Increasing kynurenine brain levels reduces ethanol consumption in mice by inhibiting dopamine release in nucleus accumbens

Giménez-Gómez, Pablo; Pérez-Hernández, Mercedes; Gutiérrez-López, Marı́a Dolores; Vidal, Rebeca; Abuin-Martínez, Cristina; O’Shea, Esther; Colado, María Isabel

doi:10.1016/j.neuropharm.2018.04.016

Cited by 26 publications

(39 citation statements)

References 78 publications

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“…Therefore, it appears that KYNA effects on extracellular dopamine are opposite to that of XA both in acute or chronic conditions, and the regulated balance between the synthesis of these two compounds participate in the modulation of dopaminergic activity in the brain. XA and KYNA have both been suggested to be implicated in the pathophysiological mechanism of schizophrenia [40] and considering the role of the dopamine hypothesis in the etiology of the disease [17,41], the present work supports a role for the kynurenine pathway activity in psychotic pathology and cognitive dysfunctions. Our present findings support a much important role for XA in the regulation of dopaminergic activity in the frontal cortex compared to the striatum.…”

Section: Discussionsupporting

confidence: 76%

A Role for Xanthurenic Acid in the Control of Brain Dopaminergic Activity

Taleb

Maammar

Klein

et al. 2021

IJMS

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Xanthurenic acid (XA) is a metabolite of the kynurenine pathway (KP) synthetized in the brain from dietary or microbial tryptophan that crosses the blood-brain barrier through carrier-mediated transport. XA and kynurenic acid (KYNA) are two structurally related compounds of KP occurring at micromolar concentrations in the CNS and suspected to modulate some pathophysiological mechanisms of neuropsychiatric and/or neurodegenerative diseases. Particularly, various data including XA cerebral distribution (from 1 µM in olfactory bulbs and cerebellum to 0.1–0.4 µM in A9 and A10), its release, and interactions with G protein-dependent XA-receptor, glutamate transporter and metabotropic receptors, strongly support a signaling and/or neuromodulatory role for XA. However, while the parent molecule KYNA is considered as potentially involved in neuropsychiatric disorders because of its inhibitory action on dopamine release in the striatum, the effect of XA on brain dopaminergic activity remains unknown. Here, we demonstrate that acute local/microdialysis-infusions of XA dose-dependently stimulate dopamine release in the rat prefrontal cortex (four-fold increase in the presence of 20 µM XA). This stimulatory effect is blocked by XA-receptor antagonist NCS-486. Interestingly, our results show that the peripheral/intraperitoneal administration of XA, which has been proven to enhance intra-cerebral XA concentrations (about 200% increase after 50 mg/kg XA i.p), also induces a dose-dependent increase of dopamine release in the cortex and striatum. Furthermore, our in vivo electrophysiological studies reveal that the repeated/daily administrations of XA reduce by 43% the number of spontaneously firing dopaminergic neurons in the ventral tegmental area. In the substantia nigra, XA treatment does not change the number of firing neurons. Altogether, our results suggest that XA may contribute together with KYNA to generate a KYNA/XA ratio that may crucially determine the brain normal dopaminergic activity. Imbalance of this ratio may result in dopaminergic dysfunctions related to several brain disorders, including psychotic diseases and drug dependence.

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Section: Discussionsupporting

confidence: 76%

A Role for Xanthurenic Acid in the Control of Brain Dopaminergic Activity

Taleb

Maammar

Klein

et al. 2021

IJMS

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“…To our knowledge, this study provides the first evidence of altered brain Kyn concentrations following chronic EtOH intake. Furthermore, we previously described no changes in plasma or brain Kyn concentrations immediately following DID (13), and the present data confirm and extend this observation to 24 h.…”

Section: Discussionsupporting

confidence: 92%

Changes in brain kynurenine levels via gut microbiota and gut‐barrier disruption induced by chronic ethanol exposure in mice

et al. 2019

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Inflammatory processes have been shown to modify tryptophan (Trp) metabolism. Gut microbiota appears to play a significant role in the induction of peripheral and central inflammation. Ethanol (EtOH) exposure alters gut permeability, but its effects on Trp metabolism and the involvement of gut microbiota have not been studied. We analyzed several parameters of gut‐barrier and of peripheral and central Trp metabolism following 2 different EtOH consumption patterns in mice, the binge model, drinking in the dark (DID), and the chronic intermittent (CI) consumption paradigm. Antibiotic treatment was used to evaluate gut microbiota involvement in the CI model. Mice exposed to CI EtOH intake, but not DID, show bacterial translocation and increased plasma LPS immediately after EtOH removal. Gut‐barrier permeability to FITC‐dextran is increased by CI, and, furthermore, intestinal epithelial tight‐junction (TJ) disruption is observed (decreased expression of zonula occludens 1 and occludin) associated with increased matrix metalloproteinase (MMP)‐9 activity and iNOS expression. CI EtOH, but not DID, increases kynurenine (Kyn) levels in plasma and limbic forebrain. Intestinal bacterial decontamination prevents the LPS increase but not the permeability to FITC‐dextran, TJ disruption, or the increase in MMP‐9 activity and iNOS expression. Although plasma Kyn levels are not affected by antibiotic treatment, the elevation of Kyn in brain is prevented, pointing to an involvement of microbiota in CI EtOH‐induced changes in brain Trp metabolism. Additionally, CI EtOH produces depressive‐like symptoms of anhedonia, which are prevented by the antibiotic treatment thus pointing to an association between anhedonia and the increase in brain Kyn and to the involvement of gut microbiota.—Giménez‐Gómez, P., Pérez‐Hernández, M., O'Shea, E., Caso, J. R., Martín‐Hernández, D., Cervera, L. A., Centelles. M. L. G.‐L., Gutiérrez‐Lopez, M. D., Colado, M. I. Changes in brain kynurenine levels via gut microbiota and gut‐barrier disruption induced by chronic ethanol exposure in mice. FASEB J. 33, 12900–12914 (2019). http://www.fasebj.org

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“…The results of the measurements of the metabolites of interest from the assessed biological matrices (mouse plasma and brain, human plasma and CSF) with the developed and validated method are summarized in Table 4. All the reported data in the current study are in line with those obtained from the scientific literature [9,10,15,16,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40].…”

Section: Application Of the Developed Methods On Different Biological supporting

confidence: 83%

HPLC method for the assessment of tryptophan metabolism utilizing separate internal standard for each detector

Cseh

Veres

Szentirmai

et al. 2019

Analytical Biochemistry

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Abbreviations: 3NLT 3-nitro-L-tyrosine, 5-HT serotonin, ACN acetonitrile, CS(s) calibration standard(s), CSF cerebrospinal fluid, FLD fluorescence detector, HCA 4-hydroxyquinazoline-2carboxylic acid, HPLC high-performance liquid chromatography, IS(s) internal standard(s), IQR interquartile range, KP kynurenine pathway, KYN kynurenine, KYNA kynurenic acid, LOD limit of detection, LOQ limit of quantification, SD standard deviation, PCA perchloric acid, TRP tryptophan, UVD UV detector, ZnAc zinc acetate, WS working solution, ww wet weight 2 AbstractThe development of a validated method, applicable for the measurement of tryptophan (TRP) and serotonin (5-HT), and that of the neuroprotective branch of the kynurenine pathway from several different biological matrices, including mouse brain, is described. Following the spectral analysis of the metabolites, they were quantified with reversed-phase high-performance liquid chromatography (HPLC), using separate internal standards (ISs) for UV (3-nitro-L-tyrosine) and fluorescent (the newly utilized 4-hydroxyquinazoline-2-carboxylic acid) detectors. With regard to validation parameters, selectivity, linearity, limit of detection, limit of quantification, precision and recovery were determined. Although the linearity ranges were different for the assessed matrices, the correlation coefficient was > 0.999 in each case. Furthermore, good intraand inter-day precision values were obtained with coefficient of variation < 5%, and bias < 6.5% (except the 5-HT level in brain samples), respectively. The recoveries varied between 82.5% and 116%. The currently developed methods yield opportunities for the assessment of concentration changes in the TRP metabolism from a wide range of biological matrices, therefore they may well be utilized in future clinical and preclinical studies, especially in view that so many metabolites with the application of ISs have not been detected from mouse brain with such a simple HPLC method before.

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Increasing kynurenine brain levels reduces ethanol consumption in mice by inhibiting dopamine release in nucleus accumbens

Cited by 26 publications

References 78 publications

A Role for Xanthurenic Acid in the Control of Brain Dopaminergic Activity

A Role for Xanthurenic Acid in the Control of Brain Dopaminergic Activity

Changes in brain kynurenine levels via gut microbiota and gut‐barrier disruption induced by chronic ethanol exposure in mice

HPLC method for the assessment of tryptophan metabolism utilizing separate internal standard for each detector

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