Department of Visual Neuroscience, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
Neuropharmacology. 2013 Mar;66:133-42. doi: 10.1016/j.neuropharm.2012.03.009. Epub 2012 Apr 2.
Xanthurenic acid (XA), a molecule arising from tryptophan metabolism by transamination of 3-hydroxykynurenine, has recently been identified as an endogenous Group II (mGlu2 and mGlu3) metabotropic glutamate (mGlu) receptor ligand in vitro. Impairments in Group II mGlu receptor expression and function have been implicated in the pathophysiology of schizophrenia, as have multiple steps in the kynurenine metabolism pathway. Therefore, we examined XA in vivo to further investigate its potential as a Group II mGlu receptor ligand using a preparation that has been previously demonstrated to efficiently reveal the action of other Group II mGlu receptor ligands in vivo. Extracellular single-neurone recordings were made in the rat ventrobasal thalamus (VB) in conjunction with iontophoresis of agonists, an antagonist and a positive allosteric modulator and/or intravenous (i.v.) injection of XA. We found the XA effect on sensory inhibition, when applied iontophoretically and i.v., was similar to that of other Group II mGlu receptor agonists in reducing inhibition evoked in the VB from the thalamic reticular nucleus upon physiological sensory stimulation. Furthermore, we postulate that XA may be the first potential endogenous allosteric agonist (termed 'endocoid') for the mGlu receptors. As the Group II receptors and kynurenine metabolism pathway have both been heavily implicated in the pathophysiology of schizophrenia, XA could play a pivotal role in antipsychotic research as this potential endocoid represents both a convergence within these two biological parameters and a novel class of Group II mGlu receptor ligand. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
黄尿酸（XA）是一种由色氨酸代谢通过 3-羟基犬尿氨酸的转氨基作用产生的分子，最近在体外被鉴定为内源性 II 组（mGlu2 和 mGlu3）代谢型谷氨酸（mGlu）受体配体。II 组 mGlu 受体表达和功能的损伤与精神分裂症的病理生理学有关，而犬尿氨酸代谢途径的多个步骤也是如此。因此，我们在体内检查了 XA，以使用先前已证明能有效地在体内揭示其他 II 组 mGlu 受体配体作用的制剂进一步研究其作为 II 组 mGlu 受体配体的潜力。在大鼠腹侧基底丘脑（VB）中进行了细胞外单细胞记录，同时进行了激动剂、拮抗剂和正变构调节剂的离子电渗和/或静脉内（i.v.）注射 XA。我们发现，当离子电渗和 i.v. 施加时，XA 对感觉抑制的影响类似于其他 II 组 mGlu 受体激动剂，可降低生理感觉刺激引起的 VB 中来自丘脑网状核的抑制。此外，我们推测 XA 可能是 mGlu 受体的第一种潜在内源性变构激动剂（称为“内源性物质”）。由于 II 组受体和犬尿氨酸代谢途径都与精神分裂症的病理生理学密切相关，因此 XA 可能在抗精神病研究中发挥关键作用，因为这种潜在的内源性物质代表了这两个生物学参数的融合，以及一类新型的 II 组 mGlu 受体配体。本文是特刊“代谢型谷氨酸受体”的一部分。
