The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice.
The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice.
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DOI：
10.1007/s00213-010-1802-2
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发表时间：
2010-05
影响因子：
3.4
通讯作者：
Markou, Athina
中科院分区：
文献类型：
--
作者：
Chen, Hwei-Hsien;Stoker, Astrid;Markou, Athina
缺乏代谢型谷氨酸受体5（mGluR 5）的小鼠表现出降低的谷氨酸能功能和行为异常，包括可能与精神分裂症相关的惊吓反应的前脉冲抑制（PPI）缺陷。因此，这些小鼠是一种动物模型，可用于临床前评价潜在的新类别的抗精神病化合物。最近的临床研究表明，通过不同的机制，如N-甲基-d-天冬氨酸（NMDA）受体甘氨酸位点的增强，II组mGluR的激活，和谷氨酸-半胱氨酸反向转运蛋白的激活，调节谷氨酸能传递的几种化合物，是有效的治疗精神分裂症。这项工作的目的是评估肌氨酸（甘氨酸转运蛋白1 [GlyT 1]的选择性抑制剂），LY 379268（II组mGluR激动剂）和N-乙酰半胱氨酸（半胱氨酸前药，间接激活胱氨酸-谷氨酸反向转运蛋白，增加突触外空间的谷氨酸水平）对mGluR 5敲除小鼠PPI缺陷的影响。肌氨酸和N-乙酰半胱氨酸，但不是LY 379268，改善PPI赤字mGluR 5敲除小鼠。II组mGluR拮抗剂LY 341495没有阻断N-乙酰半胱氨酸恢复PPI缺陷的能力，表明N-乙酰半胱氨酸的作用不归因于谷氨酸激活II组mGluR。这些研究结果提供的证据表明，mGluR 5和NMDA受体之间的相互作用参与PPI的调节，并表明，激活谷氨酸受体，而不是II组受体，增加内源性谷氨酸传输，可能会改善与mGluR 5缺乏症相关的行为异常。
Mice lacking metabotropic glutamate receptors 5 (mGluR5) exhibit reduced glutamatergic function and behavioral abnormalities, including deficits in prepulse inhibition (PPI) of the startle response that may be relevant to schizophrenia. Thus, these mice are an animal model that may be used for preclinical evaluation of potentially new classes of antipsychotic compounds. Recent clinical studies have suggested several compounds that modulate glutamatergic transmission through distinct mechanisms, such as potentiation of the N-methyl-d-aspartate (NMDA) receptor glycine site, activation of group II mGluR, and activation of glutamate-cysteine antiporters, as being efficacious in the treatment of schizophrenia. The aim of this work is to evaluate the effects of sarcosine (a selective inhibitor of the glycine transporter 1 [GlyT1]), LY379268 (a group II mGluR agonist), and N-acetylcysteine (a cysteine prodrug that indirectly activates cystine-glutamate antiporters to increase glutamate levels in the extrasynaptic space) on PPI deficits in mGluR5 knockout mice. Sarcosine and N-acetylcysteine, but not LY379268, ameliorated PPI deficits in mGluR5 knockout mice. The ability of N-acetylcysteine to restore PPI deficits was not blocked by the group II mGluR antagonist LY341495, indicating that the effects of N-acetylcysteine were not attributable to activation of group II mGluRs by glutamate. These findings provide evidence that the interactions between mGluR5 and NMDA receptors are involved in the regulation of PPI and suggest that activation of glutamate receptors, other than group II receptors, by increased endogenous glutamate transmission, may ameliorate the behavioral abnormalities associated with mGluR5 deficiency.
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影响因子：
3.4
作者：
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通讯作者：
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作者：
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作者：
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通讯作者：
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影响因子：
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作者：
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