Heresco-Levy Uriel
Department of Psychiatry, Ezrath Nashim-Sarah Herzog Memorial Hospital, Hadassah Medical School, Hebrew University, PO Box 35300, Jerusalem 91351, Israel.
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1113-23. doi: 10.1016/j.pnpbp.2003.09.007.
The neurotransmission mediated by the excitatory amino acids (EAA) glutamate (GLU) and aspartate is of interest to the pharmacotherapy of psychosis due to its role in neurodevelopment and neurotoxicity, its complex interactions with dopaminergic and other neurotransmitter systems and its pivotal importance in recent models of schizophrenia. Accumulating evidence indicates that modulation of glutamatergic neurotransmission may play an important role in the mechanisms of action of atypical antipsychotic drugs. The principles of the phencyclidine (PCP) model of schizophrenia suggest that conventional neuroleptics cannot counteract all aspects of schizophrenia symptomatology, while a more favorable outcome, including anti-negative and cognitive symptoms effects, would be expected with the use of treatment modalities targeting glutamatergic neurotransmission. Clozapine and other presently used atypical antipsychotics differ from conventional neuroleptics in the way they affect various aspects of glutamatergic receptors function. In this context, a specific hypothesis suggesting an agonistic role of clozapine at the N-methyl-D-aspartate (NMDA) subtype of GLU receptors has been postulated. Furthermore, the results of the first generation of clinical trials with glycine (GLY) site agonists of the NMDA receptor in schizophrenia suggest that this type of compounds (1) have efficacy and side effects profiles different than those of conventional neuroleptics and (2) differ in their synergic effects when used in addition to conventional neuroleptics versus clozapine and possibly additional atypical antipsychotics. These findings (1) bring further support to the hypothesis that glutamatergic effects may play an important role in the mechanism of action of atypical antipsychotics, (2) help explain the unique clinical profile of clozapine, and (3) suggest that GLY site agonists of the NMDA receptor may represent a new class of atypical antipsychotic medication. Future research in this area is bound to bring about a better understanding of the role of glutamatergic neurotransmission manipulation in the pharmacotherapy of psychosis and the development of novel pharmacological strategies targeting GLU brain systems.
由兴奋性氨基酸（EAA）谷氨酸（GLU）和天冬氨酸介导的神经传递，因其在神经发育和神经毒性中的作用、与多巴胺能及其他神经递质系统的复杂相互作用以及在近期精神分裂症模型中的关键重要性，而受到精神病药物治疗领域的关注。越来越多的证据表明，调节谷氨酸能神经传递可能在非典型抗精神病药物的作用机制中发挥重要作用。精神分裂症的苯环己哌啶（PCP）模型原理表明，传统抗精神病药物无法对抗精神分裂症症状的所有方面，而使用针对谷氨酸能神经传递的治疗方式有望获得更有利的结果，包括抗阴性症状和认知症状的效果。氯氮平和其他目前使用的非典型抗精神病药物在影响谷氨酸能受体功能的各个方面与传统抗精神病药物有所不同。在这种背景下，有人提出了一个特定假说，认为氯氮平在GLU受体的N-甲基-D-天冬氨酸（NMDA）亚型上具有激动作用。此外，第一代针对精神分裂症的NMDA受体甘氨酸（GLY）位点激动剂的临床试验结果表明，这类化合物（1）具有与传统抗精神病药物不同的疗效和副作用特征，（2）在与传统抗精神病药物联合使用时与氯氮平以及可能的其他非典型抗精神病药物相比，其协同作用有所不同。这些发现（1）进一步支持了谷氨酸能效应可能在非典型抗精神病药物作用机制中发挥重要作用的假说，（2）有助于解释氯氮平独特的临床特征，（3）表明NMDA受体的GLY位点激动剂可能代表一类新型非典型抗精神病药物。该领域未来的研究必将更好地理解谷氨酸能神经传递调控在精神病药物治疗中的作用，以及开发针对GLU脑系统的新型药理学策略。
