Abstract
Several drugs have recently been reported to induce rapid antidepressant effects in clinical trials and rodent models. Although the cellular mechanisms involved remain unclear, reports suggest that increased glutamate transmission contributes to these effects. Here, we demonstrate that the antidepressant-like efficacy of three unique drugs, with reported rapid onset antidepressant properties, is coupled with a rapid transient rise in glutamate cycling in the medial prefronal cortex (mPFC) of awake rats as measured by ex vivo 1H-[13C]-nuclear magnetic resonance spectroscopy. Rats were acutely pretreated by intraperitoneal injection with a single dose of ketamine (1, 3, 10, 30 and 80 mg kg−1), Ro 25-6981 (1, 3 and 10 mg kg−1), scopolamine (5, 25 and 100 μg kg−1) or vehicle (controls). At fixed times after drug injection, animals received an intravenous infusion of [1,6-13C2]glucose for 8 min to enrich the amino-acid pools of the brain with 13C, followed by rapid euthanasia. The mPFC was dissected, extracted with ethanol and metabolite 13C enrichments were measured. We found a clear dose-dependent effect of ketamine and Ro 25-6981 on behavior and the percentage of 13C enrichment of glutamate, glutamine and GABA (γ-aminobutyric acid). Further, we also found an effect of scopolamine on both cycling and behavior. These studies demonstrate that three pharmacologically distinct classes of drugs, clinically related through their reported rapid antidepressant actions, share the common ability to rapidly stimulate glutamate cycling at doses pertinent for their antidepressant-like efficacy. We conclude that increased cycling precedes the antidepressant action at behaviorally effective doses and suggest that the rapid change in cycling could be used to predict efficacy of novel agents or identify doses with antidepressant activity.
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Acknowledgements
We thank Amy Newton and Yulia Benitex of Bristol-Myers Squibb for the execution of the rat ketamine PK studies, and Terry Nixon, Peter Brown and Scott McIntyre for their support in maintaining the NMR spectrometer. This work was supported by National Institute of Mental Health R01-MH095104 and R01-MH081211, NARSAD, QNMR Core Center P30-NS052519, The VA National Center for PTSD and funding from Bristol-Myers Squib.
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Dr Sanacora has received consulting fees from AstraZeneca, Avanier Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly & Co., Hoffman La-Roche, Merck, Navigen, Naurex, Noven Pharmaceuticals, Servier Pharmaceuticals, Takeda, Teva and Vistagen therapeutics over the past 24 months. He has also received additional research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Johnson & Johnson, Hoffman La-Roche, Merck & Co., Naurex and Servier over the past 24 months. Free medication was provided to Dr Sanacora for an NIH-sponsored study by Sanofi-Aventis. In addition, he holds shares in BioHaven Pharmaceuticals Holding Company and is a coinventor on a US patent (no. 8 778 979) held by the Yale University. Dr Duman has received consulting fees from Taisho, Naurex, Sunovion and Johnson & Johnson, and investigator-initiated grants from Forest, Naurex, Sunovion and Eli Lilly & Co. Dr Bristow is an employee of Bristol-Myers Squibb. Dr Schaeffer was an employee of Bristol-Myers Squibb at the time the research was completed and is currently an employee of Janssen Research and Development. Dr Banasr has received research contracts from BioHaven Pharmaceuticals and Servier Pharmaceuticals. Dr Behar holds common stock in Pfizer. The remaining authors declare no conflicts of interest.
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Chowdhury, G., Zhang, J., Thomas, M. et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol Psychiatry 22, 120–126 (2017). https://doi.org/10.1038/mp.2016.34
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DOI: https://doi.org/10.1038/mp.2016.34
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