Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan.
Biomolecules. 2019 Nov 18;9(11):746. doi: 10.3390/biom9110746.
N-methyl-d-aspartate/glutamate receptor (NMDAR) is one of the major voltage-sensitive ligand-gated cation channel. Several noncompetitive NMDAR antagonists contribute to pathophysiology of schizophrenia and mood disorders; however, the effects of inhibition of NMDAR on several transmitter system have not been well clarified. Thus, this study determined the selective NMDAR antagonist, MK801 (dizocilpine), on thalamocortical, mesothalamic, and mesocortical transmissions associated with l-glutamate, GABA, serotonin, norepinephrine, and dopamine using multiprobe microdialysis. Perfusion with MK801 into the medial prefrontal cortex (mPFC) increased and decreased respective regional releases of monoamine and GABA without affecting l-glutamate. The mPFC MK801-induced monoamine release is generated by the regional GABAergic disinhibition. Perfusion with MK801 into the reticular thalamic nucleus (RTN) decreased GABA release in the mediodorsal thalamic nucleus (MDTN) but increased releases of l-glutamate and catecholamine without affecting serotonin in the mPFC. The RTN MK801-induced l-glutamate release in the mPFC was generated by GABAergic disinhibition in the MDTN, but RTN MK801-induced catecholamine release in the mPFC was generated by activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/glutamate receptor (AMPAR) which received l-glutamate release from thalamocortical glutamatergic terminals in the mPFC. Perfusion with MK801 into the dorsal raphe nucleus (DRN) decreased GABA release in the DRN but selectively increased serotonin release in the MDTN and mPFC. These DRN MK801-induced serotonin releases in the both mPFC and MDTN were also generated by GABAergic disinhibition in the DRN. These results indicate that the GABAergic disinhibition induced by NMDAR inhibition plays important roles in the MK801-induced releases of l-glutamate and monoamine in thalamic nuclei and cortex.
N-甲基-D-天冬氨酸/谷氨酸受体（NMDAR）是主要的电压门控配体门控阳离子通道之一。几种非竞争性 NMDAR 拮抗剂与精神分裂症和心境障碍的病理生理学有关；然而，抑制 NMDAR 对几种递质系统的影响尚未得到很好的阐明。因此，本研究使用多探针微透析法确定选择性 NMDAR 拮抗剂 MK801（地卓西平）对与 l-谷氨酸、GABA、血清素、去甲肾上腺素和多巴胺相关的丘脑皮质、中丘脑和中皮质传递的影响。将 MK801 灌注到前额叶皮质（mPFC）中会增加和减少相应区域的单胺和 GABA 的释放，而不影响 l-谷氨酸。mPFC 中 MK801 诱导的单胺释放是由区域 GABA 能抑制解除引起的。将 MK801 灌注到网状丘脑核（RTN）中会降低内侧背侧丘脑核（MDTN）中的 GABA 释放，但会增加 mPFC 中的 l-谷氨酸和儿茶酚胺释放，而不会影响血清素。mPFC 中 RTN MK801 诱导的 l-谷氨酸释放是由 MDTN 中的 GABA 能抑制解除引起的，但 RTN MK801 诱导的 mPFC 中的儿茶酚胺释放是由激活 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸/谷氨酸受体（AMPAR）引起的，该受体接收来自 mPFC 中丘脑皮质谷氨酸能末梢的 l-谷氨酸释放。将 MK801 灌注到中缝核（DRN）中会降低 DRN 中的 GABA 释放，但选择性地增加 MDTN 和 mPFC 中的血清素释放。DRN 中 MK801 诱导的这两种 mPFC 和 MDTN 中的血清素释放也是由 DRN 中的 GABA 能抑制解除引起的。这些结果表明，NMDAR 抑制诱导的 GABA 能抑制在丘脑核和皮质中 MK801 诱导的 l-谷氨酸和单胺释放中发挥重要作用。
