Journal of Molecular Neuroscience

, Volume 40, Issue 1, pp 204–210

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

  • Hui-Qiu Wu
  • Edna F. R. Pereira
  • John P. Bruno
  • Roberto Pellicciari
  • Edson X. Albuquerque
  • Robert Schwarcz
Article

DOI: 10.1007/s12031-009-9235-2

Cite this article as:
Wu, HQ., Pereira, E.F.R., Bruno, J.P. et al. J Mol Neurosci (2010) 40: 204. doi:10.1007/s12031-009-9235-2

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.

Keywords

CognitionDonepezilGalantamineKynurenineMicrodialysisPrefrontal cortex

Copyright information

© Humana Press 2009

Authors and Affiliations

  • Hui-Qiu Wu
    • 1
  • Edna F. R. Pereira
    • 2
  • John P. Bruno
    • 3
  • Roberto Pellicciari
    • 4
  • Edson X. Albuquerque
    • 2
  • Robert Schwarcz
    • 1
  1. 1.Maryland Psychiatric Research Center, Department of PsychiatryUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Department of Pharmacology and Experimental TherapeuticsUniversity of Maryland School of MedicineBaltimoreUSA
  3. 3.Department of Psychology and NeuroscienceThe Ohio State UniversityColumbusUSA
  4. 4.Dipartimento di Chimica e Tecnologia del FarmacoUniversità di PerugiaPerugiaItaly