Glycine site N -methyl- d -aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats

作者：Weili Zhu, Shenjun Wang, Meng-Meng Liu, Haishui Shi, Ruoxi Zhang, Jianfeng Liu, Zengbo Ding, Lin Lü · 发表于：Journal of Psychiatry and Neuroscience · 年份：2013 · DOI：10.1503/jpn.120228 · 被引用次数：62 · 研究领域：Neurotransmitter Receptor Influence on Behavior、Tryptophan and brain disorders、Neuroscience and Neuropharmacology Research

BACKGROUND: Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists exert fast-acting antidepressant effects, providing a promising way to develop a new classification of antidepressant that targets the glutamatergic system. In the present study, we examined the potential antidepressant action of 7-chlorokynurenic acid (7-CTKA), a glycine recognition site NMDA receptor antagonist, in a series of behavioural models of depression and determined the molecular mechanisms that underlie the behavioural actions of 7-CTKA. METHODS: We administered the forced swim test, novelty-suppressed feeding test, learned helplessness paradigm and chronic mild stress (CMS) paradigm in male rats to evaluate the possible rapid antidepressant-like actions of 7-CTKA. In addition, we assessed phospho-glycogen synthase kinase-3β (p-GSK3β) level, mammalian target of rapamycin (mTOR) function, and postsynaptic protein expression in the medial prefrontal cortex (mPFC) and hippocampus. RESULTS: Acute 7-CTKA administration produced rapid antidepressant-like actions in several behavioural tests. It increased p-GSK3β, enhanced mTOR function and increased postsynaptic protein levels in the mPFC. Activation of GSK3β by LY294002 completely blocked the antidepressant-like effects of 7-CTKA. Moreover, 7-CTKA did not produce rewarding properties or abuse potential. LIMITATIONS: It is possible that 7-CTKA modulates glutamatergic transmission, thereby causing enduring alterations of GSK3β and mTOR signalling, alth...