Gunduz-Bruce Handan
Yale University School of Medicine, VA Medical Center, Psychiatry Service 116A,West Haven, CT 06516, USA.
Brain Res Rev. 2009 May;60(2):279-86. doi: 10.1016/j.brainresrev.2008.07.006. Epub 2008 Jul 30.
In the past decade, the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has received support from several lines of clinical evidence, including genetic, postmortem and human psychosis modeling. Recently, superiority of a mGluR2/3 receptor agonist over placebo was demonstrated in a randomized double-blind clinical trial in patients with schizophrenia. Considering the fact that currently available antipsychotics are all dopamine blockers to varying degrees without direct effects on glutamate transmission, this clinical trial highlights the potential utility of glutamatergic agents. In healthy volunteers, the NMDA channel antagonist ketamine induces transient cognitive dysfunction, perceptual aberrations and changes reminiscent of the negative symptoms of schizophrenia. However, how ketamine produces these effects is unclear. Preclinical data on NMDAR hypofunction offer further insights into the pathogenesis of the disorder as it relates to disorganized behavior, stereotypic movements and cognitive dysfunction in the rodent. This review evaluates the existing clinical and preclinical literature in an effort to shed light on the mechanism of action of ketamine as a probe to model NMDAR hypofunction in healthy volunteers. Included in this perspective are direct and indirect effects of ketamine at the neuronal level and in the intact brain. In addition to ketamine's effects on presynaptic and postsynaptic function, effects on glia and other neurotransmitter systems are discussed. While increased extracellular glutamate levels following NMDA antagonist administration stand out as a well replicated finding, evidence suggests that ketamine's effects are not restricted to pyramidal cells, but extend to GABAergic interneurons and the glia. In the glia, ketamine has significant downstream effects on the glutathione metabolism. Further studies are needed to identify the mechanistic connections between ketamine's effects at the cellular and behavioral levels.
在过去十年中，精神分裂症的N-甲基-D-天冬氨酸受体（NMDAR）功能减退假说得到了多条临床证据的支持，包括遗传学、尸检和人类精神病模型研究。最近，在一项针对精神分裂症患者的随机双盲临床试验中，一种代谢型谷氨酸受体2/3（mGluR2/3）受体激动剂被证明优于安慰剂。鉴于目前可用的抗精神病药物均为不同程度的多巴胺阻滞剂，对谷氨酸传递无直接作用，该临床试验凸显了谷氨酸能药物的潜在效用。在健康志愿者中，NMDA通道拮抗剂氯胺酮会诱发短暂的认知功能障碍、感知异常以及类似于精神分裂症阴性症状的变化。然而，氯胺酮如何产生这些效应尚不清楚。关于NMDAR功能减退的临床前数据为该疾病的发病机制提供了进一步的见解，该机制与啮齿动物的行为紊乱、刻板运动和认知功能障碍有关。本综述评估了现有的临床和临床前文献，以阐明氯胺酮作为一种在健康志愿者中模拟NMDAR功能减退的探针的作用机制。从这个角度来看，包括氯胺酮在神经元水平和完整大脑中的直接和间接作用。除了氯胺酮对突触前和突触后功能的影响外，还讨论了其对神经胶质细胞和其他神经递质系统的影响。虽然NMDA拮抗剂给药后细胞外谷氨酸水平升高是一个得到充分重复验证的发现，但有证据表明氯胺酮的作用不仅限于锥体细胞，还扩展到γ-氨基丁酸能中间神经元和神经胶质细胞。在神经胶质细胞中，氯胺酮对谷胱甘肽代谢有显著的下游影响。需要进一步的研究来确定氯胺酮在细胞水平和行为水平上的作用之间的机制联系。
