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

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

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J Psychiatry Neurosci 2013; 38(5): 306-316

Wei-Li Zhu, PhD;* Shen-Jun Wang, PhD;* Meng-Meng Liu, PhD; Hai-Shui Shi, PhD; Ruo-Xi Zhang, MD; Jian-Feng Liu, MD; Zeng-Bo Ding, MD; Lin Lu, MD, PhD

Zhu, Wang, M.-M. Liu, Shi, Zhang, J.-F. Liu, Ding, Lu — National Institute on Drug Dependence, Peking University, Beijing, China; Lu — Key Lab for Neuroscience, Ministry of Education / Ministry of Health, Beijing, China

Abstract

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, although we did not provide direct evidence to support this possibility. Thus, the therapeutic involvement of synaptic adaptions engaged by 7-CTKA requires further study.

Conclusion: Our findings demonstrate that acute 7-CTKA administration produced rapid antidepressant-like effects, indicating that the behavioural response to 7-CTKA is mediated by GSK3β and mTOR signalling function in the mPFC.


*Contributed equally to this work.

Submitted Nov. 25, 2012; Revised Feb. 5, 12, 2013; Accepted Feb. 19, 2013.

Acknowledgements: This work was supported in part by the National Basic Research Program of China (no. 2009CB522004) and National Natural Science Foundation of China (no. 30800362, no. 81071079 and no. 81201038). We thank Prof. Hao-Wei Shen for his helpful comments on this manuscript.

Competing interests: As above. Otherwise, none declared.

Contributors: W.-L. Zhu and L. Lu designed the study. W.-L. Zhu, S.-J. Wang and M.-M. Liu carried out the experiment. S.-J. Wang and H.-S. Shi acquired the data, which M.-M. Liu, R.-X. Zhang, J.-F. Liu and Z.-B. Ding analyzed. W.-L. Zhu wrote the article, which all other authors reviewed. All authors approved publication.

DOI: 10.1503/jpn.120228

Correspondence to: L. Lu, National Institute on Drug Dependence, Peking University, 38 Xue Yuan Rd., Hai Dian District, Beijing 100191, China; linlu@bjmu.edu.cn