Glutamatergic targets for new alcohol medications.
Glutamatergic targets for new alcohol medications.
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DOI：
10.1007/s00213-013-3226-2
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发表时间：
2013-10
影响因子：
3.4
通讯作者：
Krystal, John H.
中科院分区：
文献类型：
--
作者：
Holmes, Andrew;Spanagel, Rainer;Krystal, John H.
越来越有说服力的文献指出，谷氨酸系统在调节酒精对行为的影响和酒精中毒的病理生理方面发挥了重要作用。临床前研究表明，谷氨酸信号调节乙醇的醉人和奖励效应的某些方面，并在长期酒精暴露后经历适应，这可能有助于戒断、渴望和强迫寻求药物，从而推动酒精滥用和酒精中毒。我们讨论了以谷氨酸系统为靶点作为治疗酒精使用障碍的一种新的药物治疗方法的潜力，重点讨论了谷氨酸系统的五个主要组成部分：N-甲基-D-天冬氨酸受体和特定的N-甲基-D-天冬氨酸受体，N-甲基-D-天冬氨酸受体上的甘氨酸B位点，L-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic酸性离子(AMPA)和红藻氨酸(KAR)受体，代谢性受体(MGluR)和谷氨酸转运体。长期酗酒会产生一种高谷氨酸能状态，其特征是细胞外谷氨酸水平升高，谷氨酸受体和转运体改变。在啮齿动物和人类受试者中，药物操纵谷氨酸能神经传递改变与酒精相关的行为，包括醉酒、戒断和寻酒。阻断NMDA和AMPA受体可以减少啮齿动物的酒精摄入量，但副作用可能会限制这一治疗方法。选择性地靶向NMDA和AMPA受体亚单位(例如，GluN2B、GluA3)或NMDAR甘氨酸B位点提供了一种替代方法。阻断mGluR5可以有效地影响啮齿类动物的各种与酒精相关的行为，mGluR2/3激动剂也可以抑制酒精消费。最后，谷氨酸转运体的上调可能会减轻酒精引起的过量谷氨酸的行为和神经毒性后遗症。尽管仍然存在许多挑战，但瞄准谷氨酸系统为开发酒精中毒的新疗法提供了真正的希望。
An increasingly compelling literature points to a major role for the glutamate system in mediating the effects of alcohol on behavior and the pathophysiology of alcoholism. Preclinical studies indicate that glutamate signaling mediates certain aspects of ethanol’s intoxicating and rewarding effects, and undergoes adaptations following chronic alcohol exposure that may contribute to the withdrawal, craving and compulsive drug-seeking that drive alcohol abuse and alcoholism. We discuss the potential for targeting the glutamate system as a novel pharmacotherapeutic approach to treating alcohol use disorders, focusing on five major components of the glutamate system: the N-methyl-D-aspartate (NMDA) receptor and specific NMDA subunits, the glycineB site on the NMDA receptors (NMDAR), L-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ionotropic (AMPA) and kainate (KAR) receptors, metabotropic receptors (mGluR), and glutamate transporters. Chronic alcohol abuse produces a hyperglutamatergic state, characterized by elevated extracellular glutamate and altered glutamate receptors and transporters. Pharmacologically manipulating glutamatergic neurotransmission alters alcohol-related behaviors including intoxication, withdrawal, and alcohol-seeking, in rodents and human subjects. Blocking NMDA and AMPA receptors reduces alcohol consumption in rodents, but side-effects may limit this as a therapeutic approach. Selectively targeting NMDA and AMPA receptor subunits (e.g., GluN2B, GluA3), or the NMDAR glycineB site offers an alternative approach. Blocking mGluR5 potently affects various alcohol-related behaviors in rodents, and mGluR2/3 agonism also suppresses alcohol consumption. Finally, glutamate transporter upregulation may mitigate behavioral and neurotoxic sequelae of excess glutamate caused by alcohol. Despite the many challenges that remain, targeting the glutamate system offers genuine promise for developing new treatments for alcoholism.
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影响因子：
10.6
作者：
Besheer, Joyce;Grondin, Julie J. M.;Cannady, Reginald;Sharko, Amanda C.;Faccidomo, Sara;Hodge, Clyde W.
通讯作者：
Hodge, Clyde W.
影响因子：
2.9
作者：
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通讯作者：
LEONARD, SS
影响因子：
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作者：
Abrahao, Karina Possa;Ariwodola, Olusegun J.;Weiner, Jeffrey L.
通讯作者：
Weiner, Jeffrey L.
影响因子：
6
作者：
Baltieri, Danilo Antonio;Daro, Fabio Ruiz;de Andrade, Arthur Guerra
通讯作者：
de Andrade, Arthur Guerra
影响因子：
2.8
作者：
Brager AJ;Prosser RA;Glass JD
通讯作者：
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