Skip to main content
SpringerLink
Log in

Using Our Understanding of Stress-Related Effects on Glutamate Neurotransmission to Guide the Development of Novel Treatment Strategies

  • Chapter
  • First Online:
Synaptic Stress and Pathogenesis of Neuropsychiatric Disorders

  • 824 Accesses

Abstract

The majority of treatments for neuropsychiatric disorders have been based on serendipitous discoveries, with little understanding of the pathogenic and pathophysiological mechanisms underlying these disorders. As many of these disorders are sensitive to stress, an understanding of the physiology of stress is important in avoiding and reversing stress-sensitive disorders. Increased understanding of the glutamatergic synapse has revealed a system that is affected by both stress and multiple neuropsychiatric treatments, suggesting a possible convergent target in these disorders. This chapter reviews how traditional neuropsychiatric treatments affect the glutamatergic synapse, and how future therapies may be developed to more directly target this system.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abdallah CG, Fasula M, Kelmendi B, Sanacora G, Ostroff R. Rapid antidepressant effect of ketamine in the electroconvulsive therapy setting. J ECT. 2012;28(3):157–61. doi:10.1097/YCT.0b013e31824f8296.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Alonso G. Prolonged corticosterone treatment of adult rats inhibits the proliferation of oligodendrocyte progenitors present throughout white and gray matter regions of the brain. Glia. 2000;31(3):219–31.

    CAS  PubMed  Google Scholar 

  • Alt A, Weiss B, Ogden AM, Li X, Gleason SD, Calligaro DO, Bleakman D, Witkin JM. In vitro and in vivo studies in rats with LY293558 suggest AMPA/kainate receptor blockade as a novel potential mechanism for the therapeutic treatment of anxiety disorders. Psychopharmacology (Berl). 2006;185(2):240–7. doi:10.1007/s00213-005-0292-0.

    CAS  Google Scholar 

  • Altshuler LL, Abulseoud OA, Foland-Ross L, Bartzokis G, Chang S, Mintz J, Hellemann G, Vinters HV. Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. Bipolar Disord. 2010;12(5):541–9. doi:10.1111/j.1399-5618.2010.00838.x.

    PubMed  Google Scholar 

  • Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia. 2000;32(1):1–14.

    CAS  PubMed  Google Scholar 

  • Anisman H, Zacharko RM. Multiple neurochemical and behavioral consequences of stressors: implications for depression. Pharmacol Ther. 1990;46(1):119–36.

    CAS  PubMed  Google Scholar 

  • Anwyl R. Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Brain Res Rev. 1999;29(1):83–120.

    CAS  PubMed  Google Scholar 

  • Araya-Callís C, Hiemke C, Abumaria N, Flugge G. Chronic psychosocial stress and citalopram modulate the expression of the glial proteins GFAP and NDRG2 in the hippocampus. Psychopharmacology (Berl). 2012;224(1):209–22. doi:10.1007/s00213-012-2741-x.

    Google Scholar 

  • Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG. Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci. 1994;14(9):5559–69.

    CAS  PubMed  Google Scholar 

  • Attucci S, Carlà V, Mannaioni G, Moroni F. Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges. Br J Pharmacol. 2001;132(4):799–806. doi:10.1038/sj.bjp.0703904.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Autry AE, Grillo CA, Piroli GG, Rothstein JD, McEwen BS, Reagan LP. Glucocorticoid regulation of GLT-1 glutamate transporter isoform expression in the rat hippocampus. Neuroendocrinology. 2006;83(5-6):371–9. doi:10.1159/000096092.

    CAS  PubMed  Google Scholar 

  • Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng P, Kavalali ET, Monteggia LM. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475(7354):91–5. doi:10.1038/nature10130.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ. Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci. 2000;20(21):7871–9.

    CAS  PubMed  Google Scholar 

  • Bagley J, Moghaddam B. Temporal dynamics of glutamate efflux in the prefrontal cortex and in the hippocampus following repeated stress: effects of pretreatment with saline or diazepam. Neuroscience. 1997;77(1):65–73.

    CAS  PubMed  Google Scholar 

  • Banasr M, Duman RS. Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. CNS Neurol Disord Drug Targets. 2007;6(5):311–20.

    CAS  PubMed  Google Scholar 

  • Banasr M, Duman RS. Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry. 2008;64(10):863–70. doi:10.1016/j.biopsych.2008.06.008.

    PubMed Central  PubMed  Google Scholar 

  • Banasr M, Chowdhury GMI, Terwilliger R, Newton SS, Duman RS, Behar KL, Sanacora G. Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol Psychiatry. 2010a;15(5):501–11. doi:10.1038/mp.2008.106.

    CAS  Google Scholar 

  • Barha CK, Pawluski JL, Galea LAM. Maternal care affects male and female offspring working memory and stress reactivity. Physiol Behav. 2007;92(5):939–50. doi:10.1016/j.physbeh.2007.06.022.

    CAS  PubMed  Google Scholar 

  • Barkus C, Feyder M, Graybeal C, Wright T, Wiedholz L, Izquierdo A, et al. Do GluA1 knockout mice exhibit behavioral abnormalities relevant to the negative or cognitive symptoms of schizophrenia and schizoaffective disorder? Neuropharmacology. 2011;62(3):1263–72. doi:10.1016/j.neuropharm.2011.06.005.

    PubMed Central  PubMed  Google Scholar 

  • Belozertseva IV, Kos T, Popik P, Danysz W, Bespalov AY. Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests. European Neuropsychopharmacol. 2007;17(3):172–9. doi:10.1016/j.euroneuro.2006.03.002.

    CAS  Google Scholar 

  • Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351–4.

    CAS  PubMed  Google Scholar 

  • Bernard R, Kerman IA, Thompson RC, Jones EG, Bunney WE, Barchas JD, et al. Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol Psychiatry. 2011;16(6):634–46. doi:10.1038/mp.2010.44.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bonanno G, Giambelli R, Raiteri L, Tiraboschi E, Zappettini S, Musazzi L, et al. Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J Neurosci. 2005;25(13):3270–9. doi:10.1523/JNEUROSCI.5033-04.2005.

    CAS  PubMed  Google Scholar 

  • Brakeman PR, Lanahan AA, O’Brien R, Roche K, Barnes CA, Huganir RL, Worley PF. Homer: a protein that selectively binds metabotropic glutamate receptors. Nature. 1997;386(6622):284–8. doi:10.1038/386284a0.

    CAS  PubMed  Google Scholar 

  • Brennan BP, Hudson JI, Jensen JE, McCarthy J, Roberts JL, Prescot AP, et al. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology. 2010;35(3):834–46. doi:10.1038/npp.2009.191.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brodkin J, Busse C, Sukoff SJ, Varney MA. Anxiolytic-like activity of the mGluR5 antagonist MPEP: a comparison with diazepam and buspirone. Pharmacol Biochem Behav. 2002;73(2):359–66.

    CAS  PubMed  Google Scholar 

  • Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci. 2002;22(1):183–92.

    CAS  PubMed  Google Scholar 

  • Busse CS, Brodkin J, Tattersall D, Anderson JJ, Warren N, Tehrani L, et al. The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in rodent models of anxiety. Neuropsychopharmacology. 2004;29(11):1971–9. doi:10.1038/sj.npp.1300540.

    CAS  PubMed  Google Scholar 

  • Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999;60(2):79–88.

    CAS  PubMed  Google Scholar 

  • Cartmell J, Schoepp DD. Regulation of neurotransmitter release by metabotropic glutamate receptors. J Neurochem. 2000;75(3):889–907.

    CAS  PubMed  Google Scholar 

  • Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science(New York NY). 2003;301(5631):386–9. doi:10.1126/science.1083968.

    CAS  Google Scholar 

  • Chaki S, Yoshikawa R, Hirota S, Shimazaki T, Maeda M, Kawashima N, et al. MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuropharmacology. 2004;46(4):457–67. doi:10.1016/j.neuropharm.2003.10.009.

    CAS  PubMed  Google Scholar 

  • Chaki S, Ago Y, Palucha-Paniewiera A, Matrisciano F, Pilc A. mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants. Neuropharmacology. 2013;66:40–52. doi:10.1016/j.neuropharm.2012.05.022.

    CAS  PubMed  Google Scholar 

  • Chappell AS, Gonzales C, Williams J, Witte MM, Mohs RC, Sperling R. AMPA potentiator treatment of cognitive deficits in Alzheimer disease. Neurology. 2007;68(13):1008–12. doi:10.1212/01.wnl.0000260240.46070.7c.

    CAS  PubMed  Google Scholar 

  • Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A. 2005;102(43):15653–8. doi:10.1073/pnas.0507901102.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chowdhury GMI, Behar KL, Cho W, Thomas Ma, Rothman DL, Sanacora G. 1H-[13C]-nuclear magnetic resonance spectroscopy measures of ketamine’s effect on amino acid neurotransmitter metabolism. Biol Psychiatry. 2012;71(11):1022–5. doi:10.1016/j.biopsych.2011.11.006.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Christian KM, Miracle AD, Wellman CL, Nakazawa K. Chronic stress-induced hippocampal dendritic retraction requires CA3 NMDA receptors. Neuroscience. 2011;174:26–36. doi:10.1016/j.neuroscience.2010.11.033.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Coric V, Taskiran S, Pittenger C, Wasylink S, Mathalon DH, Valentine G, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. 2005;58(5):424–8. doi:10.1016/j.biopsych.2005.04.043.

    CAS  PubMed  Google Scholar 

  • Cotter D. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry. 2001;58(6):545–53. doi:10.1001/archpsyc.58.6.545.

    CAS  PubMed  Google Scholar 

  • Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP. Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cerebral Cortex. 2002;12(4):386–94. (New York, N.Y. : 1991).

    PubMed  Google Scholar 

  • Cowen MS, Djouma E, Lawrence AJ. The metabotropic glutamate 5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine reduces ethanol self-administration in multiple strains of alcohol-preferring rats and regulates olfactory glutamatergic systems. J Pharmacol Exp Ther. 2005;315(2):590–600. doi:10.1124/jpet.105.090449.

    CAS  PubMed  Google Scholar 

  • Cravens CJ, Vargas-Pinto N, Christian KM, Nakazawa K. CA3 NMDA receptors are crucial for rapid and automatic representation of context memory. Eur J Neurosci. 2006;24(6):1771–80. doi:10.1111/j.1460-9568.2006.05044.x.

    PubMed  Google Scholar 

  • Cryan JF, Dev KK. Role of glutamate in anxiety In: Handbook of fear and anxiety. Blanchard DC, Blanchard RM (eds). 2007

    Google Scholar 

  • Czéh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci U S A. 2001;98(22):12796–801. doi:10.1073/pnas.211427898.

    PubMed Central  PubMed  Google Scholar 

  • Czéh B, Simon M, Schmelting B, Hiemke C, Fuchs E. Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology. 2006;31(8):1616–26. doi:10.1038/sj.npp.1300982.

    PubMed  Google Scholar 

  • DD DDS, Marek GJ. Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia? Curr Drug Targets CNS Neurol Disord. 2002;1(2):215–25.

    PubMed  Google Scholar 

  • Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793–802. doi:10.1001/archgenpsychiatry.2010.90.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dieterich DC, Karpova A, Mikhaylova M, Zdobnova I, König I, Landwehr M, et al. Caldendrin-Jacob: a protein liaison that couples NMDA receptor signalling to the nucleus. PLoS Biol. 2008;6(2):e34. doi:10.1371/journal.pbio.0060034.

    Google Scholar 

  • Doherty AJ, Palmer MJ, Bortolotto ZA, Hargreaves A, Kingston AE, Ornstein PL, et al. A novel, competitive mGlu(5) receptor antagonist (LY344545) blocks DHPG-induced potentiation of NMDA responses but not the induction of LTP in rat hippocampal slices. Br J Pharmacol. 2000;131(2):239–44. doi:10.1038/sj.bjp.0703574.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Du J, Suzuki K, Wei Y, Wang Y, Blumenthal R, Chen Z, et al. The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: relationship to clinical effects in mood disorders. Neuropsychopharmacology. 2007;32(4):793–802. doi:10.1038/sj.npp.1301178.

    CAS  PubMed  Google Scholar 

  • Dwyer JM, Lepack AE, Duman RS. mTOR activation is required for the antidepressant effects of mGluR2/3 blockade. Int J Neuropsychopharmacol. 2012;15(4):429–34. doi:10.1017/S1461145711001702.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Engert F, Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature. 1999;399(6731):66–70. doi:10.1038/19978.

    CAS  PubMed  Google Scholar 

  • Ettinger AB, Argoff CE. Use of antiepileptic drugs for nonepileptic conditions: psychiatric disorders and chronic pain. Neurotherapeutics. 2007;4(1):75–83. doi:10.1016/j.nurt.2006.10.003.

    CAS  PubMed  Google Scholar 

  • Fatemi SH, Folsom TD, Reutiman TJ, Pandian T, Braun NN, Haug K. Chronic psychotropic drug treatment causes differential expression of connexin 43 and GFAP in frontal cortex of rats. Schizophr Res. 2008;104(1–3):127–34. doi:10.1016/j.schres.2008.05.016.

    PubMed  Google Scholar 

  • Fell MJ, Witkin JM, Falcone JF, Katner JS, Perry KW, Hart J, et al. N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a novel metabotropic glutamate 2 potentiator with potential anxiolytic/antidepressant properties: in vivo profiling suggests a link between behavioral and central nervous system neurochemical changes. J Pharmacol Exp Ther. 2011;336(1):165–77. doi:10.1124/jpet.110.172957.

    CAS  PubMed  Google Scholar 

  • Feyissa AM, Woolverton WL, Miguel-Hidalgo JJ, Wang Z, Kyle PB, Hasler G, et al. Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(2):279–83. doi:10.1016/j.pnpbp.2009.11.018.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fitzgerald PJ, Barkus C, Feyder M, Wiedholz LM, Chen Y-C, Karlsson R-M, … Holmes A. Does gene deletion of AMPA GluA1 phenocopy features of schizoaffective disorder? Neurobiol Dis. 2010;40(3):608–21. doi:10.1016/j.nbd.2010.08.005.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fraser CM, Cooke MJ, Fisher A, Thompson ID, Stone TW. Interactions between ifenprodil and dizocilpine on mouse behaviour in models of anxiety and working memory. Eur Neuropsychopharmacol. 1996;6(4):311–6.

    CAS  PubMed  Google Scholar 

  • Fumagalli E, Funicello M, Rauen T, Gobbi M, Mennini T. Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur J Pharmacol. 2008;578(2–3):171–6. doi:10.1016/j.ejphar.2007.10.023.

    CAS  PubMed  Google Scholar 

  • Gittins RA, Harrison PJ. A morphometric study of glia and neurons in the anterior cingulate cortex in mood disorder. J Affect Disord. 2011;133(1–2):328–32. doi:10.1016/j.jad.2011.03.042.

    PubMed  Google Scholar 

  • Gladding CM, Raymond LA. Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function. Mol Cell Neurosci. 2011;48(4):308–20. doi:10.1016/j.mcn.2011.05.001.

    CAS  PubMed  Google Scholar 

  • Gould E, Cameron HA. Early NMDA receptor blockade impairs defensive behavior and increases cell proliferation in the dentate gyrus of developing rats. Behav Neurosci. 1997;111(1):49–56.

    CAS  PubMed  Google Scholar 

  • Gourley SL, Espitia JW, Sanacora G, Taylor JR. Antidepressant-like properties of oral riluzole and utility of incentive disengagement models of depression in mice. Psychopharmacology (Berl). 2012;219(3):805–14. doi:10.1007/s00213-011-2403-4.

    CAS  Google Scholar 

  • Groc L, Choquet D, Chaouloff F. The stress hormone corticosterone conditions AMPAR surface trafficking and synaptic potentiation. Nat Neurosci. 2008;11(8):868–70. doi:10.1038/nn.2150.

    CAS  PubMed  Google Scholar 

  • Groeneweg FL, Karst H, de Kloet ER, Joëls M. Rapid non-genomic effects of corticosteroids and their role in the central stress response. J Endocrinol. 2011;209(2):153–67. doi:10.1530/JOE-10-0472.

    CAS  PubMed  Google Scholar 

  • Guttmann RP, Baker D, Seifert KM, Cohen AS, Coulter DA, Lynch DR. Specific proteolysis of the NR2 subunit—at multiple sites by calpain. Journal of Neurochemistry. 2001; 78(5)1083–93.

    Google Scholar 

  • Guttmann RP, Sokol S, Baker D, Simpkins KL, Dong Y, Lynch DR. Proteolysis of the N-methyl-d-aspartate—receptor by calpain in situ. The Journal of pharmacology and experimental therapeutics 2002;302(3)1023–30.

    Google Scholar 

  • Hammen C. Stress and depression. Annu Rev Clin Psychol. 2005;1:293–319. doi:10.1146/annurev.clinpsy.1.102803.143938.

    PubMed  Google Scholar 

  • Hansson E, Rönnbäck L. Altered neuronal-glial signaling in glutamatergic transmission as a unifying mechanism in chronic pain and mental fatigue. Neurochem Res. 2004;29(5):989–96.

    CAS  PubMed  Google Scholar 

  • Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci. 2010;11(10):682–96. doi:10.1038/nrn2911.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002;5(5):405–14. doi:10.1038/nn835.

    CAS  PubMed  Google Scholar 

  • Hughes ZA, Neal SJ, Smith DL, Sukoff Rizzo SJ, Pulicicchio CM, Lotarski S, et al. Negative allosteric modulation of metabolic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression. Neuropharmacology. 2012;66:202–14. doi:10.1016/j.neuropharm.2012.04.007.

    PubMed  Google Scholar 

  • Ibrahim L, Diazgranados N, Luckenbaugh DA, Machado-Vieira R, Baumann J, Mallinger AG, Zarate CA. Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(4):1155–9. doi:10.1016/j.pnpbp.2011.03.019.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Iyo AH, Feyissa AM, Chandran A, Austin MC, Regunathan S, Karolewicz B. Chronic corticosterone administration down-regulates metabotropic glutamate receptor 5 protein expression in the rat hippocampus. Neuroscience. 2010;169(4):1567–74. doi:10.1016/j.neuroscience.2010.06.023

    CAS  PubMed Central  PubMed  Google Scholar 

  • Izquierdo A, Wellman CL, Holmes A. Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J Neurosci. 2006;26(21):5733–8. doi:10.1523/JNEUROSCI.0474-06.2006

    CAS  PubMed  Google Scholar 

  • Jackson ME, Moghaddam B. Distinct patterns of plasticity in prefrontal cortex neurons that encode slow and fast responses to stress. Eur J Neurosci. 2006;24(6):1702–10. doi:10.1111/j.1460-9568.2006.05054.x.

    PubMed Central  PubMed  Google Scholar 

  • Johnson MP, Barda D, Britton TC, Emkey R, Hornback WJ, Jagdmann GE, et al. Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s). Psychopharmacology (Berl). 2005;179(1):271–83. doi:10.1007/s00213-004-2099-9.

    CAS  Google Scholar 

  • Johnston-Wilson NL, Sims CD, Hofmann J-P, Anderson L, Shore AD, Torrey EF, Yolken RH. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. Mol Psychiatry. 2000;5(2):142–9. doi:10.1038/sj.mp.4000696.

    CAS  PubMed  Google Scholar 

  • Kapus GL, Gacsályi I, Vegh M, Kompagne H, Hegedus E, Leveleki C, et al. Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents: effects of GYKI 52466 and its novel analogues. Psychopharmacology (Berl). 2008;198(2):231–41. doi:10.1007/s00213-008-1121-z.

    CAS  Google Scholar 

  • Karpova A, Mikhaylova M, Bera S, Bär J, Reddy PP, Behnisch T, et al. Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus. Cell. 2013;152(5):1119–33. doi:10.1016/j.cell.2013.02.002.

    CAS  PubMed  Google Scholar 

  • Karst H, Joëls M. Corticosterone slowly enhances miniature excitatory postsynaptic current amplitude in mice CA1 hippocampal cells. J Neurophysiol. 2005;94(5):3479–86. doi:10.1152/jn.00143.2005.

    CAS  PubMed  Google Scholar 

  • Kendler KS, Karkowski LM, Prescott CA. Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry. 1999a;156(6):837–41.

    CAS  Google Scholar 

  • Kendler KS, Karkowski LM, Prescott CA. The assessment of dependence in the study of stressful life events: validation using a twin design. Psychol Med. 1999b;29(6):1455–60.

    CAS  Google Scholar 

  • Kessler RC, Avenevoli S, McLaughlin KA, Green JG, Lakoma MD, Petukhova M, et al. Lifetime co-morbidity of DSM-IV disorders in the US national comorbidity survey replication adolescent supplement (NCS-A). Psychol Med. 2012;42(9):1997–2010. doi:10.1017/S0033291712000025.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci. 2002;3(6):453–62. doi:10.1038/nrn849.

    CAS  PubMed  Google Scholar 

  • Kim JJ, Foy MR, Thompson RF. Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate receptor activation. Proc Natl Acad Sci U S A. 1996;93(10):4750–3.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kiselycznyk C, Svenningsson P, Delpire E, Holmes A. Genetic, pharmacological and lesion analyses reveal a selective role for corticohippocampal GLUN2B in a novel repeated swim stress paradigm. Neuroscience. 2011;193:259–268. doi:10.1016/j.neuroscience.2011.06. 015.

    CAS  PubMed  Google Scholar 

  • Kiselycznyk C, Zhang X, Huganir RL, Holmes A, Svenningsson P. Reduced phosphorylation of GluA1 subunits relates to anxiety-like behaviours in mice. Int J Neuropsychopharmacol. 2013;16(4):919–24. doi:10.1017/S1461145712001174.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Knapp RJ, Goldenberg R, Shuck C, Cecil A, Watkins J, Miller C, et al. Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model. Eur J Pharmacol. 2002;440(1):27–35.

    CAS  PubMed  Google Scholar 

  • 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(1):107–11. doi:10.1016/j.bbr.2011.05.035.

    CAS  PubMed  Google Scholar 

  • Kotlinska J, Liljequist S. The putative AMPA receptor antagonist, LY326325, produces anxiolytic-like effects without altering locomotor activity in rats. Pharmacol Biochem Behav. 1998;60(1):119–24.

    CAS  PubMed  Google Scholar 

  • Kovačević T, Skelin I, Minuzzi L, Rosa-Neto P, Diksic M. Reduced metabotropic glutamate receptor 5 in the Flinders sensitive line of rats, an animal model of depression: an autoradiographic study. Brain Res Bull. 2012;87(4–5):406–12. doi:10.1016/j.brainresbull.2012.01.010.

    PubMed Central  PubMed  Google Scholar 

  • Krebs C, Fernandes HB, Sheldon C, Raymond LA, Baimbridge KG. Functional NMDA receptor subtype 2B is expressed in astrocytes after ischemia in vivo and anoxia in vitro. J Neurosci. 2003;23(8):3364–72.

    CAS  PubMed  Google Scholar 

  • Krugers HJ, Hoogenraad CC, Groc L. Stress hormones and AMPA plasticity and memory. Nat Rev Neurosci. 2010;10:675–81.

    Google Scholar 

  • Lalo U, Pankratov Y, Kirchhoff F, North RA, Verkhratsky A. NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes. J Neurosci. 2006;26(10):2673–83. doi:10.1523/JNEUROSCI.4689-05.2006.

    CAS  PubMed  Google Scholar 

  • Li X, Tizzano JP, Griffey K, Clay M, Lindstrom T, Skolnick P. Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Neuropharmacology. 2001;40(8):1028–33.

    CAS  PubMed  Google Scholar 

  • Li X, Need AB, Baez M, Witkin JM. Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice. J Pharmacol Exp Ther. 2006;319(1):254–9. doi:10.1124/jpet.106.103143.

    CAS  PubMed  Google Scholar 

  • Li N, Lee B, Liu R-J, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959–64. doi:10.1126/science.1190287. (New York NY).

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lindholm JSO, Autio H, Vesa L, Antila H, Lindemann L, Hoener MC, et al. The antidepressant-like effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY 451646 are preserved in bdnf + /− heterozygous null mice. Neuropharmacology. 2012;62(1):391–7. doi:10.1016/j.neuropharm.2011.08.015.

    CAS  PubMed  Google Scholar 

  • Lipton SA. NMDA receptors, glial cells, and clinical medicine. Neuron. 2006;50(1):9–11.

    CAS  PubMed  Google Scholar 

  • Liu Q, Li B, Zhu H-Y, Wang Y-Q, Yu J, Wu G-C. Clomipramine treatment reversed the glial pathology in a chronic unpredictable stress-induced rat model of depression. Eur Neuropsychopharmacol. 2009;19(11):796–805. doi:10.1016/j.euroneuro.2009.06.010.

    CAS  PubMed  Google Scholar 

  • Lowy MT, Gault L, Yamamoto BK. Adrenalectomy attenuates stress-induced elevations in extracellular glutamate concentrations in the hippocampus. J Neurochem. 1993;61(5):1957–60.

    CAS  PubMed  Google Scholar 

  • Luine V, Martinez C, Villegas M, Magariños AM, McEwen BS. Restraint stress reversibly enhances spatial memory performance. Physiol Behav. 1996;59(1):27–32.

    CAS  PubMed  Google Scholar 

  • Lujan R, Nusser Z, Roberts JD, Shigemoto R, Somogyi P. Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur J Neurosci. 1996;8(7):1488–500.

    CAS  PubMed  Google Scholar 

  • Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10(6):434–45. doi:10.1038/nrn2639.

    CAS  PubMed  Google Scholar 

  • Maeng S, Zarate CA, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63(4):349–52. doi:10.1016/j.biopsych.2007.05.028.

    CAS  PubMed  Google Scholar 

  • Magariños AM, McEwen BS. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors. Neuroscience. 1995a;69(1):83–8.

    Google Scholar 

  • Magariños AM, McEwen BS. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience. 1995b;69(1):89–98.

    Google Scholar 

  • Magariños AM, Deslandes A, McEwen BS. Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress. Eur J Pharmacol. 1999;371(2-3):113–22.

    PubMed  Google Scholar 

  • Malarkey EB, Parpura V. Mechanisms of glutamate release from astrocytes. Neurochem Int. 2008;52(1–2):142–54. doi:10.1016/j.neuint.2007.06.005.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Martel M-A, Ryan TJ, Bell KFS, Fowler JH, McMahon A, Al-Mubarak B, et al. The subtype of GluN2 C-terminal domain determines the response to excitotoxic insults. Neuron. 2012;74(3):543–56. doi:10.1016/j.neuron.2012.03.021.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Martin KP, Wellman CL. NMDA receptor blockade alters stress-induced dendritic remodeling in medial prefrontal cortex. Cerebral Cortex. 2011;21(10):2366–73. doi:10.1093/cercor/bhr021. (New York, N.Y. : 1991)

    PubMed Central  PubMed  Google Scholar 

  • Matheus MG, Guimarães FS. Antagonism of non-NMDA receptors in the dorsal periaqueductal grey induces anxiolytic effect in the elevated plus maze. Psychopharmacology (Berl). 1997;132(1):14–8.

    CAS  Google Scholar 

  • Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol. 2010;13(1):71–82. doi:10.1017/S1461145709000169.

    CAS  PubMed  Google Scholar 

  • Mathews DC, Zarate J. Current status of ketamine and related compounds for depression. J Clin Psychiatry. 2013;74(05):516–7. doi:10.4088/JCP.13ac08382.

    PubMed Central  PubMed  Google Scholar 

  • Mathur P, Graybeal C, Feyder M, Davis MI, Holmes A. Fear memory impairing effects of systemic treatment with the NMDA NR2B subunit antagonist, Ro 25-6981, in mice: attenuation with ageing. Pharmacol Biochem Behav. 2009;91(3):453–60. doi:10.1016/j.pbb.2008.08.028.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Matrisciano F, Storto M, Ngomba RT, Cappuccio I, Caricasole A, Scaccianoce S, et al. Imipramine treatment up-regulates the expression and function of mGlu2/3 metabotropic glutamate receptors in the rat hippocampus. Neuropharmacology. 2002;42(8):1008–15.

    CAS  PubMed  Google Scholar 

  • Matrisciano F, Scaccianoce S, Del Bianco P, Panaccione I, Canudas AM, Battaglia G, et al. Metabotropic glutamate receptors and neuroadaptation to antidepressants: imipramine-induced down-regulation of beta-adrenergic receptors in mice treated with metabotropic glutamate 2/3 receptor ligands. J Neurochem. 2005;93(5):1345–52. doi:10.1111/j.1471-4159.2005.03141.x.

    CAS  PubMed  Google Scholar 

  • Matrisciano F, Panaccione I, Zusso M, Giusti P, Tatarelli R, Iacovelli L, et al. Group-II metabotropic glutamate receptor ligands as adjunctive drugs in the treatment of depression: a new strategy to shorten the latency of antidepressant medication? Mol Psychiatry. 2007;12(8):704–6. doi:10.1038/sj.mp.4002005.

    CAS  PubMed  Google Scholar 

  • Matrisciano F, Caruso A, Orlando R, Marchiafava M, Bruno V, Battaglia G, et al. Defective group-II metaboropic glutamate receptors in the hippocampus of spontaneously depressed rats. Neuropharmacology. 2008;55(4):525–31. doi:10.1016/j.neuropharm.2008.05.014.

    CAS  PubMed  Google Scholar 

  • Matsuzaki M, Honkura N, Ellis-Davies GCR, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429(6993):761–6. doi:10.1038/nature02617.

    CAS  PubMed  Google Scholar 

  • McCullumsmith RE, Meador-Woodruff JH. Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. Neuropsychopharmacology. 2002;26(3):368–75. doi:10.1016/S0893-133X(01)00370-0.

    CAS  PubMed  Google Scholar 

  • McElroy SL, Zarate CA, Cookson J, Suppes T, Huffman RF, Greene P, Ascher J. A 52-week, open-label continuation study of lamotrigine in the treatment of bipolar depression. J Clin Psychiatry. 2004;65(2):204–10.

    CAS  PubMed  Google Scholar 

  • McEwen BS, Chattarji S, Diamond DM, Jay TM, Reagan LP, Svenningsson P, Fuchs E. The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation. Mol Psychiatry. 2010;15(3):237–49. doi:10.1038/mp.2009.80.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Metsis M, Timmusk T, Arenas E, Persson H. Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation. Proc Natl Acad Sci U S A. 1993;90(19):8802–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Milanese M, Tardito D, Musazzi L, Treccani G, Mallei A, Bonifacino T, et al. Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked glutamate release from hippocampal synaptosomes. BMC Neurosci. 2013;14:75. doi:10.1186/1471-2202-14-75.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mineur YS, Picciotto MR, Sanacora G. Antidepressant-like effects of ceftriaxone in male C57BL/6J mice. Biol Psychiatry. 2007;61(2):250–2. doi:10.1016/j.biopsych.2006.04.037.

    CAS  PubMed  Google Scholar 

  • Mitterauer BJ. Ketamine may block NMDA receptors in astrocytes causing a rapid antidepressant effect. Front Synaptic Neurosci. 2012;4:8. doi:10.3389/fnsyn.2012.00008.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Moghaddam B. Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem. 1993;60(5):1650–7.

    CAS  PubMed  Google Scholar 

  • Moghaddam B. Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders. Biol Psychiatry. 2002;51(10):775–87.

    CAS  PubMed  Google Scholar 

  • 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(8):2921–7.

    Google Scholar 

  • Molina-Hernández M, Tellez-Alcántara NP, Pérez-García J, Olivera-Lopez JI, Jaramillo MT. Antidepressant-like and anxiolytic-like actions of the mGlu5 receptor antagonist MTEP, microinjected into lateral septal nuclei of male Wistar rats. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(6):1129–35. doi:10.1016/j.pnpbp.2006.04.022.

    PubMed  Google Scholar 

  • Morley-Fletcher S, Mairesse J, Soumier A, Banasr M, Fagioli F, Gabriel C,et al. Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats. Psychopharmacology (Berl). 2011;217(3):301–13. doi:10.1007/s00213-011-2280-x.

    CAS  Google Scholar 

  • Moryl E, Danysz W, Quack G. Potential antidepressive properties of amantadine, memantine and bifemelane. Pharmacol Toxicol. 1993;72(4–5):394–7. doi:10.1111/j.1600-0773.1993.tb01351.x.

    CAS  PubMed  Google Scholar 

  • Muhonen LH, Lönnqvist J, Juva K, Alho H. Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence. J Clin Psychiatry. 2008;69(3):392–9.

    CAS  PubMed  Google Scholar 

  • Mula M, Pini S, Cassano GB. The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence. J Clin Psychopharmacol. 2007;27(3):263–72. doi:10.1097/jcp.0b013e318059361a.

    CAS  PubMed  Google Scholar 

  • Müller HK, Wegener G, Liebenberg N, Zarate CA, Popoli M, Elfving B. Ketamine regulates the presynaptic release machinery in the hippocampus. J Psychiatr Res. 2013;47(7):892–9. doi:10.1016/j.jpsychires.2013.03.008.

    PubMed Central  PubMed  Google Scholar 

  • Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CM, Perez AM, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134–42. doi:10.1176/appi.ajp.2013.13030392.

    PubMed Central  PubMed  Google Scholar 

  • Musazzi L, Milanese M, Farisello P, Zappettini S, Tardito D, Barbiero VS, et al. Acute stress increases depolarization-evoked glutamate release in the rat prefrontal/frontal cortex: the dampening action of antidepressants. PloS ONE. 2010;5(1):e8566. doi:10.1371/journal.pone.0008566.

    Google Scholar 

  • Musazzi L, Treccani G, Mallei A, Popoli M. The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors. Biol Psychiatry. 2012;73(12):1180–8. doi:10.1016/j.biopsych.2012.11.009.

    PubMed  Google Scholar 

  • Nations KR, Dogterom P, Bursi R, Schipper J, Greenwald S, Zraket D, et al. Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2012;26(12):1525–39. doi:10.1177/0269881112458728.

    PubMed  Google Scholar 

  • O’Shea RD. Roles and regulation of glutamate transporters in the central nervous system. Clin Exp Pharmacol Physiol. 2002;29(11):1018–23.

    PubMed  Google Scholar 

  • Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A. 1998;95(22):13290–5. doi:10.1073/pnas.95.22.13290.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Palucha A, Pilc A. Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol Ther. 2007;115(1):116–47. doi:10.1016/j.pharmthera.2007.04.007.

    CAS  PubMed  Google Scholar 

  • Pałucha A, Brański P, Szewczyk B, Wierońska JM, Kłak K, Pilc A. Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist. Pharmacol Biochem Behav. 2005;81(4):901–6. doi:10.1016/j.pbb.2005.06.015.

    PubMed  Google Scholar 

  • Pałucha-Poniewiera A, Wierońska JM, Brański P, Stachowicz K, Chaki S, Pilc A. On the mechanism of the antidepressant-like action of group II mGlu receptor antagonist, MGS0039. Psychopharmacology (Berl). 2010;212(4):523–35. doi:10.1007/s00213-010-1978-5.

    Google Scholar 

  • Palygin O, Lalo U, Pankratov Y. Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes. Br J Pharmacol. 2011;163(8):1755–66. doi:10.1111/j.1476-5381.2011.01374.x.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Paul IA, Skolnick P. Glutamate and depression: clinical and preclinical studies. Ann N Y Acad Sci. 2003;1003:250–72.

    CAS  PubMed  Google Scholar 

  • Pecknold JC, McClure DJ, Appeltauer L, Wrzesinski L, Allan T. Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study. J Clin Psychopharmacol. 1982;2(2):129–33.

    CAS  PubMed  Google Scholar 

  • Pilc A, Kłodzińska A, Brański P, Nowak G, Pałucha A, Szewczyk B, et al. Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats. Neuropharmacology. 2002;43(2):181–7.

    CAS  PubMed  Google Scholar 

  • Pilc A, Chaki S, Nowak G, Witkin JM. Mood disorders: regulation by metabotropic glutamate receptors. Biochem Pharmacol. 2008;75(5):997–1006. doi:10.1016/j.bcp.2007.09.021.

    CAS  PubMed  Google Scholar 

  • Pisani A, Gubellini P, Bonsi P, Conquet F, Picconi B, Centonze D, et al. Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons. Neuroscience. 2001;106(3):579–87.

    CAS  PubMed  Google Scholar 

  • Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs. 2008;22(9):761–86.

    CAS  PubMed  Google Scholar 

  • Popoli M. Agomelatine: innovative pharmacological approach in depression. CNS Drugs. 2009;23(Suppl 2):27–34. doi:10.2165/11318640-000000000-00000.

    CAS  PubMed  Google Scholar 

  • Porter RHP, Jaeschke G, Spooren W, Ballard TM, Büttelmann B, Kolczewski S, et al. Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther. 2005;315(2):711–21. doi:10.1124/jpet.105.089839.

    CAS  PubMed  Google Scholar 

  • 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(6):631–7. doi:10.1097/JCP.0b013e31818a6cea.

    CAS  PubMed  Google Scholar 

  • Rajkowska G, Miguel-Hidalgo JJ. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets. 2007;6(3):219–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rajkowska G, Stockmeier CA. Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets. 2013;14(11):1225–36.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, … Stockmeier CA (1999). Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 45(9):1085–98. doi:10.1016/S0006-3223(99)00041-4.

    CAS  PubMed  Google Scholar 

  • Reynolds IJ, Miller RJ. Tricyclic antidepressants block N-methyl-D-aspartate receptors: similarities to the action of zinc. Br J Pharmacol. 1988;95(1):95–102.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Reznikov LR, Grillo CA, Piroli GG, Pasumarthi RK, Reagan LP, Fadel J. Acute stress-mediated increases in extracellular glutamate levels in the rat amygdala: differential effects of antidepressant treatment. Eur J Neurosci. 2007;25(10):3109–14. doi:10.1111/j.1460-9568.2007.05560.x.

    PubMed  Google Scholar 

  • Rogóz Z, Skuza G, Maj J, Danysz W. Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats. Neuropharmacology. 2002;42(8):1024–30.

    PubMed  Google Scholar 

  • Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005;433(7021):73–7. doi:10.1038/nature03180.

    CAS  PubMed  Google Scholar 

  • Rutherford EC, Pomerleau F, Huettl P, Strömberg I, Gerhardt GA. Chronic second-by-second measures of L-glutamate in the central nervous system of freely moving rats. J Neurochem. 2007;102(3):712–22. doi:10.1111/j.1471-4159.2007.04596.x.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sanacora G, Banasr M. From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. Biol Psychiatry. 2013;73(12):1172–9. doi:10.1016/j.biopsych.2013.03.032.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sanacora G, Kendell SF, Fenton L, Coric V, Krystal JH. Riluzole augmentation for treatment-resistant depression. Am J Psychiatry. 2004;161(11):2132. doi:10.1176/appi.ajp.161.11.2132.

    PubMed  Google Scholar 

  • Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7(5):426–37. doi:10.1038/nrd2462.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sapolsky RM. The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry. 2000;48(8):755–65.

    CAS  PubMed  Google Scholar 

  • Sapolsky RM. Neuroprotective gene therapy against acute neurological insults. Nat Rev Neurosci. 2003;4(1):61–9. doi:10.1038/nrn1006.

    CAS  PubMed  Google Scholar 

  • Schneiderman N, Ironson G, Siegel SD. Stress and health: psychological, behavioral, and biological determinants. Annu Rev Clin Psychol. 2005;1:607–28. doi:10.1146/annurev.clinpsy.1.102803.144141.

    PubMed Central  PubMed  Google Scholar 

  • Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V, et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PloS ONE. 2009;4(8):e6585. doi:10.1371/journal.pone.0006585.

    Google Scholar 

  • Shigeri Y, Seal RP, Shimamoto K. Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Res Brain Res Rev. 2004;45(3):250–65. doi:10.1016/j.brainresrev.2004.04.004.

    CAS  PubMed  Google Scholar 

  • Sillaber I, Panhuysen M, Henniger MSH, Ohl F, Kühne C, Pütz B, et al. Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine. Psychopharmacology (Berl). 2008;200(4):557–72. doi:10.1007/s00213-008-1232-6.

    CAS  Google Scholar 

  • Sinha R. Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci. 2008;1141:105–30. doi:10.1196/annals.1441.030.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry. 1996;29(1):23–6. doi:10.1055/s-2007-979537.

    CAS  PubMed  Google Scholar 

  • Skolnick P, Legutko B, Li X, Bymaster FP. Current perspectives on the development of non-biogenic amine-based antidepressants. Pharmacol Res. 2001;43(5):411–23. doi:10.1006/phrs.2000.0806.

    CAS  PubMed  Google Scholar 

  • Skolnick P, Popik P, Trullas R. Glutamate-based antidepressants: 20 years on. Trends Pharmacol Sci. 2009;30(11):563–9. doi:10.1016/j.tips.2009.09.002.

    CAS  PubMed  Google Scholar 

  • Stein-Behrens B, Mattson MP, Chang I, Yeh M, Sapolsky R. Stress exacerbates neuron loss and cytoskeletal pathology in the hippocampus. J Neurosci. 1994;14(9):5373–80.

    CAS  PubMed  Google Scholar 

  • Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY, et al. Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry. 2004;56(9):640–50. doi:10.1016/j.biopsych.2004.08.022.

    PubMed Central  PubMed  Google Scholar 

  • Sun W, McConnell E, Pare J-F, Xu Q, Chen M, Peng W, et al. Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science. 2013;339(6116):197–200. doi:10.1126/science.1226740. (New York NY).

    CAS  PubMed Central  PubMed  Google Scholar 

  • Svenningsson P, Bateup H, Qi H, Takamiya K, Huganir RL, Spedding M, et al. Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine. Eur J Neurosci. 2007;26(12):3509–17. doi:10.1111/j.1460-9568.2007.05952.x.

    PubMed  Google Scholar 

  • Swanson CJ, Bures M, Johnson MP, Linden A-M, Monn JA, Schoepp DD. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov. 2005;4(2):131–44. doi:10.1038/nrd1630.

    CAS  PubMed  Google Scholar 

  • Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, et al. A induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A. 2013;110(27):E2518–27. doi:10.1073/pnas.1306832110.

    Google Scholar 

  • Tamaru Y, Nomura S, Mizuno N, Shigemoto R. Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites. Neuroscience. 2001;106(3):481–503.

    CAS  PubMed  Google Scholar 

  • Tardito D, Milanese M, Bonifacino T, Musazzi L, Grilli M, Mallei A, et al. Blockade of stress-induced increase of glutamate release in the rat prefrontal/frontal cortex by agomelatine involves synergy between melatonergic and 5-HT2C receptor-dependent pathways. BMC Neurosci. 2010;11:68. doi:10.1186/1471-2202-11-68.

    PubMed Central  PubMed  Google Scholar 

  • Tardito D, Molteni R, Popoli M, Racagni G. Synergistic mechanisms involved in the antidepressant effects of agomelatine. Eur Neuropsychopharmacol. 2012;22(Suppl 3):S482–6. doi:10.1016/j.euroneuro.2012.06.016.

    Google Scholar 

  • Tatarczyńska E, Klodzińska A, Chojnacka-Wójcik E, Palucha A, Gasparini F, Kuhn R, Pilc A. Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol. 2001;132(7):1423–30. doi:10.1038/sj.bjp.0703923.

    PubMed Central  PubMed  Google Scholar 

  • Trantham-Davidson H, LaLumiere RT, Reissner KJ, Kalivas PW, Knackstedt LA. Ceftriaxone normalizes nucleus accumbens synaptic transmission, glutamate transport, and export following cocaine self-administration and extinction training. J Neurosci. 2012;32(36):12406–10. doi:10.1523/JNEUROSCI.1976-12.2012.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990;185(1):1–10.

    CAS  PubMed  Google Scholar 

  • Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, et al. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron. 1999;23(3):583–92.

    CAS  PubMed  Google Scholar 

  • Uranova NA, Vostrikov VM, Orlovskaya DD, Rachmanova VI. Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley neuropathology consortium. Schizophr Res. 2004;67(2–3), 269–75. doi:10.1016/S0920-9964(03)00181-6.

    PubMed  Google Scholar 

  • Valentine GW, Mason GF, Gomez R, Fasula M, Watzl J, Pittman B, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res. 2011;191(2):122–7. doi:10.1016/j.pscychresns.2010.10.009.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Van der Loos MLM, Mulder PGH, Hartong EGTM, Blom MBJ, Vergouwen AC, de Keyzer HJUEM, et al. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(2):223–31.

    PubMed  Google Scholar 

  • Vekovischeva OY, Aitta-aho T, Verbitskaya E, Sandnabba K, Korpi ER. Acute effects of AMPA-type glutamate receptor antagonists on intermale social behavior in two mouse lines bidirectionally selected for offensive aggression. Pharmacol Biochem Behav. n.d.;87(2):241–9. doi:10.1016/j.pbb.2007.04.020.

    Google Scholar 

  • Venero C, Borrell J. Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: a microdialysis study in freely moving rats. Eur J Neurosci. 1999;11(7):2465–73.

    CAS  PubMed  Google Scholar 

  • Verkhratsky A, Kirchhoff F. NMDA receptors in glia. Neuroscientist. 2007;13(1):28–37. doi:10.1177/1073858406294270.

    CAS  PubMed  Google Scholar 

  • Voleti B, Navarria A, Liu R-J, 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(10):742–9. doi:10.1016/j.biopsych.2013.04.025.

    CAS  PubMed  Google Scholar 

  • Watanabe Y, Gould E, Cameron HA, Daniels DC, McEwen BS. Phenytoin prevents stress- and corticosterone-induced atrophy of CA3 pyramidal neurons. Hippocampus. 1992;2(4):431–5. doi:10.1002/hipo.450020410.

    CAS  PubMed  Google Scholar 

  • Webster MJ, Knable MB, Johnston-Wilson N, Nagata K, Inagaki M, Yolken RH. Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. Brain Behav Immun. 2001;15(4):388–400. doi:10.1006/brbi.2001.0646.

    CAS  PubMed  Google Scholar 

  • Wieroñska JM, Brañski P, Szewczyk B, Papp M, Gruca P, Moryl E, Pilc A. Preliminary communication changes in the expression of metabotropic glutamate receptor 5 (mglur5) in the rat hippocampus in an animal model of depression. Polish Journal of Pharmacology 2001;5:5–8.

    Google Scholar 

  • Wieronska JM, Szewczyk B, Branski P, Palucha A, Pilc A. Antidepressant-like effect of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist in the olfactory bulbectomized rats. Amino Acids. 2002;23(1–3):213–6. doi:10.1007/s00726-001-0131-5.

    CAS  PubMed  Google Scholar 

  • Wierońska JM, Legutko B, Dudys D, Pilc A. Olfactory bulbectomy and amitriptyline treatment influences mGlu receptors expression in the mouse brain hippocampus. Pharmacol Rep. 2008;60(6):844–55.

    PubMed  Google Scholar 

  • Witkin JM, Marek GJ, Johnson BG, Schoepp DD. Metabotropic glutamate receptors in the control of mood disorders. CNS Neurol Disord Drug Targets. 2007;6(2):87–100.

    CAS  PubMed  Google Scholar 

  • Xia P, Chen HV, Zhang D, Lipton SA. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci. 2010;30(33):11246–50. doi:10.1523/JNEUROSCI.2488-10.2010.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xu J, Kurup P, Zhang Y, Goebel-Goody SM, Wu PH, Hawasli AH, et al. Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J Neurosci. 2009;29(29):9330–43. doi:10.1523/JNEUROSCI.2212-09.2009.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yoshimizu T, Shimazaki T, Ito A, Chaki S. An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats. Psychopharmacology (Berl). 2006;186(4):587–93. doi:10.1007/s00213-006-0390-7.

    CAS  Google Scholar 

  • Yoshizumi M, Eisenach JC, Hayashida K. Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes. Eur J Pharmacol. 2012;677(1–3):87–92. doi:10.1016/j.ejphar.2011.12.015.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yuen EY, Liu W, Karatsoreos IN, Feng J, McEwen BS, Yan Z. Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc Natl Acad Sci U S A. 2009;106(33):14075–9. doi:10.1073/pnas.0906791106.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yuen EY, Liu W, Karatsoreos IN, Ren Y, Feng J, McEwen BS, Yan Z. Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory. Mol Psychiatry. 2011;16(2):156–70. doi:10.1038/mp.2010.50.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zarate CA, Quiroz J, Payne J, Manji HK. Modulators of the glutamatergic system: implications for the development of improved therapeutics in mood disorders. Psychopharmacol Bull. 2002;36(4):35–83.

    PubMed  Google Scholar 

  • Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006a;63(8):856–64. doi:10.1001/archpsyc.63.8.856.

    CAS  Google Scholar 

  • Zarate CA, Singh JB, Quiroz JA, De Jesus G, Denicoff KK, Luckenbaugh DA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006b;163(1):153–5. doi:10.1176/appi.ajp.163.1.153.

    Google Scholar 

  • Zarate CA, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71(11):939–46. doi:10.1016/j.biopsych.2011.12.010.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zheng K, Scimemi A, Rusakov DA. Receptor actions of synaptically released glutamate: the role of transporters on the scale from nanometers to microns. Biophys J. 2008;95(10):4584–96. doi:10.1529/biophysj.108.129874.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zink M, Vollmayr B, Gebicke-Haerter PJ, Henn FA. Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression. Neuropharmacology. 2010;58(2):465–73. doi:10.1016/j.neuropharm.2009.09.005.

    CAS  PubMed  Google Scholar 

  • Zink M, Rapp S, Donev R, Gebicke-Haerter PJ, Thome J. Fluoxetine treatment induces EAAT2 expression in rat brain. J Neural Trans. 2011;118(6):849–55. doi:10.1007/s00702-010-0536-y. (Vienna, Austria: 1996).

    CAS  Google Scholar 

  • Zschocke J, Bayatti N, Clement AM, Witan H, Figiel M, Engele J, Behl C. Differential promotion of glutamate transporter expression and function by glucocorticoids in astrocytes from various brain regions. J Biol Chem. 2005;280(41):34924–32. doi:10.1074/jbc.M502581200.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, Yale University, 300 George Street, Suite 901, 06511, New Haven, CT, USA

    Carly Kiselycznyk & Gerard Sanacora

  2. Department of Psychiatry, Yale University, 100 York St. Suite 2J, 06511, New Haven, CT, USA

    Carly Kiselycznyk

Authors
  1. Carly Kiselycznyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerard Sanacora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerard Sanacora .

Editor information

Editors and Affiliations

  1. Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy

    Maurizio Popoli

  2. Department of Psychology, University of South Florida, Tampa, Florida, USA

    David Diamond

  3. Psychiatry Depression Research Program, Yale School of Medicine, New Haven, Connecticut, USA

    Gerard Sanacora

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Kiselycznyk, C., Sanacora, G. (2014). Using Our Understanding of Stress-Related Effects on Glutamate Neurotransmission to Guide the Development of Novel Treatment Strategies. In: Popoli, M., Diamond, D., Sanacora, G. (eds) Synaptic Stress and Pathogenesis of Neuropsychiatric Disorders. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1056-4_17

Download citation

Publish with us

Policies and ethics

Search

Navigation