Olney J W, Farber N B
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Neuropsychopharmacology. 1995 Dec;13(4):335-45. doi: 10.1016/0893-133X(95)00079-S.
Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate (Glu) receptor have become the focus of considerable attention as potential neurotherapeutic agents in view of mounting evidence implicating NMDA receptors in acute central nervous system (CNS) injury syndromes such as stroke, trauma, and status epilepticus. In addition, NMDA receptor antagonists are of potential interest for the clinical management of neuropathic pain and preventing the development of tolerance to opiate analgesics. A potentially serious obstacle to the development of NMDA antagonists as neurotherapeutic drugs is the paradoxical fact that whereas these agents do have significant neurotherapeutic potential, they also have psychotogenic and neurotoxic properties. We have been intensively investigating the mechanisms underlying these adverse properties and have discovered several methods of suppressing or preventing their expression. In addition, we have been exploring the possibility that a common mechanism may underlie the psychotogenic and neurotoxic actions of these agents and that this mechanism may have relevance to the pathogenesis of idiopathic psychotic processes such as schizophrenia. In this chapter, we will review our findings pertaining to NMDA antagonists in the dual context of their value as tools for exploring mechanisms underlying neuropsychiatric disturbances, particularly schizophrenia, and their potential promise as therapeutic agents. For additional references and a more complete elaboration of our hypothesis pertaining to NMDA receptor dysfunction and schizophrenia, please see a recent review (Olney and Farber 1995).
鉴于越来越多的证据表明N-甲基-D-天冬氨酸（NMDA）亚型的谷氨酸（Glu）受体在急性中枢神经系统（CNS）损伤综合征如中风、创伤和癫痫持续状态中起作用，该受体的拮抗剂作为潜在的神经治疗药物已成为相当受关注的焦点。此外，NMDA受体拮抗剂对于神经性疼痛的临床管理以及预防对阿片类镇痛药产生耐受性也具有潜在的意义。NMDA拮抗剂作为神经治疗药物开发的一个潜在严重障碍是一个矛盾的事实，即尽管这些药物确实具有显著的神经治疗潜力，但它们也具有致幻和神经毒性特性。我们一直在深入研究这些不良特性背后的机制，并发现了几种抑制或预防其表达的方法。此外，我们一直在探索一种可能性，即这些药物的致幻和神经毒性作用可能有一个共同的机制，并且这种机制可能与诸如精神分裂症等特发性精神病过程的发病机制有关。在本章中，我们将在NMDA拮抗剂作为探索神经精神障碍特别是精神分裂症潜在机制的工具的价值以及作为治疗药物的潜在前景这一双重背景下，综述我们的研究结果。有关更多参考文献以及我们关于NMDA受体功能障碍和精神分裂症假说的更完整阐述，请参阅最近的一篇综述（Olney和Farber，1995年）。
