Abstract
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.
Highlights
Under physiological conditions in the mammalian brain, about 95% of the essential amino-acid tryptophan available from the diet is metabolized through the kynurenine pathway (KP, Figure 1) in competition with the formation of serotonin and melatonin via5-hydroxytryptophan (5-HTP) synthesis [1] and the decarboxylation of tryptophan into tryptamine
Sci. 2021, 22, 6974 monooxygenase (KMO), whose inhibition increases the concentration of kynurenic acid (KYNA) and in theory decreases the production of Xanthurenic acid (XA) [8,9,10]
XAconfirmed effects were assessed by dopamine release frontal cortex
Summary
Under physiological conditions in the mammalian brain, about 95% of the essential amino-acid tryptophan available from the diet is metabolized through the kynurenine pathway (KP, Figure 1) in competition with the formation of serotonin and melatonin via. The principal pathway is degradation through kyn and the synthesis of two related analogues, kynurenic and xanthurenic acid. These two compounds and the synthesis of two related analogues, kynurenic and xanthurenic acid These two com have opposite effects on dopamine disposal in the brain. XA appears pivotal in the modulation of neurobiological functions, the role of XA in the regulation of brain dopaminergic activity remains unclear. Its putative role in the pathophysiology of schizophrenia is supported by its reduced brain and serum levels in patients [30,31] These data prompted us to investigate the effect of XA on brain dopaminergic activity. Here we combined various approaches, including microdialysis infusion of XA, dopamine quantification using high performance liquid chromatography coupled with electrochemical detection, stereotaxic method and in vivo electrophysiological recording of dopaminergic neurons to determine the pharmacological action of XA on dopamine release and dopaminergic activity in the rat brain
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