Translational Schizophrenia Research Center, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
Eur Neuropsychopharmacol. 2012 Dec;22(12):902-10. doi: 10.1016/j.euroneuro.2012.03.006. Epub 2012 May 5.
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.
中脑边缘多巴胺系统的过度活跃是精神分裂症的一个关键特征，也是阳性精神分裂症症状的客观神经相关物。已知 N-甲基-D-天冬氨酸（NMDA）受体在调节纹状体多巴胺释放中起着重要作用。此外，谷氨酸能功能的紊乱越来越与精神分裂症的阳性和阴性症状的病理生理学联系在一起。先前的研究表明，亚慢性连续给予 NMDA 拮抗剂苯环己哌啶（PCP）可诱导啮齿动物纹状体多巴胺释放对安非他命（AMPH）的类似精神分裂症样过度反应，而甘氨酸和原型甘氨酸转运抑制剂（GTI）NFPS 可逆转这些反应。本研究调查了新型高亲和力和耐受性良好的 GTIs，R231857、R231860 和 Org29335 ，以逆转类似精神分裂症的 AMPH 诱导的 DA 释放增强，以及部分甘氨酸位点激动剂 d-环丝氨酸的作用。如前所述，PCP 对基础 DA 水平没有显著影响，但显著增强了前额叶皮层中 AMPH 诱导的 DA 释放。所有测试的 GTIs 以及 d-环丝氨酸均显著降低了 PCP 诱导的前额叶皮层 DA 释放的增强。PCP 或 GTIs 均未显著影响纹状体 DA 释放。总的来说，这些发现表明，针对 NMDA 受体甘氨酸调节位点的治疗方法可能会显著逆转 NMDA 受体拮抗剂引起的额叶 DA 系统失调，这与对精神分裂症的阳性症状（除了阴性症状）的潜在有益作用一致。
