Glutainate, dopamine, and schizophrenia - From pathophysiology to treatment
Glutainate, dopamine, and schizophrenia - From pathophysiology to treatment
复制标题
DOI：
10.1196/annals.1300.063
复制
发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Abi-Dargham, A
中科院分区：
文献类型：
--
作者：
Laruelle, M;Kegeles, LS;Abi-Dargham, A
与精神分裂症相关的基本病理过程尚不清楚，但多项证据表明，这种情况与(1)纹状体多巴胺（DA） D-2受体的过度刺激，(2)前额叶DA -D- 2受体的刺激不足，以及(3)涉及谷氨酸（GLU）在n -甲基-D-天冬氨酸（NMDA）受体传递的前额叶连接改变有关。本章首先简要讨论了这些异常的当前知识状况，重点介绍了临床分子影像学研究的结果。纹状体D-2受体过度刺激的证据基于强有力的药理学证据，最近也得到了脑成像研究的支持。前额皮质（PFC） D-1受体刺激不足的假设几乎完全来自临床前研究。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的药理学数据。然后回顾与精神分裂症相关的DA和GLU系统之间的相互作用。动物和影像学数据支持一般模型，即精神分裂症中假定的DA失衡（纹状体过量和皮质缺乏）可能继发于PFC及其连接的NMDA功能低下。同样重要的是，这种DA失衡对纹状体和皮层NMDA功能的潜在影响，这在后面会被讨论。综上所述，我们认为精神分裂症与GLU和DA传递异常密切相关：PFC中的NMDA功能低下及其连接可能会导致DA系统失调，进而进一步削弱NMDA介导的连通性和可塑性。
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) D-2 receptors, (2) deficient stimulation of prefrontal DA D, 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 D-2 receptors rests on strong pharmacological evidence and has recently received support from brain imaging studies. The hypothesis of deficient prefrontal cortex (PFC) D-1 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.