Long-term systemic administration of kynurenic acid brain region specifically elevates the abundance of functional CB 1 receptors in rats

• Published in: Neurochemistry international 2020-05, p.104752
• Main Authors: Zádor, Ferenc, Nagy-Grócz, Gábor, Dvorácskó, Szabolcs, Bohár, Zsuzsanna, Cseh, Edina Katalin, Zádori, Dénes, Párdutz, Árpád, Szűcs, Edina, Tömböly, Csaba, Borsodi, Anna, Benyhe, Sándor, Vécsei, László
• Format: Article
• Language: English
• ISSN: 1872-9754

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 (CB R) binding and G-protein activity. Based on competition and [ S]GTPγS G-protein binding assays in rat brain, KYNA alone did not show significant binding towards the CB R, nor did it alter CB R 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 CB R 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 CB Rs 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 CB Rs, 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.