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首页> 外文期刊>CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) >Glutamate: The New Frontier in Pharmacotherapy for Cocaine Addiction
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Glutamate: The New Frontier in Pharmacotherapy for Cocaine Addiction

机译：谷氨酸：可卡因成瘾的药物治疗新领域

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Considerable research into the neurobiology of cocaine addiction has shed light on the role of glutamate. Findings from models of relapse to cocaine-seeking indicate that the glutamatergic system is critically involved, as glutamate levels in the nucleus accumbens increase during reinstatement and glutamate receptor activation is necessary for reinstatement to drug-seeking. Thus, it would seem beneficial to block the increased glutamate release, but full antagonists of ionotropic glutamate receptors produce undesirable side effects. Therefore, modulation of glutamatergic transmission would be advantageous and provide novel pharmacotherapeutic avenues. Pharmacotherapies have been developed that have the potential to modulate excessive glutamatergic transmission through ionotropic and metabotropic (mGluR) glutamate receptors. Compounds that modulate glutamatergic transmission through ionotropic glutamate receptors include the non-competitive N-methyl-D-aspartic acid antagonists, amantadine and memantine, and the partial N-methyl-D-aspartic acid agonist d-cycloserine. They have shown promise in preclinical models of cocaine addiction. The mGluR2/3 agonist LY379268 is effective in inhibiting cocaine seeking in preclinical animal models and could decrease stress-induced relapse due to its anxiolytic effects. Similarly, the mGluR1/5 antagonists, 2-methyl-6-(phenylethynyl)pyridine and 3-[2- methyl-4-thiazolyl)ethynyl]pyridine, have shown to be effective in preclinical models of cocaine addiction. The cysteine pro-drug, N-acetylcysteine, restores the inhibitory tone on presynaptic glutamate receptors and has been effective in reducing cue-induced craving and cocaine use in humans. Furthermore, anticonvulsants, such as topiramate or lamotrigine, have shown efficacy in treating cocaine dependence or reducing relapse in humans. Future pharmacotherapy may focus on manipulating signal transduction proteins and pathways, which include Homer/N-methyl-D-aspartic acid complexes, to provide effective treatment for cocaine addiction.
机译：对可卡因成瘾的神经生物学的大量研究揭示了谷氨酸的作用。从复发到可卡因寻求模型的发现表明，谷氨酸能系统是至关重要的，因为在恢复过程中伏隔核中的谷氨酸水平增加，而谷氨酸受体的激活对于恢复寻求药物是必需的。因此，阻断增加的谷氨酸盐的释放似乎是有益的，但是离子型谷氨酸盐受体的完全拮抗剂会产生不良的副作用。因此，调节谷氨酸能传递将是有利的，并提供新颖的药物治疗途径。已经开发了具有通过离子型和代谢型（mGluR）谷氨酸受体调节过量谷氨酸能传递的潜力的药物疗法。通过离子型谷氨酸受体调节谷氨酸能传递的化合物包括非竞争性N-甲基-D-天冬氨酸拮抗剂，金刚烷胺和美金刚，以及部分N-甲基-D-天冬氨酸激动剂d-环丝氨酸。他们在可卡因成瘾的临床前模型中显示出希望。 mGluR2 / 3激动剂LY379268可有效抑制临床前动物模型中的可卡因搜寻，并由于其抗焦虑作用而可降低应激诱导的复发。类似地，mGluR1 / 5拮抗剂2-甲基-6-（苯基乙炔基）吡啶和3- [2-甲基-4-噻唑基）乙炔基]吡啶在可卡因成瘾的临床前模型中显示有效。半胱氨酸前药N-乙酰半胱氨酸可恢复对突触前谷氨酸受体的抑制作用，并已有效减少了线索诱导的对人的渴望和可卡因的使用。此外，抗惊厥药，例如托吡酯或拉莫三嗪，在治疗可卡因依赖性或减少人类复发方面显示出功效。未来的药物治疗可能集中于操纵信号转导蛋白和途径，包括Homer / N-甲基-D-天冬氨酸复合物，以提供可卡因成瘾的有效治疗方法。

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