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基底神经节中的代谢型谷氨酸受体2:成瘾治疗的新前沿

mGlu2 Receptors in the Basal Ganglia: A New Frontier in Addiction Therapy.

作者信息

Mao Li-Min, Puthumana Elizabeth, Wang John Q

机构信息

Department of Biomedical Sciences, University of Missouri-Kansas City, School of Medicine, Kansas City, MO 64108, USA.

Department of Anesthesiology, University of Missouri-Kansas City, School of Medicine, Kansas City, MO 64108, USA.

出版信息

Front Biosci (Landmark Ed). 2025 Aug 28;30(8):26637. doi: 10.31083/FBL26637.

Abstract

Glutamate is an important neurotransmitter in the mammalian brain. Among the receptors that glutamate interacts with is metabotropic glutamate (mGlu) receptor 2, a Gα-coupled receptor. These receptors are primarily located on glutamatergic nerve terminals and act as presynaptic autoreceptors to produce feedback inhibition of glutamate release. Abundant mGlu2 receptors are distributed in major glutamatergic pathways in the basal ganglia, especially the corticostriatal and thalamostriatal projections in the striatum. These receptors are involved in the regulation of motivation, reward processing, learning, motor, and cognitive functions. As an inhibitory presynaptic receptor, mGlu2 is linked to the addictive properties of drugs of abuse, a topic summarized in this review. Chronic exposure to multiple addictive drugs and alcohol causes the adaptive downregulation of mGlu2 receptors in their expression and function in the key regions of the limbic reward circuit. This downregulation contributes to the remodeling of limbic excitatory synaptic transmission and plasticity critical for enduring drug-seeking behavior. Normalization of mGlu2 activity by pharmacological or genetic approaches attenuates drug taking and seeking. Here, we highlight that recent progress in mGlu2 biology research demonstrates the pivotal roles of mGlu2 receptors in different aspects of drug addiction. mGlu2 subtype-selective agents (both orthosteric and allosteric compounds) thus have the potential to be developed into novel pharmacotherapies for addictive conditions.

摘要

谷氨酸是哺乳动物大脑中一种重要的神经递质。谷氨酸与之相互作用的受体中,代谢型谷氨酸(mGlu)受体2是一种与Gα偶联的受体。这些受体主要位于谷氨酸能神经末梢,作为突触前自身受体发挥作用,对谷氨酸释放产生反馈抑制。丰富的mGlu2受体分布于基底神经节的主要谷氨酸能通路中,尤其是纹状体中的皮质纹状体和丘脑纹状体投射。这些受体参与动机、奖赏处理、学习、运动和认知功能的调节。作为一种抑制性突触前受体,mGlu2与滥用药物的成瘾特性有关,本综述将对此主题进行总结。长期接触多种成瘾药物和酒精会导致边缘奖赏回路关键区域中mGlu2受体的表达和功能出现适应性下调。这种下调有助于边缘兴奋性突触传递的重塑以及对持久觅药行为至关重要的可塑性。通过药理学或遗传学方法使mGlu2活性正常化可减轻药物摄取和觅药行为。在此我们强调,mGlu2生物学研究的最新进展证明了mGlu2受体在药物成瘾不同方面的关键作用。因此,mGlu2亚型选择性药物(包括正构和变构化合物)有潜力被开发成为治疗成瘾性疾病的新型药物疗法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b4f7/12419489/65a72d671822/nihms-2108523-f0001.jpg

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