The NMDA receptor hypofunction model of psychosis
The NMDA receptor hypofunction model of psychosis
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DOI：
10.1196/annals.1300.008
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Farber, NB
中科院分区：
文献类型：
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作者：
Farber, NB
NMDA谷氨酸受体的拮抗剂，包括苯环己哌啶（PCP）、氯胺酮和CGS-19755，可引起人类认知和行为变化。在啮齿类动物中，这些物质产生无数的组织病理学和神经化学变化。多项证据表明，大量这些药物诱导的效应是相同的一般去抑制过程的剂量依赖性表现，其中NMDA拮抗剂消除GABA能抑制，导致乙酰胆碱和谷氨酸同时过量释放。脑内NMDA受体功能减退（NRHypo）严重程度的逐渐增加对脑功能产生越来越大的影响。即使是相对低剂量的NMDA拮抗剂药物诱导的NMDA受体的兴奋不足，也可以产生特定形式的记忆功能障碍，而没有临床上明显的精神病。更严重的NRHypo可以产生与精神分裂症恶化非常相似的临床综合征。最后，成人大脑中持续和严重的NRHypo与一种具有良好特征的神经病理学特征的神经毒性形式相关。在本文中，几个这些影响的NMDA拮抗剂和可能的机制负责生产它们将进行审查。此外，还将考虑NRHypo在特发性精神障碍的病理生理学中的可能作用。
Antagonists of the NMDA glutamate receptor, including phencyclidine (PCP), ketamine, and CGS-19755, produce cognitive and behavioral changes in humans. In rodents these agents produce a myriad of histopathological and neurochemical changes. Several lines of evidence suggest that a large number of these drug-induced effects are dose-dependent manifestations of the same general disinhibition process in which NMDA antagonists abolish GABAergic inhibition, resulting in the simultaneous excessive release of acetylcholine and glutamate. Progressive increases in the severity of NMDA receptor hypofunction (NRHypo) within the brain produce an increasing range of effects on brain function. Underexcitation of NMDA receptors, induced by even relatively low doses of NMDA antagonist drugs, can produce specific forms of memory dysfunction without clinically evident psychosis. More severe NRHypo can produce a clinical syndrome very similar to a psychotic schizophrenic exacerbation. Finally, sustained and severe NRHypo in the adult brain is associated with a form of neurotoxicity with well-characterized neuropathological features. In this paper several of these effects of NMDA antagonists and a likely mechanism responsible for producing them will be reviewed. In addition the possible role of NRHypo in the pathophysiology of idiopathic psychotic disorders will be considered.