Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.
Neuropharmacology. 2009 Aug;57(2):172-82. doi: 10.1016/j.neuropharm.2009.05.002. Epub 2009 May 27.
LY341495 is a metabotropic glutamate receptor (mGluR) antagonist showing selectivity to mGluR2/3 but having measurable antagonist efficacy across all mGluR subtypes at 10-1000 fold higher concentrations. In vivo in rodents it increases locomotor activity and wakefulness, enhances cognition and modulates emotions. It also induces widespread neuronal activation measured as c-Fos expression. To further investigate the receptor subtypes through which LY341495 might act in vivo we analyzed how its effects are altered in mGluR2-knockout (KO) and mGluR3-KO brains. In most regions, LY341495 (3 mg/kg, i.p., 2.5 h) -induced c-Fos expression was not altered in either KO brain. However, in mGluR3-KO mice, LY341495 was almost inactive in the central extended amygdala [central nucleus of the amygdala, lateral (CeL) and bed nucleus of the stria terminalis, laterodorsal (BSTLD)], suggesting that acute blockade of mGluR3 is activating these neurons in wildtype brain. In the ventrolateral nucleus of the thalamus (VL), LY341495 produced a significantly enhanced response in mGluR3-KO mice and attenuated response in mGluR2-KO mice. We also analyzed locomotion in familiar environment and found that locomotor activity was dose-dependently increased by LY341495 (1-30 mg/kg, i.p.) regardless of the genotype. In unfamiliar environment, both KO strains showed enhanced sensitivity to LY341495 in reducing locomotor habituation. Together our results indicate that certain effects of LY341495 may not be mediated by a blockade of either mGluR2 or mGluR3, but may involve other mGluR subtypes. Alternatively, functions of mGluR2 and mGluR3 may be redundant, resulting similar effects irrespective the receptor subtype being antagonized in vivo by LY341495.
LY341495 是一种代谢型谷氨酸受体（mGluR）拮抗剂，对 mGluR2/3 具有选择性，但在 10-1000 倍更高浓度下对所有 mGluR 亚型均具有可测量的拮抗剂效力。在体内，它会增加啮齿动物的运动活动和清醒度，增强认知并调节情绪。它还会诱导广泛的神经元激活，表现为 c-Fos 表达。为了进一步研究 LY341495 在体内可能作用的受体亚型，我们分析了其在 mGluR2 敲除（KO）和 mGluR3-KO 大脑中的作用如何改变。在大多数区域，LY341495（3mg/kg，ip，2.5h）诱导的 c-Fos 表达在 KO 脑内均未改变。然而，在 mGluR3-KO 小鼠中，LY341495 在中央延伸杏仁核中的作用几乎无效[杏仁核中央核、外侧（CeL）和终纹床核背外侧（BSTLD）]，表明急性阻断 mGluR3 会激活野生型大脑中的这些神经元。在丘脑腹外侧核（VL）中，LY341495 在 mGluR3-KO 小鼠中产生了显著增强的反应，而在 mGluR2-KO 小鼠中产生了减弱的反应。我们还分析了在熟悉环境中的运动，发现 LY341495（1-30mg/kg，ip）剂量依赖性地增加了运动活动，而与基因型无关。在不熟悉的环境中，两种 KO 株在减少运动习惯化方面对 LY341495 的敏感性均增强。我们的研究结果表明，LY341495 的某些作用可能不是通过阻断 mGluR2 或 mGluR3 介导的，而是可能涉及其他 mGluR 亚型。或者，mGluR2 和 mGluR3 的功能可能是冗余的，因此无论 LY341495 在体内拮抗哪种受体亚型，都会产生相似的作用。
