Long-term systemic administration of kynurenic acid brain region specifically elevates the abundance of functional CB1 receptors in rats

Ferenc Zádor, Gábor Nagy-Grócz, Szabolcs Dvorácskó, Zsuzsanna Bohár, Edina Katalin Cseh, Dénes Zádori, A. Párdutz, Edina Szűcs, C. Tömböly, A. Borsodi, S. Benyhe, László Vécsei

Research output: Contribution to journalArticle

Abstract

Kynurenic acid (KYNA) is one of the most significant metabolite of the kynurenine pathway both in terms of functional and potential therapeutic value. It is an N-methyl-D-aspartate (NMDA) receptor antagonist, but it can also activate the G-protein coupled receptor 35 (GPR35), which shares several structural and functional properties with cannabinoid receptors. Previously our group demonstrated that systemic chronic KYNA treatment altered opioid receptor G-protein activity. Opioid receptors also overlap in many features with cannabinoid receptors. Thus, our aim was to examine the direct in vitro and systemic, chronic in vivo effect of KYNA on type 1 cannabinoid receptor (CB1R) binding and G-protein activity. Based on competition and [35S]GTPγS G-protein binding assays in rat brain, KYNA alone did not show significant binding towards the CB1R, nor did it alter CB1R ligand binding and agonist activity in vitro. When rats were chronically treated with KYNA (single daily, i.p., 128 mg/kg for 9 days), the KYNA plasma and cerebrospinal fluid levels significantly increased compared to vehicle treated group. Furthermore, in G-protein binding assays, in the whole brain the amount of G-proteins in basal and in maximum activity coupled to the CB1R also increased due to the treatment. At the same time, the overall stimulatory properties of the receptor remained unaltered in vehicle and KYNA treated samples. Similar observations were made in rat hippocampus, but not in the cortex and brainstem. In saturation binding assays the density of CB1Rs in rat whole brain and hippocampus were also significantly enhanced after the same treatment, without significantly affecting ligand binding affinity. Thus, KYNA indirectly and brain region specifically increases the abundance of functional CB1Rs, without modifying the overall binding and activity of the receptor. Supposedly, this can be a compensatory mechanism on the part of the endocannabinoid system induced by the long-term KYNA exposure.

Original languageEnglish
Article number104752
JournalNeurochemistry international
Volume138
DOIs
Publication statusPublished - Sep 2020

Keywords

  • G-protein
  • Hippocampus
  • Kynurenic acid
  • Radioligand binding
  • type 1 cannabinoid receptor
  • [S]GTPγS binding

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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