Serotonin model of schizophrenia: emerging role of glutamate mechanisms
Serotonin model of schizophrenia: emerging role of glutamate mechanisms
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DOI：
10.1016/s0165-0173(99)00046-6
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发表时间：
2000-03-01
影响因子：
--
通讯作者：
Marek, GJ
中科院分区：
文献类型：
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作者：
Aghajanian, GK;Marek, GJ
5-羟色胺（5-HT）假说起源于早期关于致幻药物LSD （d -麦角酸二乙胺）与外周系统5-羟色胺相互作用的研究。最近的研究表明，两种主要的致幻剂，吲哚胺（如LSD）和苯乙胺（如美斯卡林），通过对5-HT2受体的共同作用产生中枢作用。这篇综述的重点是两个大脑区域，蓝斑和大脑皮层，在这两个区域，吲哚胺和苯乙胺致幻剂的作用被证明是由5-HT2A受体介导的：在每种情况下，致幻剂（通过5-HT2A受体）都被发现能增强谷氨酸能的传递。在前额叶皮层，5- ht2a受体的刺激增加了谷氨酸的释放，表现为V层锥体细胞顶端树突区兴奋性突触后电位/电流（EPSPs/EPSCs）的频率显著增加；抑制组II/III代谢性谷氨酸激动剂在突触前作用，AMPA/kainate谷氨酸拮抗剂在突触后作用于非nmda谷氨酸受体，可阻断这种作用。精神分裂症的一种主要替代药物模型，以前被认为与致幻剂完全不同，是基于谷氨酸受体NMDA亚型拮抗剂（如苯环利定和氯胺酮）的拟精神特性。然而，最近发现NMDA拮抗剂的许多作用也可能(1)涉及5-HT2A受体，(2)通过非NMDA（即AMPA/kainate）谷氨酸受体的过度活性介导。此外，谷氨酸传递的药理学操作（例如，通过抑制性代谢谷氨酸激动剂）提供了这两类药物作用之间意想不到的相似之处。鉴于对致幻剂和NMDA拮抗剂作用中谷氨酸能传递改变的重要性的新认识，本综述总结了对精神分裂症病理生理学和治疗的影响。(C) 2000 Elsevier Science B.V.版权所有
The serotonin (5-HT) hypothesis of schizophrenia arose from early studies on interactions between the hallucinogenic drug LSD (D-lysergic acid diethylamide) and 5-HT in peripheral systems. More recent studies have shown that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and phenethylamines (e.g., mescaline), produce their central effects through a common action upon 5-HT2 receptors. This review focuses on two brain regions, the locus coeruleus and the cerebral cortex, where the actions of indoleamine and the phenethylamine hallucinogens have been shown to be mediated by 5-HT2A receptors: in each case, the hallucinogens (via 5-HT2A receptors) have been found to enhance glutamatergic transmission. In the prefrontal cortex, 5-HT2A-receptors stimulation increases the release of glutamate, as indicated by a marked increase in the frequency of excitatory postsynaptic potentials/currents (EPSPs/EPSCs) in the apical dendritic region of layer V pyramidal cells; this effect is blocked by inhibitory group II/III metabotropic glutamate agonists acting presynaptically and by an AMPA/kainate glutamate antagonist, acting postsynaptically at non-NMDA glutamate receptors. A major alternative drug model of schizophrenia, previously believed to be entirely distinct from that of the psychedelic hallucinogens, is based on the psychotomimetic properties of antagonists of the NMDA subtype of glutumate receptor (e.g., phencylidine and ketamine). However, recently it has been found that many of the effects of the NMDA antagonists may also (1) involve 5-HT2A receptors and (2) be mediated through excess activity at non-NMDA (i.e., AMPA/kainate) glutamate receptors. Moreover, pharmacological manipulations of glutamate transmission (e.g., by inhibitory metabotropic glutamate agonists) provide unexpected parallels between the actions of these two classes of drugs. Given an emerging recognition of the importance of alterations in glutamatergic transmission in the actions of both psychedelic hallucinogens an NMDA antagonists, this review concludes with of implications for the pathophysiology and therapy of schizophrenia. (C) 2000 Elsevier Science B.V. All rights reserved.