Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia

Erhardt, Sophie; Blennow, Kaj; Nordin, Conny; Skogh, Elisabeth; Lindström, Leif; Engberg, Göran

doi:10.1016/s0304-3940(01)02242-x

Cited by 408 publications

(300 citation statements)

References 15 publications

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“…Our hypothesis was based on evidence implicating glutamatergic and cholinergic receptors in sensory gating (Adler et al, 1986;Luntz-Leybman et al, 1992;Miller et al, 1992a;Bickford and Wear, 1995) and on data showing that cortical and CSF KYNA levels are elevated in schizophrenia (Erhardt et al, 2001;Schwarcz et al, 2001), a disorder characterized by marked auditory gating deficits (Adler et al, 1982;Boutros et al, 1991;Jin et al, 1997;Clementz et al, 1998a, b;Patterson et al, 2000). Since KYNA penetrates the bloodbrain barrier very poorly (Fukui et al, 1991), an indirect approach was implemented, involving blockade of the PBCD-sensitive transporter alone and in conjunction with the administration of KYNA's immediate bioprecursor KYN.…”

Section: Discussionmentioning

confidence: 99%

“…This impairment does not appear to be attributable to the glutamate receptor antagonist properties of the compound but is likely to involve other mechanisms including an interaction with a7nAChRs. The recently documented increase in KYNA levels in the brain and CSF of schizophrenic patients (Erhardt et al, 2001;Schwarcz et al, 2001) could contribute to the well-characterized abnormality in sensory processing in the disease.…”

Section: Discussionmentioning

confidence: 99%

“…One possibility is that these impairments are related to an increase in brain levels of endogenous neuroactive compounds that modulate the activity of these neurotransmitters or their receptors. Brain and cerebrospinal fluid (CSF) levels of one such candidate, kynurenic acid (KYNA), a tryptophan metabolite and endogenous excitatory amino acid (EAA) receptor antagonist, are elevated in schizophrenic patients (Erhardt et al, 2001;Schwarcz et al, 2001). In addition to its well-characterized action as a competitive antagonist of the glycine coagonist binding site (glycine B site) on the NMDA receptor, KYNA also functions as a noncompetitive antagonist of the a7nAChR (Hilmas et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Shepard

Joy

Clerkin

et al. 2003

Neuropsychopharmacol

123

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Brain levels of kynurenic acid (KYNA), an endogenous antagonist of glycine B /NMDA and a-7 nicotinic acetylcholine receptors, are elevated in individuals with schizophrenia. Both receptors are broadly implicated in the pathophysiology of this disease, particularly in the deficits many patients show in filtering the sensorium. In the present study, we sought to determine whether elevated brain levels of KYNA disrupt auditory gating in anesthetized rats. A mid-latency evoked potential was recorded from the hippocampus in response to a pair of auditory tones. Gating was assessed by determining the ratio of the amplitude of test and conditioning responses (T/C ratio) in rats that had received KYNA's precursor L-kynurenine (KYN; 150 mg/kg, i.p.) together with probenecid (PBCD; 200 mg/kg, i.p.) 2 h prior to the start of the recording session. KYNA levels in the hippocampus of KYN+PBCD-treated rats were increased 500-fold, and accompanied by a significant increase in T/C ratio consistent with a disruption in sensory gating. PBCD alone increased hippocampal KYNA 12-fold, but did not significantly elevate T/C ratio. L-701,324 (3-30 mg/kg, i.v.), a centrally acting glycine B site antagonist, also failed to disrupt gating; however, large quantities of the competitive NMDA receptor antagonist DL-2-amino-5-phosphopentanoate (200 nmol, i.c.v.) markedly increased T/C ratio. Thus, while total blockade of NMDA receptors disrupts auditory gating, partial blockade achieved by antagonism of its glycine coagonist binding site does not. These observations indicate that the disruption in auditory processing in rats with greatly elevated KYNA levels is not attributable to the compound's antagonist actions at the glycine B receptor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Shepard

Joy

Clerkin

et al. 2003

Neuropsychopharmacol

123

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“…The present findings are also relevant for the pathophysiology of schizophrenia since both glutamate receptor and a7 nAChR dysfunction have been implicated in the disease process (Carlsson and Carlsson, 1990;Freedman et al, 1995;Tamminga, 1998;Leonard et al, 2000;Schilstr + om et al, 2000;Coyle and Tsai, 2004). Thus, the elevated levels of KYNA measured in the brain and cerebrospinal fluid (Erhardt et al, 2001a;Schwarcz et al, 2001) may contribute to the presumed hypoglutamatergic and hypocholinergic tone in schizophrenic individuals. Since brain KYNA levels are decreased 4 and 6 days after repeated nicotine administration, excessive smoking in the schizophrenic population could constitute an attempt to self-medicate (cf Introduction).…”

Section: Discussionmentioning

confidence: 63%

“…It is therefore conceivable that nicotine-induced fluctuations in brain KYNA levels influence the activity of a7 nAChRs (Hilmas et al, 2001). This concept, and the recent demonstration that KYNA levels are elevated in cortical brain regions and cerebrospinal fluid of schizophrenic patients (Erhardt et al, 2001a;Schwarcz et al, 2001) and that elevations in brain KYNA disrupt auditory sensory gating (Shepard et al, 2003), prompted us to examine the consequences of acute and prolonged nicotine administration on the disposition of KYNA and its bioprecursor kynurenine in rats. Our data, some of which have been communicated in a preliminary fashion (Hilmas et al, 2001), revealed that nicotine causes biphasic, brainspecific changes in KYNA levels without affecting the brain concentrations of kynurenine.…”

Section: Introductionmentioning

confidence: 99%

Prolonged Nicotine Administration Results in Biphasic, Brain-Specific Changes in Kynurenate Levels in the Rat

Rassoulpour

Albuquerque

et al. 2004

Neuropsychopharmacol

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The content of the endogenous NMDA and a7 nicotinic acetylcholine receptor antagonist kynurenate (KYNA) is increased in the cerebral cortex and cerebrospinal fluid of patients with schizophrenia. In view of the very high incidence of smoking in schizophrenic individuals, a study was designed to examine the effect of acute and prolonged nicotine administration on brain KYNA levels in experimental animals. Adult male rats received subcutaneous nicotine injections twice daily for up to 10 days, and animals were routinely killed 1 h after the last injection. Neither acute treatment nor a 2-day regimen with 1 mg/kg nicotine ( ¼ 0.35 mg/kg pure base) caused changes in cerebral KYNA levels. Four-or 6 day-treatment with this dose resulted in 20-40% decreases in cerebral KYNA content. Animals treated with 1 or 10 mg/kg nicotine for 10 days showed dose-dependent, significant increases in KYNA in hippocampus, striatum, and cortex, but not in the serum. Discontinuation of nicotine treatment for 7 days restored brain KYNA to control levels. Separate animals, implanted with osmotic minipumps delivering 2 mg/kg of nicotine/day for 10 days also showed significant elevations in brain KYNA. Hippocampal microdialysis, performed in animals receiving nicotine (1 mg/kg) for 10 days, revealed a significant increase in basal extracellular KYNA levels compared to controls, whereas acute treatment with this dose produced no such change. Measurements of KYNA's bioprecursor kynurenine in brain or blood did not reveal any nicotine-induced changes. These results indicate that nicotine has a brain-specific, biphasic effect on the transamination of kynurenine to KYNA. Such nicotine-induced fluctuations in brain KYNA may cause functional changes in processes that regulate glutamatergic and cholinergic neurotransmission in the normal and diseased brain.

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Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes

Wonodi

Stine

Sathyasaikumar

et al. 2011

Arch Gen Psychiatry

143

103

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Context Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, is an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors and modulates glutamate, dopamine, and acetylcholine signaling. Cortical kynurenic acid concentrations are elevated in the brain and cerebrospinal fluid of schizophrenia patients. The proximal cause may be an impairment of kynurenine 3-monooxygenase (KMO), a rate-limiting enzyme at the branching point of the kynurenine pathway. Objectives To examine KMO messenger RNA expression and KMO enzyme activity in postmortem tissue from the frontal eye field (FEF; Brodmann area 6) obtained from schizophrenia individuals compared with healthy control individuals and to explore the relationship between KMO single-nucleotide polymorphisms and schizophrenia oculomotor endophenotypes. Design Case-control postmortem and clinical study. Setting Maryland Brain Collection, outpatient clinics. Participants Postmortem specimens from schizophrenia patients (n=32) and control donors (n=32) and a clinical sample of schizophrenia patients (n=248) and healthy controls (n=228). Main Outcome Measures Comparison of quantitative KMO messenger RNA expression and KMO enzyme activity in postmortem FEF tissue between schizophrenia patients and controls and association of KMO single-nucleotide polymorphisms with messenger RNA expression in postmortem FEF and schizophrenia and oculomotor endophenotypes (ie, smooth pursuit eye movements and oculomotor delayed response). Results In postmortem tissue, we found a significant and correlated reduction in KMO gene expression and KMO enzyme activity in the FEF in schizophrenia patients. In the clinical sample, KMO rs2275163 was not associated with a diagnosis of schizophrenia but showed modest effects on predictive pursuit and visuospatial working memory endophenotypes. Conclusion Our results provide converging lines of evidence implicating reduced KMO activity in the etiopathophysiology of schizophrenia and related neurocognitive deficits.

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Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia

Cited by 408 publications

References 15 publications

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Prolonged Nicotine Administration Results in Biphasic, Brain-Specific Changes in Kynurenate Levels in the Rat

Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes

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