Abstract
Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDAR glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open-field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/kainate receptor activation, as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 h) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels, as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of ‘metaplasticity’ by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.
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15 May 2013
A Correction to this paper has been published: https://doi.org/10.1038/npp.2013.42
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Acknowledgements
This research was supported by grants from The Ralph and Marian Falk Medical Research Trust (Chicago, IL) to JRM, The Hope for Depression Research Foundation (New York, NY) to JRM and JSB, and NIH grants MH094835 to JSB, NS044421 to PKS, and DA01442 to RLB and KLN. Research and grant support was provided by National Institutes of Health, Virginia Foundation for Health Youth, Sonexa Pharmaceuticals, Neurosearch A/S to RLB. We thank the Northwestern University Behavioral Phenotyping Core and Histology Core for their assistance and Ms Mary Schmidt for her expert technical assistance. We also thank Derek Small and Ronald Burch for their helpful discussions.
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JRM is the founder of Naurex, Inc. He has founders' shares of stock in the company. JRM receives financial compensation as a consultant. PKS, RAK and JB have been a consultants for Naurex, Inc. for the past 3 years, and have received financial compensation and stock. ALG is an employee of Naurex, Inc. She has received financial compensation and stock. Over the past 3 years, KLN has received compensation from Merz Pharma and WIL Research for consultation services unrelated to the current manuscript. Naurex, Inc. had provided funds for conducting the experiments described in the text, Figure 5. RBL has the following sources of personal financial support 2009–2012: Virginia Commonwealth University, National Academy of Sciences, Food and Drug Administration, US Department of State, Consumer Healthcare Products Association, Forest Research Institute, UCB Pharma, Astra-Zeneca, Centre for Mental Health and Addiction, Global Biodevelopment, Jurox Pharmaceuticals, Elsevier Science, Merz Pharmaceuticals, Servier, JG Perpich Company, Reckitt-Benckiser, Kendle Toronto, Abbott Laboratories, Washington University. JDL is a paid consultant for Naurex and also has stock in the company. Over the last 3 years he has received financial compensation and/or stock with the following companies: AgeneBio, Nektar, and CoLucid. XLZ receives salary support from a grant from Naurex to PKS. He receives no consulting fees and has no stock in Naurex. All the authors have no other consultantship and have not received any financial compensation from any other private companies for the last 3 years.
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Burgdorf, J., Zhang, Xl., Nicholson, K. et al. GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects. Neuropsychopharmacol 38, 729–742 (2013). https://doi.org/10.1038/npp.2012.246
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