Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, 56000 Cheras, Kuala Lumpur, Malaysia.
BRAINetwork Centre for Neurocognitive Science, School of Health Sciences, Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.
Curr Drug Targets. 2018;19(8):907-915. doi: 10.2174/1389450118666170511144302.
In the past decade, many studies have highlighted the role of metabotropic glutamate receptor subtype 5 (mGlu5) modulators in attenuating alcohol-related biological effects such as alcohol consumption, alcohol-seeking and relapse-like behaviors. Taken together, these findings suggest that pharmacological agents acting at mGlu5 could be promising tools in curbing inebriation. mGlu5s are present abundantly in brain regions known to be involved in emotion regulation, motivation and drug administration. On a cellular level, they are primarily located at the postsynaptic part of the neuron where the receptor is functionally linked to various downstream proteins that are involved in cell signaling and gene transcription that mediate the alcohol-induced neuroplasticity. As well, the discovery of a functional link between mGlu5 and a specific isozyme, Protein Kinase C epsilon (PKCε) in mediating the attenuating effects of selective negative allosteric modulators of mGlu5 such as methyl- 6(phenylethynyl)pyridine (MPEP) and 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) has sparked interesting speculations. In this article, we shall review the following: the effects of acute and chronic alcohol intake on mGlu5 signaling; the effects of mGlu5 ligands on alcohol-related neurobehavioral changes that are currently being studied both at pre-clinical and clinical stages; and the mechanisms underlying the pharmacological effects of these drugs.
在过去的十年中，许多研究强调了代谢型谷氨酸受体亚型 5（mGlu5）调节剂在减轻与酒精相关的生物学效应（如饮酒、觅酒和复发样行为）中的作用。这些发现表明，作用于 mGlu5 的药理学药物可能是抑制醉酒的有前途的工具。mGlu5 在已知参与情绪调节、动机和药物管理的大脑区域中大量存在。在细胞水平上，它们主要位于神经元的突触后部分，在那里，受体与各种下游蛋白功能相连，这些蛋白参与细胞信号转导和基因转录，介导酒精引起的神经可塑性。此外，mGlu5 与特定同工型蛋白激酶 C epsilon（PKCε）之间的功能联系的发现，在介导 mGlu5 的选择性负变构调节剂（如甲基-6（苯乙炔基）吡啶（MPEP）和 3-（（2-甲基-4-噻唑基）乙炔基）吡啶（MTEP））的减弱作用方面引发了有趣的推测。在本文中，我们将回顾以下内容：急性和慢性酒精摄入对 mGlu5 信号转导的影响；mGlu5 配体对目前在临床前和临床阶段研究的与酒精相关的神经行为变化的影响；以及这些药物的药理学效应的机制。
