Effects of novel, high affinity glycine transport inhibitors on frontostriatal dopamine release in a rodent model of schizophrenia
Effects of novel, high affinity glycine transport inhibitors on frontostriatal dopamine release in a rodent model of schizophrenia
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DOI：
10.1016/j.euroneuro.2012.03.006
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发表时间：
2012-12-01
影响因子：
5.6
通讯作者：
Javitt, Daniel C.
中科院分区：
文献类型：
--
作者：
Balla, Andrea;Schneider, Samantha;Javitt, Daniel C.
额纹状体脑系统多巴胺能亢进是精神分裂症的一个重要特征，也是精神分裂症阳性症状的客观神经相关因素。已知N-甲基-D-天冬氨酸（NMDA）受体在调节额纹状体多巴胺释放中起重要作用。此外，多巴胺能功能的紊乱越来越多地与精神分裂症的阳性和阴性症状的病理生理学有关。先前的研究表明，亚慢性连续给药的NMDA拮抗剂苯环己哌啶（PCP）诱导精神分裂症样高反应性的额纹状体多巴胺释放安非他明（AMPH）在啮齿类动物中，和甘氨酸和原型甘氨酸转运抑制剂（GTI）NFPS逆转的影响。本研究探讨了新的，高亲和力和耐受性良好的GTI，R231857，R231860和Org 29335，逆转精神分裂症样增强AMPH诱导的DA释放的有效性，沿着的部分甘氨酸位点激动剂D-环丝氨酸的影响。如前所述，PCP对基础DA水平没有显著影响，但显著增强AMPH诱导的前额叶皮层DA释放。所有的GTI测试，以及D-环丝氨酸，显着减少PCP诱导的增强DA释放在前额皮质。PCP和GTI均不显著影响纹状体DA的释放。总体而言，这些研究结果表明，治疗的目标是甘氨酸的NMDA受体的调节位点可能会显着逆转NMDA受体拮抗剂诱导的额叶DA系统的失调，与潜在的积极的有益影响，除了消极的精神分裂症的症状。(C)2012 Elsevier B. V.和ECNR保留所有权利。
Dopaminergic hyperactivity within frontostriatal brain systems is a key feature of schizophrenia, and an objective neural correlate of positive schizophrenia symptoms. N-methyl-D-aspartate (NMDA) receptors are known to play a prominent role in regulation of frontostriatal dopamine release. Furthermore, disturbances in glutamatergic function are increasingly being linked to pathophysiology of both positive and negative symptoms of schizophrenia. Prior studies have demonstrated that subchronic continuous administration of the NMDA antagonist phencyclidine (PCP) induces schizophrenia-like hyper-reactivity of frontostriatal dopamine release to amphetamine (AMPH) in rodents, and that effects were reversed by glycine and the prototypic glycine transport inhibitor (GTI) NFPS. The present study investigates effectiveness of the novel, high affinity and well tolerated GTIs, R231857; R231860 and Org29335, to reverse schizophrenia-like enhancement of AMPH-induced DA release, along with effects of the partial glycine-site agonist D-cycloserine. As previously, PCP had no significant effect on basal DA levels, but significantly enhanced AMPH-induced DA release in prefrontal cortex. All GTIs tested, as well as D-cycloserine, significantly reduced PCP-induced enhancement of DA release in prefrontal cortex. Neither PCP nor GTIs significantly affected striatal DA release. Overall, these findings suggest that treatments which target the glycine modulatory site of the NMDA receptor may significantly reverse NMDA receptor antagonist-induced dysregulation of frontal DA systems, consistent with potential beneficial effects on positive-, in addition to negative-, symptoms of schizophrenia. (C) 2012 Elsevier B.V. and ECNR All rights reserved.