  Google Scholar 

  • Carpenedo, R., Pittaluga, A., Cozzi, A., et al. (2001). Presynaptic kynurenate-sensitive receptors inhibit glutamate release. European Journal of Neuroscience, 13, 2141–2147.

    Article  CAS  PubMed  Google Scholar 

  • Chan, W. K., Wong, P. T., & Sheu, F. (2007). Frontal cortical α7 and α4ß2 nicotinic acetylcholine receptors in working and reference memory. Neuropharmacology, 52, 1641–1649.

    Article  CAS  PubMed  Google Scholar 

  • Chess, A. C., Simoni, M. K., Alling, T. E., & Bucci, D. J. (2007). Elevations of endogenous kynurenic acid produce spatial working memory deficits. Schizophrenia Bulletin, 33, 797–804.

    Article  PubMed  Google Scholar 

  • Couey, J. J., Meredith, R. M., Spijker, S., et al. (2007). Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex. Neuron, 54, 73–87.

    Article  CAS  PubMed  Google Scholar 

  • Csillik, B., Nemcsók, J., Boncz, I., & Knyihár-Csillik, E. (1998). Nitric oxide synthase and the acetylcholine receptor in the prefrontal cortex: Metasynaptic organization of the brain. Neurobiology (Budapest), 6, 383–404.

    CAS  Google Scholar 

  • Del Arco, A., & Mora, F. (2005). Glutamate-dopamine in vivo interaction in the prefrontal cortex modulates the release of dopamine and acetylcholine in the nucleus accumbens of the awake rat. Journal of Neural Transmission, 112, 97–109.

    Article  PubMed  Google Scholar 

  • Del Arco, A., & Mora, F. (2008). Prefrontal cortex-nucleus accumbens interaction: In vivo modulation by dopamine and glutamate in the prefrontal cortex. Pharmacology, Biochemistry and Behavior, 90, 226–235.

    Article  Google Scholar 

  • Dickinson, J. A., Kew, J. N., & Wonnacott, S. (2008). Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms. Molecular Pharmacology, 74, 348–359.

    Article  CAS  PubMed  Google Scholar 

  • Erhardt, S., Blennow, K., Nordin, C., Skogh, E., Lindström, L. H., & Engberg, G. (2001). Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neuroscience Letters, 313, 96–98.

    Article  CAS  PubMed  Google Scholar 

  • Geerts, H., Guillaumat, P. O., Grantham, C., Bode, W., Anciaux, K., & Sachak, S. (2005). Brain levels and acetylcholinesterase inhibition with galantamine and donepezil in rats, mice, and rabbits. Brain Research, 1033, 186–193.

    Article  CAS  PubMed  Google Scholar 

  • Gioanni, Y., Rougeot, C., Clarke, P. B., Lepousé, C., Thierry, A. M., & Vidal, C. (1999). Nicotinic receptors in the rat prefrontal cortex: Increase in glutamate release and facilitation of mediodorsal thalamo-cortical transmission. European Journal of Neuroscience, 11, 18–30.

    Article  CAS  PubMed  Google Scholar 

  • Grilli, M., Raiteri, L., Patti, L., et al. (2006). Modulation of the function of presynaptic alpha7 and non-alpha7 nicotinic receptors by the tryptophan metabolites, 5-hydroxyindole and kynurenate in mouse brain. British Journal of Pharmacology, 149, 724–732.

    Article  CAS  PubMed  Google Scholar 

  • Guan, Z. Z., Zhang, X., Blennow, K., & Nordberg, A. (1999). Decreased protein level of nicotinic receptor alpha7 subunit in the frontal cortex from schizophrenic brain. NeuroReport, 10, 1779–1782.

    Article  CAS  PubMed  Google Scholar 

  • Guidetti, P., Okuno, E., & Schwarcz, R. (1997). Characterization of rat brain kynurenine aminotransferases I and II. Journal of Neuroscience Research, 50, 457–465.

    Article  CAS  PubMed  Google Scholar 

  • Guidetti, P., Hoffman, G. E., Melendez-Ferro, M., Albuquerque, E. X., & Schwarcz, R. (2007). Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry. Glia, 55, 78–92.

    Article  PubMed  Google Scholar 

  • Hashimoto, K., Ishima, T., Fujita, Y., et al. (2008). Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective alpha7 nicotinic receptor agonist SSR180711. Biological Psychiatry, 63, 92–97.

    Article  CAS  PubMed  Google Scholar 

  • Hilmas, C., Pereira, E. F., Alkondon, M., Rassoulpour, A., Schwarcz, R., & Albuquerque, E. X. (2001). The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: Physiopathological implications. Journal of Neuroscience, 21, 7463–7473.

    CAS  PubMed  Google Scholar 

  • Holtze, M., Asp, L., Schwieler, L., Engberg, G., & Karlsson, H. (2008). Induction of the kynurenine pathway by neurotropic influenza A virus infection. Journal of Neuroscience Research, 86, 3674–3683.

    Article  CAS  PubMed  Google Scholar 

  • Keefe, R. S. E., Bilder, R. M., Davis, S. M., et al. (2007). Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Archives of General Psychiatry, 64, 633–647.

    Article  CAS  PubMed  Google Scholar 

  • Kerns, J. G., Nuechterlein, K. H., Braver, T. S., & Barch, D. M. (2008). Executive functioning component mechanisms and schizophrenia. Biological Psychiatry, 64, 26–33.

    Article  PubMed  Google Scholar 

  • Kessler, M., Terramani, T., Lynch, G., & Baudry, M. (1989). A glycine site associated with N-methyl-d-aspartic acid receptors: Characterization and identification of a new class of antagonists. Journal of Neurochemistry, 52, 1319–1328.

    Article  CAS  PubMed  Google Scholar 

  • Konradsson-Geuken, Å., Gash, C. R., Alexander, K., et al. (2009). Second-by-second analysis of alpha7 nicotinic receptor regulation of glutamate release in the prefrontal cortex of awake rats. Synapse, 63, 1069–1082.

    Google Scholar 

  • Krenz, I., Kalkan, D., Wevers, A., et al. (2001). Parvalbumin-containing interneurons of the human cerebral cortex express nicotinic acetylcholine receptor proteins. Journal of Chemical Neuroanatomy, 21, 239–246.

    Article  CAS  PubMed  Google Scholar 

  • Leonard, S., & Freedman, R. (2006). Genetics of chromosome 15q13–q14 in schizophrenia. Biological Psychiatry, 60, 115–122.

    Article  CAS  PubMed  Google Scholar 

  • Lewis, D. A., & Moghaddam, B. (2006). Cognitive dysfunction in schizophrenia: Convergence of gamma-aminobutyric acid and glutamate alterations. Archives of Neurology, 63, 1372–1376.

    Article  PubMed  Google Scholar 

  • Lopes, C., Pereira, E. F. R., Wu, H.-Q., et al. (2007). Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at alpha7* nicotinic receptors. Journal of Pharmacology and Experimental Therapeutics, 322, 48–58.

    Article  CAS  PubMed  Google Scholar 

  • Marchi, M., Risso, F., Viola, C., Cavazzani, P., & Raiteri, M. (2002). Direct evidence that release-stimulating alpha7* nicotinic cholinergic receptors are localized on human and rat brain glutamatergic axon terminals. Journal of Neurochemistry, 80, 1071–1078.

    Article  CAS  PubMed  Google Scholar 

  • Moghaddam, B., & Homayoun, H. (2008). Divergent plasticity of prefrontal cortex networks. Neuropsychopharmacology, 33, 42–55.

    Article  PubMed  Google Scholar 

  • Moroni, F., Russi, P., Lombardi, G., Beni, M., & Carlà, V. (1988). Presence of kynurenic acid in the mammalian brain. Journal of Neurochemistry, 51, 177–180.

    Article  CAS  PubMed  Google Scholar 

  • Müller, N., & Schwarz, M. J. (2007). The immunological basis of glutamatergic disturbance in schizophrenia: Towards an integrated view. Journal of Neural Transmission. Supplementum, 72, 269–280.

    Article  Google Scholar 

  • Olincy, A., Harris, J. G., Johnson, L. L., et al. (2006). Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Archives of General Psychiatry, 63, 630–638.

    Article  CAS  PubMed  Google Scholar 

  • Pellicciari, R., Rizzo, R., Costantino, G., et al. (2006). Modulators of the kynurenine pathway of tryptophan metabolism: Synthesis and preliminary biological evaluation of (S)-4-(ethylsulfonyl)benzoylalanine, a potent and selective kynurenine aminotransferase II (KAT II) inhibitor. ChemMedChem, 1, 528–531.

    CAS  PubMed  Google Scholar 

  • Perkins, M. N., & Stone, T. W. (1982). An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Research, 247, 184–187.

    Article  CAS  PubMed  Google Scholar 

  • Pichat, P., Bergis, O. E., Terranova, J. P., et al. (2007). SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (II) efficacy in experimental models predictive of activity against cognitive symptoms of schizophrenia. Neuropsychopharmacology, 32, 17–34.

    Article  CAS  PubMed  Google Scholar 

  • Rassoulpour, A., Wu, H.-Q., Ferré, S., & Schwarcz, R. (2005). Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. Journal of Neurochemistry, 93, 762–765.

    Article  CAS  PubMed  Google Scholar 

  • Rousseau, S. J., Jones, I. W., Pullar, I. A., & Wonnacott, S. (2005). Presynaptic alpha7 and non-alpha7 nicotinic acetylcholine receptors modulate [3H]d-aspartate release from rat frontal cortex in vitro. Neuropharmacology, 49, 59–72.

    Article  CAS  PubMed  Google Scholar 

  • Samochocki, M., Höffle, A., Fehrenbacher, A., et al. (2003). Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. Journal of Pharmacology and Experimental Therapeutics, 305, 1024–1036.

    Article  CAS  Google Scholar 

  • Sarter, M., Nelson, C. L., & Bruno, J. P. (2005). Cortical cholinergic transmission and cortical information processing in schizophrenia. Schizophrenia Bulletin, 31, 117–138.

    Article  PubMed  Google Scholar 

  • Schilström, B., Ivanov, V. B., Wiker, C., & Svensson, T. H. (2007). Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors. Neuropsychopharmacology, 32, 43–53.

    Article  PubMed  Google Scholar 

  • Schubert, M. H., Young, K. A., & Hicks, P. B. (2006). Galantamine improves cognition in schizophrenic patients stabilized on risperidone. Biological Psychiatry, 60, 530–533.

    Article  CAS  PubMed  Google Scholar 

  • Schwarcz, R., & Hunter, C. A. (2007). Toxoplasma gondii and schizophrenia: linkage through astrocyte-derived kynurenic acid? Schizophrenia Bulletin, 33, 652–653.

    Article  PubMed  Google Scholar 

  • Schwarcz, R., & Pellicciari, R. (2002). Manipulation of brain kynurenines: Glial targets, neuronal effects, and clinical opportunities. Journal of Pharmacology and Experimental Therapeutics, 303, 1–10.

    Article  CAS  Google Scholar 

  • Schwarcz, R., Rassoulpour, A., Wu, H.-Q., Medoff, D., Tamminga, C. A., & Roberts, R. C. (2001). Increased cortical kynurenate content in schizophrenia. Biological Psychiatry, 50, 521–530.

    Article  CAS  PubMed  Google Scholar 

  • Shank, R. P., Leo, G. C., & Zielke, H. R. (1993). Cerebral metabolic compartmentation as revealed by nuclear magnetic resonance analysis of D-[1–13C]glucose metabolism. Journal of Neurochemistry, 61, 315–323.

    Article  CAS  PubMed  Google Scholar 

  • Stephens, S. H., Logel, J., Barton, A., et al. (2009). Association of the 5′-upstream regulatory region of the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7) with schizophrenia. Schizophrenia Research, 109, 102–112.

    Article  PubMed  Google Scholar 

  • Swartz, K. J., During, M. J., Freese, A., & Beal, M. F. (1990). Cerebral synthesis and release of kynurenic acid: An endogenous antagonist of excitatory amino acid receptors. Journal of Neuroscience, 10, 2965–2973.

    CAS  PubMed  Google Scholar 

  • Turski, W. A., Gramsbergen, J. B., Traitler, H., & Schwarcz, R. (1989). Rat brain slices produce and liberate kynurenic acid upon exposure to L-kynurenine. Journal of Neurochemistry, 52, 1629–1636.

    Article  CAS  PubMed  Google Scholar 

  • Wang, H., Yu, M., Ochani, M., et al. (2003). Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature, 421, 384–388.

    Article  CAS  PubMed  Google Scholar 

  • Wu, H.-Q., Pellicciari, R., & Schwarcz, R. (2006). Bidirectional regulation of extracellular dopamine by endogenous kynurenic acid in the rat medial prefrontal cortex. Society for Neuroscience Abstracts, 32, 624.3.

    Google Scholar 

  • Wu, H.-Q., Marinozzi, M., Pellicciari, R., & Schwarcz, R. (2007). Endogenous kynurenic acid modulates extracellular glutamate levels in the rat hippocampus. Society for Neuroscience Abstracts, 32, 500.15.

    Google Scholar 

  • Zahr, N. M., Mayer, D., Pfefferbaum, A., & Sullivan, E. V. (2008). Low striatal glutamate levels underlie cognitive decline in the elderly: Evidence from in vivo molecular spectroscopy. Cerebral Cortex, 18, 2241–2250.

    Article  PubMed  Google Scholar 

  • Zmarowski, A., Wu, H.-Q., Schwarcz, R., & Bruno, J. P. (2008). Elevations in brain kynurenic acid impair cognitive flexibility in rats: relevance to schizophrenia. Society for Neuroscience Abstracts, 33, 657.11.

    Google Scholar 

  • Zmarowski, A., Wu, H.-Q., Brooks, J. M., et al. (2009). Astrocyte-derived kynurenic acid modulates basal and evoked cortical acetylcholine release. European Journal of Neuroscience, 29, 529–538.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by USPHS grant NS25296.

Author information

Authors and Affiliations

  1. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD, 21228, USA

    Hui-Qiu Wu & Robert Schwarcz

  2. Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Edna F. R. Pereira & Edson X. Albuquerque

  3. Department of Psychology and Neuroscience, The Ohio State University, Columbus, OH, 43210, USA

    John P. Bruno

  4. Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Perugia, Italy

    Roberto Pellicciari

Authors
  1. Hui-Qiu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edna F. R. Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John P. Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roberto Pellicciari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edson X. Albuquerque
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert Schwarcz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Schwarcz.

Additional information

Proceedings of the XIII International Symposium on Cholinergic Mechanisms

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, HQ., Pereira, E.F.R., Bruno, J.P. et al. The Astrocyte-Derived α7 Nicotinic Receptor Antagonist Kynurenic Acid Controls Extracellular Glutamate Levels in the Prefrontal Cortex. J Mol Neurosci 40, 204–210 (2010). https://doi.org/10.1007/s12031-009-9235-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-009-9235-2

Keywords

Search

Navigation