Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects

Molecular Psychiatry volume 22, pages 120–126 (2017)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Martinowich K, Jimenez DV, Zarate CA Jr, Manji HK . Rapid antidepressant effects: moving right along. Mol Psychiatry 2013; 18: 856–863.

    Article  CAS  Google Scholar 

  2. Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry 2015; 172: 950–966.

    Article  Google Scholar 

  3. Sanacora G, Smith MA, Pathak S, Su HL, Boeijinga PH, McCarthy DJ et al. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol Psychiatry 2014; 9: 978–985.

    Article  Google Scholar 

  4. Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW . An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-d-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 2008; 28: 631–637.

    Article  CAS  Google Scholar 

  5. Drevets WC, Zarate CA Jr, Furey ML . Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: a review. Biol psychiatry 2013; 73: 1156–1163.

    Article  CAS  Google Scholar 

  6. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329: 959–964.

    Article  CAS  Google Scholar 

  7. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011; 475: 91–95.

    Article  CAS  Google Scholar 

  8. Koike H, Iijima M, Chaki S . Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 2011; 224: 107–111.

    Article  CAS  Google Scholar 

  9. Voleti B, Navarria A, Liu RJ, Banasr M, Li N, Terwilliger R et al. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry 2013; 74: 742–749.

    Article  CAS  Google Scholar 

  10. Moghaddam B, Adams B, Verma A, Daly D . Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 1997; 17: 2921–2927.

    Article  CAS  Google Scholar 

  11. Homayoun H, Moghaddam B . NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 2007; 27: 11496–11500.

    Article  CAS  Google Scholar 

  12. Chowdhury GM, Behar KL, Cho W, Thomas MA, Rothman DL, Sanacora G . (1)H-[(1)(3)C]-nuclear magnetic resonance spectroscopy measures of ketamine's effect on amino acid neurotransmitter metabolism. Biol Psychiatry 2012; 71: 1022–1025.

    Article  CAS  Google Scholar 

  13. Witkin JM, Overshiner C, Li X, Catlow JT, Wishart GN, Schober DA et al. M1 and m2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine. J Pharmacol Exp Ther 2014; 351: 448–456.

    Article  CAS  Google Scholar 

  14. Chowdhury GM, Patel AB, Mason GF, Rothman DL, Behar KL . Glutamatergic and GABAergic neurotransmitter cycling and energy metabolism in rat cerebral cortex during postnatal development. J Cereb Blood Flow Metab 2007; 27: 1895–1907.

    Article  CAS  Google Scholar 

  15. Hyder F, Patel AB, Gjedde A, Rothman DL, Behar KL, Shulman RG . Neuronal–glial glucose oxidation and glutamatergic–GABAergic function. J Cereb Blood Flow Metab 2006; 26: 865–877.

    Article  CAS  Google Scholar 

  16. Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D . Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 1997; 154: 805–811.

    Article  CAS  Google Scholar 

  17. Nishizawa N, Nakao S, Nagata A, Hirose T, Masuzawa M, Shingu K . The effect of ketamine isomers on both mice behavioral responses and c-Fos expression in the posterior cingulate and retrosplenial cortices. Brain Res 2000; 857: 188–192.

    Article  CAS  Google Scholar 

  18. Littlewood CL, Jones N, O'Neill MJ, Mitchell SN, Tricklebank M, Williams SC . Mapping the central effects of ketamine in the rat using pharmacological MRI. Psychopharmacology 2006; 186: 64–81.

    Article  CAS  Google Scholar 

  19. Stone JM, Erlandsson K, Arstad E, Squassante L, Teneggi V, Bressan RA et al. Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy: a [(123)I]CNS-1261 SPET study. Psychopharmacology 2008; 197: 401–408.

    Article  CAS  Google Scholar 

  20. Miyamoto S, Leipzig JN, Lieberman JA, Duncan GE . Effects of ketamine, MK-801, and amphetamine on regional brain 2-deoxyglucose uptake in freely moving mice. Neuropsychopharmacology 2000; 22: 400–412.

    Article  CAS  Google Scholar 

  21. Miyamoto S, Mailman RB, Lieberman JA, Duncan GE . Blunted brain metabolic response to ketamine in mice lacking D(1 A) dopamine receptors. Brain Res 2001; 894: 167–180.

    Article  CAS  Google Scholar 

  22. Duncan GE, Moy SS, Knapp DJ, Mueller RA, Breese GR . Metabolic mapping of the rat brain after subanesthetic doses of ketamine: potential relevance to schizophrenia. Brain Res 1998; 787: 181–190.

    Article  CAS  Google Scholar 

  23. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 2008; 63: 349–352.

    Article  CAS  Google Scholar 

  24. Haller J, Nagy R, Toth M, Pelczer KG, Mikics E . NR2B subunit-specific NMDA antagonist Ro25-6981 inhibits the expression of conditioned fear: a comparison with the NMDA antagonist MK-801 and fluoxetine. Behav Pharmacol 2011; 22: 113–121.

    Article  CAS  Google Scholar 

  25. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H et al. Glutamate N-methyl-d-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011; 69: 754–761.

    Article  CAS  Google Scholar 

  26. Shaffer CL, Osgood SM, Smith DL, Liu J, Trapa PE . Enhancing ketamine translational pharmacology via receptor occupancy normalization. Neuropharmacology 2014; 86: 174–180.

    Article  CAS  Google Scholar 

  27. Domino EF, Zsigmond EK, Domino LE, Domino KE, Kothary SP, Domino SE . Plasma levels of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay. Anesth Analg 1982; 61: 87–92.

    Article  CAS  Google Scholar 

  28. Lucki I . The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav Pharmacol 1997; 8: 523–532.

    Article  CAS  Google Scholar 

  29. Iltis I, Koski DM, Eberly LE, Nelson CD, Deelchand DK, Valette J et al. Neurochemical changes in the rat prefrontal cortex following acute phencyclidine treatment: an in vivo localized (1)H MRS study. NMR Biomed 2009; 22: 737–744.

    Article  CAS  Google Scholar 

  30. Gao XM, Shirakawa O, Du F, Tamminga CA . Delayed regional metabolic actions of phencyclidine. Eur J Pharmacol 1993; 241: 7–15.

    Article  CAS  Google Scholar 

  31. Rowland LM, Bustillo JR, Mullins PG, Jung RE, Lenroot R, Landgraf E et al. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatry 2005; 162: 394–396.

    Article  Google Scholar 

  32. Homayoun H, Jackson ME, Moghaddam B . Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats. J Neurophysiol 2005; 93: 1989–2001.

    Article  CAS  Google Scholar 

  33. Nagy D, Stoiljkovic M, Menniti FS, Hajos M . Differential effects of an NR2B NAM and ketamine on synaptic potentiation and gamma synchrony: relevance to rapid-onset antidepressant efficacy. Neuropsychopharmacology 2015; e-pub ahead of print 21 October 2015.

  34. Duman RS, Aghajanian GK . Synaptic dysfunction in depression: potential therapeutic targets. Science 2012; 338: 68–72.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. K L Behar and G Sanacora: These authors share co-last authorship.

Authors and Affiliations

  1. Department of Psychiatry and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, CT, USA

    G M I Chowdhury, M Thomas, X Ma & K L Behar

  2. Department of Psychiatry and the Ribicoff Research Facilities, Yale University School of Medicine, Yale University, New Haven, CT, USA

    J Zhang, M Banasr, B Pittman, R S Duman & G Sanacora

  3. Mental Health Centre, Shantou University Medical College, Shantou, Guangdong, People's Republic of China

    J Zhang

  4. Centre for Addiction and Mental Health Toronto, Toronto, Ontario, Canada

    M Banasr

  5. Bristol-Myers Squibb, Wallingford, CT, USA

    L Bristow

  6. Janssen Research and Development, Titusville, NJ, USA

    E Schaeffer

  7. Diagnostic Radiology and Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, CT, USA

    D L Rothman

Authors
  1. G M I Chowdhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Banasr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. X Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Pittman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Bristow
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E Schaeffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R S Duman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D L Rothman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. K L Behar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. G Sanacora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to G M I Chowdhury or G Sanacora.

Ethics declarations

Competing interests

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.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2016.34

This article is cited by

Search

Advanced search

Quick links