Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment.
Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment.
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发表时间：
2003
影响因子：
5.2
通讯作者：
M. Laruelle;L. Kegeles;A. Abi-Dargham
中科院分区：
文献类型：
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作者：
M. Laruelle;L. Kegeles;A. Abi-Dargham
与精神分裂症相关的基本病理过程仍不确定，但多种证据表明，这种情况与 (1) 纹状体多巴胺 (DA) D2 受体过度刺激，(2) 前额叶 DA D1 受体刺激不足，以及 (3) 涉及 N-甲基-d-天冬氨酸 (NMDA) 谷氨酸 (GLU) 传递的前额叶连接改变有关。 受体。本章首先简要讨论了这些异常的当前知识状况，重点是临床分子影像研究的结果。纹状体 D2 受体过度刺激的证据有赖于强有力的药理学证据，并且最近得到了脑成像研究的支持。前额皮质 (PFC) D1 受体刺激缺陷的假说几乎完全源自临床前研究。最近出现了与这一假设相符的初步成像数据。 NMDA 功能减退假说主要来源于间接药理学数据。然后回顾了与精神分裂症相关的 DA 和 GLU 系统之间的相互作用。动物和影像数据支持一般模型，即精神分裂症中假定的 DA 失衡（纹状体过多和皮质缺乏）可能继发于 PFC 中的 NMDA 功能减退及其联系。同样重要的是这种 DA 失衡对纹状体和皮质中 NMDA 功能的潜在后果，随后将进行讨论。总之，有人提出精神分裂症与 GLU 和 DA 传输异常相关：PFC 及其连接中的 NMDA 功能减退可能会产生 DA 系统的失调模式，进而进一步削弱 NMDA 介导的连接性和可塑性。
The fundamental pathological process(es) associated with schizophrenia remain(s) uncertain, but multiple lines of evidence suggest that this condition is associated with (1) excessive stimulation of striatal dopamine (DA) D2 receptors, (2) deficient stimulation of prefrontal DA D1 receptors and, (3) alterations in prefrontal connectivity involving glutamate (GLU) transmission at N-methyl-d-aspartate (NMDA) receptors. This chapter first briefly discusses the current knowledge status for these abnormalities, with emphasis on results derived from clinical molecular imaging studies. The evidence for hyperstimulation of striatal D2 receptors rests on strong pharmacological evidence and has recently received support from brain imaging studies. The hypothesis of deficient prefrontal cortex (PFC) D1 receptor stimulation is almost entirely derived from preclinical studies. Preliminary imaging data compatible with this hypothesis have recently emerged. The NMDA hypofunction hypothesis originates mainly from indirect pharmacological data. The interactions between DA and GLU systems relevant to schizophrenia are then reviewed. Animal and imaging data supporting the general model that the putative DA imbalance in schizophrenia (striatal excess and cortical deficiency) might be secondary to NMDA hypofunction in the PFC and its connections are presented. Equally important are the potential consequences of this DA imbalance for NMDA function in the striatum and the cortex, which are subsequently discussed. In conclusion, it is proposed that schizophrenia is associated with strongly interconnected abnormalities of GLU and DA transmission: NMDA hypofunction in the PFC and its connections might generate a pattern of dysregulation of DA systems that, in turn, further weakens NMDA-mediated connectivity and plasticity.