Clozapine Normalizes a Glutamatergic Transmission Abnormality Induced by an Impaired NMDA Receptor in the Thalamocortical Pathway via the Activation of a Group III Metabotropic Glutamate Receptor
Clozapine Normalizes a Glutamatergic Transmission Abnormality Induced by an Impaired NMDA Receptor in the Thalamocortical Pathway via the Activation of a Group III Metabotropic Glutamate Receptor
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DOI：
10.3390/biom9060234
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发表时间：
2019-06-01
期刊：
影响因子：
5.5
通讯作者：
Okada, Motohiro
中科院分区：
文献类型：
--
作者：
Fukuyama, Kouji;Kato, Ryo;Okada, Motohiro
金标准抗精神病药物治疗难治性精神分裂症的药理学机制，如氯氮平（CLZ），仍不清楚。我们通过多探针微透析和原代培养星形胶质细胞研究MK801和CLZ对丘脑皮质谷氨酸通路三方突触传递的影响，探讨CLZ的作用机制。内侧前额叶皮层（mPFC）的l-谷氨酸释放不受MK801局部给药的影响，但通过RTN-MDTN通路的gaba能解抑制，在丘脑中背核（MDTN）和丘脑网状核（RTN）中增强。局部给药治疗相关浓度的CLZ进入mPFC和MDTN增加，但不影响mPFC的l-谷氨酸释放。将治疗相关浓度的CLZ局部注入mPFC，通过突触前III组代谢谷氨酸受体（III- mglur）激活，减少mk801诱导的mPFC l-谷氨酸释放。然而，毒性浓度的CLZ激活了与半通道相关的l-谷氨酸释放。本研究表明RTN是一个候选的产生区域，在该区域受损的n -甲基-d-天冬氨酸(NMDA)/谷氨酸受体可能产生丘脑皮质高谷氨酸能传递。此外，我们确定了CLZ在治疗难治性精神分裂症中的优势及其严重不良反应的几种机制：(1)通过激活mPFC突触前III-mGluR来预防丘脑皮质高谷氨酸能传递；(2)激活星形胶质细胞释放与半通道相关的l-谷氨酸。这些作用可能有助于CLZ独特的临床特征。
Pharmacological mechanisms of gold-standard antipsychotics against treatment-refractory schizophrenia, such as clozapine (CLZ), remain unclear. We aimed to explore the mechanisms of CLZ by investigating the effects of MK801 and CLZ on tripartite synaptic transmission in the thalamocortical glutamatergic pathway using multi-probe microdialysis and primary cultured astrocytes. l-glutamate release in the medial prefrontal cortex (mPFC) was unaffected by local MK801 administration into mPFC but was enhanced in the mediodorsal thalamic nucleus (MDTN) and reticular thalamic nucleus (RTN) via GABAergic disinhibition in the RTN-MDTN pathway. The local administration of therapeutically relevant concentrations of CLZ into mPFC and MDTN increased and did not affect mPFC l-glutamate release. The local administration of the therapeutically relevant concentration of CLZ into mPFC reduced MK801-induced mPFC l-glutamate release via presynaptic group III metabotropic glutamate receptor (III-mGluR) activation. However, toxic concentrations of CLZ activated l-glutamate release associated with hemichannels. This study demonstrated that RTN is a candidate generator region in which impaired N-methyl-d-aspartate (NMDA)/glutamate receptors likely produce thalamocortical hyperglutamatergic transmission. Additionally, we identified several mechanisms of CLZ relating to its superiority in treatment-resistant schizophrenia and its severe adverse effects: (1) the prevention of thalamocortical hyperglutamatergic transmission via activation of mPFC presynaptic III-mGluR and (2) activation of astroglial l-glutamate release associated with hemichannels. These actions may contribute to the unique clinical profile of CLZ.