Increased cortical kynurenate content in schizophrenia

Schwarcz, Robert; Rassoulpour, Arash; Wu, Hui; Medoff, Deborah R.; Tamminga, Carol A.; Roberts, Rosalinda C.

doi:10.1016/s0006-3223(01)01078-2

Cited by 531 publications

(403 citation statements)

References 62 publications

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“…Numerous reports have indicated that cerebral KYNA levels are moderately increased in patients with AD (Baran et al, 1999), DS (Baran et al, 1996), and schizophrenia (Ravikumar et al, 2000;Erhardt et al, 2001;Schwarcz et al, 2001), and slightly, albeit significantly decreased in patients with end-stage Parkinson's disease (PD) (Ogawa et al, 1992) and Huntington's disease (HD, Beal et al, 1990). The physiopathologic consequences of relatively modest variations in brain levels of KYNA raised the possibility of the existence of a high-affinity target for this tryptophan metabolite in neurons.…”

Section: Kynurenic Acid (Kyna)mentioning

confidence: 99%

“…Considering that nAChRs modulate glutamatergic and dopaminergic activities in the brain (see Wonnacott, 1997 and references therein) and that elevated levels of KYNA have been found in the CSF and plasma of schizophrenic patients (Ravikumar et al, 2000;Erhardt et al, 2001;Schwarcz et al, 2001), it is tempting to speculate that disruption of reciprocal glia-neuron signaling mechanisms involving KYNA and nAChRs is causally related to the disease. It is possible, for instance, that chronic ␣7 nAChR inhibition in the hippocampus by elevated levels of KYNA leads to auditory gating deficit, which appears to be a factor predisposing the development of schizophrenia (reviewed in Freedman et al, 2000).…”

Section: Kynurenic Acid (Kyna)mentioning

confidence: 99%

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Unconventional ligands and modulators of nicotinic receptors

et al. 2002

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ABSTRACT:Evidence gathered from epidemiologic and behavioral studies have indicated that neuronal nicotinic receptors (nAChRs) are intimately involved in the pathogenesis of a number of neurologic disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia. In the mammalian brain, neuronal nAChRs, in addition to mediating fast synaptic transmission, modulate fast synaptic transmission mediated by the major excitatory and inhibitory neurotransmitters glutamate and GABA, respectively. Of major interest, however, is the fact that the activity of the different subtypes of neuronal nAChR is also subject to modulation by substances of endogenous origin such as choline, the tryptophan metabolite kynurenic acid, neurosteroids, and ␤-amyloid peptides and by exogenous substances, including the so-called nicotinic allosteric potentiating ligands, of which galantamine is the prototype, and psychotomimetic drugs such as phencyclidine and ketamine. The present article reviews and discusses the effects of unconventional ligands on nAChR activity and briefly describes the potential benefits of using some of these compounds in the treatment of neuropathologic conditions in which nAChR function/expression is known to be altered.

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Section: Kynurenic Acid (Kyna)mentioning

confidence: 99%

Section: Kynurenic Acid (Kyna)mentioning

confidence: 99%

Unconventional ligands and modulators of nicotinic receptors

et al. 2002

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“…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%

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

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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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“…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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Increased cortical kynurenate content in schizophrenia

Cited by 531 publications

References 62 publications

Unconventional ligands and modulators of nicotinic receptors

Unconventional ligands and modulators of nicotinic receptors

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

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