Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum

Rassoulpour, Arash; Wu, Hui‐Qiu; Ferré, Sergi; Schwarcz, Robert

doi:10.1111/j.1471-4159.2005.03134.x

Cited by 152 publications

(141 citation statements)

References 32 publications

(62 reference statements)

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“…It has generally been reported to be neuroprotective at values ranging from 1 to 1000 mmol/L (Stone, 2000), although the precise nature of this neuroprotection has been questioned , with the suggestion that it might be mediated through a mechanism not involving iGluR . Recently, it has been shown that KynA might be active at nicotinic acetylcholine a7-containing receptors (Alkondon et al, 2004), with subsequent effects on dopaminergic neurotransmission (Rassoulpour et al, 2005).…”

Section: Kynurenine Pathway Metabolitesmentioning

confidence: 99%

A Metabolomic Approach to Ionotropic Glutamate Receptor Subtype Function: A Nuclear Magnetic Resonance in vitro Investigation

Rae

Moussa

Griffin

et al. 2005

J Cereb Blood Flow Metab

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A range of behaviours are elucidated via ionotropic glutamate receptors (iGluR). In this work, we examined the acute activation of iGluRs by a range of receptor ligands and effectors to see whether distinguishable metabolic sequelae were elucidated by the activity. We used a guinea-pig brain cortical tissue slice model using targeted receptor ligands ((RS)-(tetrazol-5-yl)glycine (TZG),, as well as compounds (quinolinic acid and kynurenic acid (KynA)) involved in some neuroinflammatory responses. The data were derived using 13 C and 1 H NMR spectroscopy, and analysed by metabolomic approaches and multivariate statistics. The metabolic effects of agonists at the three major classes of iGluR were easily separated from each other using this method. The classical N-methyl-D-aspartate receptor agonist TZG and the antagonist CGS 19755 produced excitatory and inhibitory metabolic responses, respectively, while the blocker MK-801 resulted in a significant decrease in net metabolism and produced the largest decrease in all metabolite pool sizes seen by any glutamatergic ligand we have studied. Quinolinic acid and KynA produced similar acute metabolic responses, which were unlike those to TZG or CGS 19755, but similar to that of D-Ser. D-Ser was highly stimulatory of net flux into the Krebs cycle. These data show that the metabolic response to iGluR perturbation in vitro is a sensitive discriminator of function.

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Section: Kynurenine Pathway Metabolitesmentioning

confidence: 99%

A Metabolomic Approach to Ionotropic Glutamate Receptor Subtype Function: A Nuclear Magnetic Resonance in vitro Investigation

Rae

Moussa

Griffin

et al. 2005

J Cereb Blood Flow Metab

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“…Microdialysis studies in the striatum and the prefrontal cortex of awake rats showed that exogenous application of KYNA in the mid-nanomolar range, that is, 2-5 times endogenous levels, reduces the extracellular concentrations of dopamine and glutamate (Amori et al, 2009;Carpenedo et al, 2001;Moroni et al, 2005;Rassoulpour et al, 2005;Wu et al, 2010). Moreover, in the prefrontal cortex, nanomolar KYNA significantly decreases the amphetamine-induced stimulation of acetylcholine release (Zmarowski et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

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137

158

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Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the a7 nicotinic acetylcholine receptor (a7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up-or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 ml) or ESBA (10 mM, 10 ml), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 mM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

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“…In the dopaminergic mesolimbic system, a major circuit in the mediation of natural and drug reward, non-␣ 7 nACh receptors are present both in the ventral tegmental area (VTA), where they are localized on and can directly activate dopaminergic neurons (Mansvelder and McGehee, 2002;Picciotto, 2003;Dani and Bertrand, 2007), and in the striatum, where they are localized on dopaminergic terminals and control dopamine release (Tribollet et al, 2004;Quarta et al, 2007). In contrast, ␣ 7 nACh receptors are present in both the VTA and the striatum but are localized on glutamatergic terminals, where they control glutamate release and, consequently, dopamine release (Fu et al, 2000;Kaiser and Wonnacott, 2000;Rassoulpour et al, 2005;Dani and Bertrand, 2006).…”

Section: Introductionmentioning

confidence: 99%

Nicotinic α₇Receptors as a New Target for Treatment of Cannabis Abuse

Solinas¹,

Scherma²,

Fattore³

et al. 2007

J. Neurosci.

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Increasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here, we show that homomeric ␣ 7 nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence. In rats, systemic administration of the selective ␣ 7 nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA), but not the selective heteromeric non-␣ 7 nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine, (1) antagonized the discriminative effects of ␦-9-tetrahydrocannabinol (THC), the main active ingredient in cannabis, (2) reduced intravenous selfadministration of the synthetic cannabinoid CB1 receptor agonist WIN55, 212-2 [(R)-(ϩ)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)-methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone, mesylate salt], and (3) decreased THC-induced dopamineelevations in the shell of the nucleus accumbens. Altogether, our results indicate that blockade of ␣ 7 nicotinic receptors reverses abuserelated behavioral and neurochemical effects of cannabinoids. Importantly, MLA reversed the effects of cannabinoids at doses that did not produce depressant or toxic effects, further pointing to ␣ 7 nicotinic antagonists as potentially useful agents in the treatment of cannabis abuse in humans.

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Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum

Cited by 152 publications

References 32 publications

A Metabolomic Approach to Ionotropic Glutamate Receptor Subtype Function: A Nuclear Magnetic Resonance in vitro Investigation

A Metabolomic Approach to Ionotropic Glutamate Receptor Subtype Function: A Nuclear Magnetic Resonance in vitro Investigation

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Nicotinic α₇Receptors as a New Target for Treatment of Cannabis Abuse

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Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum

Cited by 152 publications

References 32 publications

A Metabolomic Approach to Ionotropic Glutamate Receptor Subtype Function: A Nuclear Magnetic Resonance in vitro Investigation

A Metabolomic Approach to Ionotropic Glutamate Receptor Subtype Function: A Nuclear Magnetic Resonance in vitro Investigation

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Nicotinic α7Receptors as a New Target for Treatment of Cannabis Abuse

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Product

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Nicotinic α₇Receptors as a New Target for Treatment of Cannabis Abuse