Olive M Foster
Center for Drug and Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President Street, MSC 861, Charleston, SC 29425, USA.
Curr Drug Abuse Rev. 2009 Jan;2(1):83-98. doi: 10.2174/1874473710902010083.
There is now compelling evidence that the excitatory amino acid neurotransmitter glutamate plays a pivotal role in drug addiction and alcoholism. As a result, there has been increasing interest in developing glutamate-based therapies for the treatment of addictive disorders. Receptors for glutamate are primarily divided into two classes: ionotropic glutamate receptors (iGluRs) that mediate fast excitatory glutamate transmission, and metabotropic glutamate receptors (mGluRs), which are G-protein coupled receptors that mediate slower, modulatory glutamate transmission. Most iGluR antagonists, while showing some efficacy in animal models of addiction, exhibit serious side effects when tested in humans. mGluR ligands, on the other hand, which have been advanced to testing in clinical trials for various medical conditions, have demonstrated the ability to reduce drug reward, reinforcement, and relapse-like behaviors in animal studies. mGluR ligands that have been shown to be primarily effective are Group I (mGluR1 and mGluR5) negative allosteric modulators and Group II (mGluR2 and mGluR3) orthosteric presynaptic autoreceptor agonists. In this review, we will summarize findings from animal studies suggesting that these mGluR ligands may be of potential benefit in reducing on-going drug self-administration and may aid in the prevention of relapse. The neuroanatomical distribution of mGluR1, mGluR2/3, and mGluR5 receptors and the pharmacological properties of Group I negative allosteric modulators and Group II agonists will also be overviewed. Finally, we will discuss the current status of mGluR ligands in human clinical trials.
目前有确凿证据表明，兴奋性氨基酸神经递质谷氨酸在药物成瘾和酒精中毒中起关键作用。因此，人们对开发基于谷氨酸的疗法来治疗成瘾性疾病的兴趣与日俱增。谷氨酸受体主要分为两类：介导快速兴奋性谷氨酸传递的离子型谷氨酸受体（iGluRs），以及作为G蛋白偶联受体介导较慢的调节性谷氨酸传递的代谢型谷氨酸受体（mGluRs）。大多数离子型谷氨酸受体拮抗剂虽然在成瘾动物模型中显示出一定疗效，但在人体试验时会出现严重副作用。另一方面，已推进到针对各种医学病症进行临床试验的代谢型谷氨酸受体配体，在动物研究中已证明有能力减少药物奖赏、强化及类似复发的行为。已显示主要有效的代谢型谷氨酸受体配体是I组（mGluR1和mGluR5）负性变构调节剂和II组（mGluR2和mGluR3）正构突触前自身受体激动剂。在本综述中，我们将总结动物研究的结果，这些结果表明这些代谢型谷氨酸受体配体可能在减少持续的药物自我给药方面具有潜在益处，并可能有助于预防复发。我们还将概述mGluR1、mGluR2/3和mGluR5受体的神经解剖分布以及I组负性变构调节剂和II组激动剂的药理学特性。最后，我们将讨论代谢型谷氨酸受体配体在人体临床试验中的现状。
