Advertisement

CNS Drugs

, Volume 32, Issue 3, pp 197–227 | Cite as

Convergent Mechanisms Underlying Rapid Antidepressant Action

  • Panos Zanos
  • Scott M. Thompson
  • Ronald S. Duman
  • Carlos A. ZarateJr.
  • Todd D. Gould
Review Article

Abstract

Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-d-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.

Notes

Compliance with Ethical Standards

Funding

This work was supported by a National Institutes of Health Grant (MH107615) and a Harrington Discovery Institute Scholar-Innovator Grant to Todd D. Gould, and a National Institutes of Health Grant (MH086828) to Scott M. Thompson.

Conflict of interest

Todd D. Gould has received consulting fees from Janssen Pharmaceuticals, and research funding from Janssen Pharmaceuticals and Roche Pharmaceuticals during the preceding 3 years. Ronald S. Duman has received consulting fees from Janssen Pharmaceuticals and Taisho, and research funding from Janssen Pharmaceuticals and Taisho, Allergan, Naurex, Navitor, and Relmada during the preceding 3 years. Carlos A. Zarate Jr. is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. Panos Zanos, Carlos A. Zarate Jr., and Todd D. Gould are listed as co-authors in patent applications related to the pharmacology and use of (2S,6S)- and (2R,6R)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. Scott M. Thompson is listed as a co-inventor on a patent application for the use of negative allosteric modulators of GABAA receptors containing alpha 5 subunits as fast-acting antidepressants.

References

  1. 1.
    Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095–105.PubMedCrossRefGoogle Scholar
  2. 2.
    Insel TR, Wang PS. The STAR*D trial: revealing the need for better treatments. Psychiatr Serv. 2009;60(11):1466–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Pychiatry. 2006;163(11):1905–17.CrossRefGoogle Scholar
  4. 4.
    Gelenberg AJ, Chesen CL. How fast are antidepressants? J Clin Psychiatry. 2000;61(10):712–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Insel TR, Scolnick EM. Cure therapeutics and strategic prevention: raising the bar for mental health research. Mol Psychiatry. 2006;11(1):11–7.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5(1):65–78.PubMedCrossRefGoogle Scholar
  7. 7.
    Segman RH, Shapira B, Gorfine M, Lerer B. Onset and time course of antidepressant action: psychopharmacological implications of a controlled trial of electroconvulsive therapy. Psychopharmacology (Berl). 1995;119(4):440–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, et al. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. J Clin Psychiatry. 2004;65(4):485–91.PubMedCrossRefGoogle Scholar
  9. 9.
    Kellner CH, Knapp RG, Petrides G, Rummans TA, Husain MM, Rasmussen K, et al. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry. 2006;63(12):1337–44.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Dierckx B, Heijnen WT, van den Broek WW, Birkenhager TK. Efficacy of electroconvulsive therapy in bipolar versus unipolar major depression: a meta-analysis. Bipolar Disord. 2012;14(2):146–50.PubMedCrossRefGoogle Scholar
  11. 11.
    Post RM, Uhde TW, Rubinow DR, Huggins T. Differential time course of antidepressant effects after sleep deprivation, ECT, and carbamazepine: clinical and theoretical implications. Psychiatry Res. 1987;22(1):11–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Nutt DJ, Gleiter CH, Glue P. Neuropharmacological aspects of ECT: in search of the primary mechanism of action. Convuls Ther. 1989;5(3):250–60.PubMedGoogle Scholar
  13. 13.
    Nobler MS, Sackeim HA, Moeller JR, Prudic J, Petkova E, Waternaux C. Quantifying the speed of symptomatic improvement with electroconvulsive therapy: comparison of alternative statistical methods. Convuls Ther. 1997;13(4):208–21.PubMedGoogle Scholar
  14. 14.
    Houck W, Abonour R, Vance G, Einhorn LH. Secondary leukemias in refractory germ cell tumor patients undergoing autologous stem-cell transplantation using high-dose etoposide. J Clin Oncol. 2004;22(11):2155–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Wu JC, Bunney WE. The biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis. Am J Psychiatry. 1990;147(1):14–21.PubMedCrossRefGoogle Scholar
  16. 16.
    Wiegand M, Riemann D, Schreiber W, Lauer CJ, Berger M. Effect of morning and afternoon naps on mood after total sleep deprivation in patients with major depression. Biol Psychiatry. 1993;33(6):467–76.PubMedCrossRefGoogle Scholar
  17. 17.
    Zarate CA Jr, Mathews DC, Furey ML. Human biomarkers of rapid antidepressant effects. Biol Psychiatry. 2013;73(12):1142–55.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Sinner B, Graf BM. Ketamine. Handb Exp Pharmacol. 2008;182:313–33.CrossRefGoogle Scholar
  19. 19.
    Mion G. History of anaesthesia: the ketamine story: past, present and future. Eur J Anaesthesiol. 2017;34(9):571–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351–4.PubMedCrossRefGoogle Scholar
  21. 21.
    Zarate CA Jr, 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. 2006;63(8):856–64.PubMedCrossRefGoogle Scholar
  22. 22.
    Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ, et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety. 2014;31(4):335–43.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-d-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71(12):1605–11.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014;76(12):970–6.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172(10):950–66.PubMedCrossRefGoogle Scholar
  26. 26.
    McGirr A, Berlim MT, Bond DJ, Fleck MP, Yatham LN, Lam RW. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med. 2015;45(4):693–704.PubMedCrossRefGoogle Scholar
  27. 27.
    Romeo B, Choucha W, Fossati P, Rotge JY. Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression. Psychiatry Res. 2015;230(2):682–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Kishimoto T, Chawla JM, Hagi K, Zarate CA, Kane JM, Bauer M, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46(7):1459–72.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2017.  https://doi.org/10.1176/appi.ajp.2017.17040472. (epub ahead of print).
  30. 30.
    Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51(3):199–214.PubMedCrossRefGoogle Scholar
  31. 31.
    Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399–405.PubMedCrossRefGoogle Scholar
  32. 32.
    Ramaker MJ, Dulawa SC. Identifying fast-onset antidepressants using rodent models. Mol Psychiatry. 2017;22(5):656–65.PubMedCrossRefGoogle Scholar
  33. 33.
    Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013;19(6):370–80.PubMedCrossRefGoogle Scholar
  34. 34.
    Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg. 1998;87(5):1186–93.PubMedGoogle Scholar
  35. 35.
    Singh JB, Fedgchin M, Daly E, Xi L, Melman C, De Bruecker G, et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol Psychiatry. 2016;80(6):424–31.PubMedCrossRefGoogle Scholar
  36. 36.
    Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Zarate CA Jr, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Liu R-J, Fuchikami M, Dwyer JM, Lepack AE, Duman RS, Aghajanian GK. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology. 2013;38(11):2268–77.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry. 2014;4(10):e469.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA, et al. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res. 2014;58:161–6.PubMedCrossRefGoogle Scholar
  42. 42.
    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(5994):959–64.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    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(7354):91–5.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev. 2012;64(2):238–58.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481–6.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Zanos P, Bhat S, Terrillion CE, Smith RJ, Tonelli LH, Gould TD. Sex-dependent modulation of age-related cognitive decline by the L-type calcium channel gene Cacna1c (Cav 1.2). Eur J Neurosci. 2015;42(8):2499–507.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    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(4):349–52.PubMedCrossRefGoogle Scholar
  48. 48.
    Belujon P, Grace AA. Restoring mood balance in depression: ketamine reverses deficit in dopamine-dependent synaptic plasticity. Biol Psychiatry. 2014;76(12):927–36.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Koike H, Iijima M, Chaki S. Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists. Neuropharmacology. 2011;61(8):1419–23.PubMedCrossRefGoogle Scholar
  50. 50.
    Zhang H, Xue W, Wu R, Gong T, Tao W, Zhou X, et al. Rapid antidepressant activity of ethanol extract of Gardenia jasminoides Ellis is associated with upregulation of BDNF expression in the hippocampus. Evid Based Complement Alternat Med. 2015;2015:761238.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Beurel E, Song L, Jope RS. Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry. 2011;16(11):1068–70.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Carrier N, Kabbaj M. Sex differences in the antidepressant-like effects of ketamine. Neuropharmacology. 2013;70:27–34.PubMedCrossRefGoogle Scholar
  53. 53.
    Gideons ES, Kavalali ET, Monteggia LM. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc Natl Acad Sci USA. 2014;111(23):8649–54.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Iijima M, Fukumoto K, Chaki S. Acute and sustained effects of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test. Behav Brain Res. 2012;235(2):287–92.PubMedCrossRefGoogle Scholar
  55. 55.
    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(8):754–61.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Louderback KM, Wills TA, Muglia LJ, Winder DG. Knockdown of BNST GluN2B-containing NMDA receptors mimics the actions of ketamine on novelty-induced hypophagia. Transl Psychiatry. 2013;3(3):e331.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD, Stanton PK, et al. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology. 2013;38(5):729–42.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Yang B, Zhang JC, Han M, Yao W, Yang C, Ren Q, et al. Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression. Psychopharmacology (Berl). 2016;233(19–20):3647–57.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Donahue RJ, Muschamp JW, Russo SJ, Nestler EJ, Carlezon WA Jr. Effects of striatal DeltaFosB overexpression and ketamine on social defeat stress-induced anhedonia in mice. Biol Psychiatry. 2014;76(7):550–8.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, et al. Comparison of ketamine, 7,8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depression. Psychopharmacology (Berl). 2015;232(23):4325–35.PubMedCrossRefGoogle Scholar
  61. 61.
    Brachman RA, McGowan JC, Perusini JN, Lim SC, Pham TH, Faye C, et al. Ketamine as a prophylactic against stress-induced depressive-like behavior. Biol Psychiatry. 2016;79(9):776–86.PubMedCrossRefGoogle Scholar
  62. 62.
    Gould TD, Georgiou P, Brenner LA, Brundin L, Can A, Courtet P, et al. Animal models to improve our understanding and treatment of suicidal behavior. Transl Psychiatry. 2017;7(4):e1092.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry. 2018;75(2):139–48.PubMedCrossRefGoogle Scholar
  64. 64.
    Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry. 2015;5:e632.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Fukumoto K, Toki H, Iijima M, Hashihayata T, J-i Yamaguchi, Hashimoto K, et al. Antidepressant potential of (R)-ketamine in rodent models: comparison with (S)-ketamine. J Pharmacol Exp Ther. 2017;361(1):9–16.PubMedCrossRefGoogle Scholar
  66. 66.
    Zanos P, Gould TD. Intracellular signaling pathways involved in (S)- and (R)-ketamine antidepressant actions. Biol Psychiatry. 2018;83(1):2–4PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Morgan CJ, Mofeez A, Brandner B, Bromley L, Curran HV. Ketamine impairs response inhibition and is positively reinforcing in healthy volunteers: a dose-response study. Psychopharmacology (Berl). 2004;172(3):298–308.PubMedGoogle Scholar
  68. 68.
    Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, et al. NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology. 1996;14(5):301–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Curran HV, Monaghan L. In and out of the K-hole: a comparison of the acute and residual effects of ketamine in frequent and infrequent ketamine users. Addiction. 2001;96(5):749–60.PubMedCrossRefGoogle Scholar
  70. 70.
    Wolff K, Winstock AR. Ketamine : from medicine to misuse. CNS Drugs. 2006;20(3):199–218.PubMedCrossRefGoogle Scholar
  71. 71.
    Burke RE. The relative selectivity of anticholinergic drugs for the M1 and M2 muscarinic receptor subtypes. Mov Disord. 1986;1(2):135–44.PubMedCrossRefGoogle Scholar
  72. 72.
    Browne RG. Effects of antidepressants and anticholinergics in a mouse “behavioral despair” test. Eur J Pharmacol. 1979;58(3):331–4.PubMedCrossRefGoogle Scholar
  73. 73.
    Betin C, DeFeudis FV, Blavet N, Clostre F. Further characterization of the behavioral despair test in mice: positive effects of convulsants. Physiol Behav. 1982;28(2):307–11.PubMedCrossRefGoogle Scholar
  74. 74.
    Kasper S, Moises HW, Beckmann H. The anticholinergic biperiden in depressive disorders. Pharmacopsychiatria. 1981;14(6):195–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Gillin JC, Sutton L, Ruiz C, Darko D, Golshan S, Risch SC, et al. The effects of scopolamine on sleep and mood in depressed patients with a history of alcoholism and a normal comparison group. Biol Psychiatry. 1991;30(2):157–69.PubMedCrossRefGoogle Scholar
  76. 76.
    Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry. 2006;63(10):1121–9.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Drevets WC, Furey ML. Replication of scopolamine’s antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biol Psychiatry. 2010;67(5):432–8.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Furey ML, Khanna A, Hoffman EM, Drevets WC. Scopolamine produces larger antidepressant and antianxiety effects in women than in men. Neuropsychopharmacology. 2010;35(12):2479–88.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Howland RH. The antidepressant effects of anticholinergic drugs. J Psychosoc Nurs Ment Health Serv. 2009;47(6):17–20.CrossRefGoogle Scholar
  80. 80.
    Gillin JC, Lauriello J, Kelsoe JR, Rapaport M, Golshan S, Kenny WM, et al. No antidepressant effect of biperiden compared with placebo in depression: a double-blind 6-week clinical trial. Psychiatry Res. 1995;58(2):99–105.PubMedCrossRefGoogle Scholar
  81. 81.
    Navarria A, Wohleb ES, Voleti B, Ota KT, Dutheil S, Lepack AE, et al. Rapid antidepressant actions of scopolamine: Role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors. Neurobiol Dis. 2015;82:254–61.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Wohleb ES, Wu M, Gerhard DM, Taylor SR, Picciotto MR, Alreja M, et al. GABA interneurons mediate the rapid antidepressant-like effects of scopolamine. J Clin Invest. 2016;126(7):2482–94.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Geoffroy M, Scheel-Kruger J, Christensen AV. Effect of imipramine in the “learned helplessness” model of depression in rats is not mimicked by combinations of specific reuptake inhibitors and scopolamine. Psychopharmacology (Berl). 1990;101(3):371–5.PubMedCrossRefGoogle Scholar
  84. 84.
    Anisman H, Remington G, Sklar LS. Effect of inescapable shock on subsequent escape performance: catecholaminergic and cholinergic mediation of response initiation and maintenance. Psychopharmacology (Berl). 1979;61(2):107–24.PubMedCrossRefGoogle Scholar
  85. 85.
    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(10):742–9.PubMedCrossRefGoogle Scholar
  86. 86.
    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(2):448–56.PubMedCrossRefGoogle Scholar
  87. 87.
    Martinowich K, Jimenez DV, Zarate CA Jr, Manji HK. Rapid antidepressant effects: moving right along. Mol Psychiatry. 2013;18(8):856–63.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Vyklicky V, Korinek M, Smejkalova T, Balik A, Krausova B, Kaniakova M, et al. Structure, function, and pharmacology of NMDA receptor channels. Physiol Res. 2014;63(Suppl. 1):S191–203.PubMedGoogle Scholar
  89. 89.
    Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990;185(1):1–10.PubMedCrossRefGoogle Scholar
  90. 90.
    Paul IA, Nowak G, Layer RT, Popik P, Skolnick P. Adaptation of the N-methyl-d-aspartate receptor complex following chronic antidepressant treatments. J Pharmacol Exp Ther. 1994;269(1):95–102.PubMedGoogle Scholar
  91. 91.
    Nowak G, Li Y, Paul IA. Adaptation of cortical but not hippocampal NMDA receptors after chronic citalopram treatment. Eur J Pharmacol. 1996;295(1):75–85.PubMedCrossRefGoogle Scholar
  92. 92.
    Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16(7):472–86.PubMedCrossRefGoogle Scholar
  93. 93.
    Jimenez-Sanchez L, Campa L, Auberson YP, Adell A. The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression. Neuropsychopharmacology. 2014;39(11):2673–80.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Kiselycznyk C, Jury NJ, Halladay LR, Nakazawa K, Mishina M, Sprengel R, et al. NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism. Behav Brain Res. 2015;287:89–95.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Li SX, Han Y, Xu LZ, Yuan K, Zhang RX, Sun CY, et al. Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects. Mol Psychiatry. 2017.  https://doi.org/10.1038/mp.2017.85. (epub ahead of print).
  96. 96.
    Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554:317PubMedCrossRefGoogle Scholar
  97. 97.
    Zhu W-L, Wang S-J, Liu M-M, Shi H-S, Zhang R-X, Liu J-F, et al. Glycine site N-methyl-d-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats. J Psychiatry Neurosci. 2013;38(5):306–16.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Liu B-B, Luo L, Liu X-L, Geng D, Liu Q, Yi L-T. 7-Chlorokynurenic acid (7-CTKA) produces rapid antidepressant-like effects: through regulating hippocampal microRNA expressions involved in TrkB-ERK/Akt signaling pathways in mice exposed to chronic unpredictable mild stress. Psychopharmacology. 2015;232(3):541–50.PubMedCrossRefGoogle Scholar
  99. 99.
    Zhang JC, Li SX, Hashimoto K. R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacol Biochem Behav. 2014;116:137–41.PubMedCrossRefGoogle Scholar
  100. 100.
    Yang C, Qu Y, Fujita Y, Ren Q, Ma M, Dong C, et al. Possible role of the gut microbiota-brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model. Transl Psychiatry. 2017;7(12):1294.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Sarkar A, Kabbaj M. Sex differences in effects of ketamine on behavior, spine density, and synaptic proteins in socially isolated rats. Biol Psychiatry. 2016;80(6):448–56.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Can A, Zanos P, Moaddel R, Kang HJ, Dossou KSS, Wainer IW, et al. Effects of ketamine and ketamine metabolites on evoked striatal dopamine release, dopamine receptors, and monoamine transporters. J Pharmacol Exp Ther. 2016;359(1):159–70.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Zarate CA Jr, Brutsche N, Laje G, Luckenbaugh DA, Venkata SL, Ramamoorthy A, et al. Relationship of ketamine’s plasma metabolites with response, diagnosis, and side effects in major depression. Biol Psychiatry. 2012;72(4):331–8.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Pham TH, Defaix C, Xu X, Deng S-X, Fabresse N, Alvarez J-C, et al. Common neurotransmission recruited in recruited in (R,S)-ketamine and (2R,6R)-hydroxynorketamine-induced sustained antidepressant-like effects. Biol Psychiatry. 2017. S0006-3223(17)32130–3.  https://doi.org/10.1016/j.biopsych.2017.10.020. (epub ahead of print).
  105. 105.
    Yang C, Qu Y, Abe M, Nozawa D, Chaki S, Hashimoto K. (R)-Ketamine shows greater potency and longer lasting antidepressant effects than its metabolite (2R,6R)-hydroxynorketamine. Biol Psychiatry. 2017;82(5):e43–4.PubMedCrossRefGoogle Scholar
  106. 106.
    Shirayama Y, Hashimoto K. Lack of antidepressant effects of (2R,6R)-hydroxynorketamine in a rat learned helplessness model: comparison with (R)-ketamine. Int J Neuropsychopharmacol. 2018;21(1):84–8.PubMedCrossRefGoogle Scholar
  107. 107.
    Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. Reply to: effects of a ketamine metabolite on synaptic NMDAR function. Nature. 2017;546(7659):E4–5.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Suzuki K, Nosyreva E, Hunt KW, Kavalali ET, Monteggia LM. Effects of a ketamine metabolite on synaptic NMDAR function. Nature. 2017;546(7659):E1–3.PubMedCrossRefGoogle Scholar
  109. 109.
    Morris PJ, Moaddel R, Zanos P, Moore CE, Gould T, Zarate CA, et al. Synthesis and N-methyl-d-aspartate (NMDA) receptor activity of ketamine metabolites. Org Lett. 2017;19(17):4572–5.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Zarate CA Jr, 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. 2006;163(1):153–5.PubMedCrossRefGoogle Scholar
  111. 111.
    Lenze EJ, Skidmore ER, Begley AE, Newcomer JW, Butters MA, Whyte EM. Memantine for late-life depression and apathy after a disabling medical event: a 12-week, double-blind placebo-controlled pilot study. Int J Geriatr Psychiatry. 2012;27(9):974–80.PubMedCrossRefGoogle Scholar
  112. 112.
    Ferguson JM, Shingleton RN. An open-label, flexible-dose study of memantine in major depressive disorder. Clin Neuropharmacol. 2007;30(3):136–44.PubMedCrossRefGoogle Scholar
  113. 113.
    Moaddel R, Abdrakhmanova G, Kozak J, Jozwiak K, Toll L, Jimenez L, et al. Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in alpha7 nicotinic acetylcholine receptors. Eur J Pharmacol. 2013;698(1–3):228–34.PubMedCrossRefGoogle Scholar
  114. 114.
    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;19(9):978–85.PubMedCrossRefGoogle Scholar
  115. 115.
    Sanacora G, Johnson MR, Khan A, Atkinson SD, Riesenberg RR, Schronen JP, et al. Adjunctive lanicemine (AZD6765) in patients with major depressive disorder and history of inadequate response to antidepressants: a randomized, placebo-controlled study. Neuropsychopharmacology. 2017;42(4):844–53.PubMedCrossRefGoogle Scholar
  116. 116.
    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.PubMedCrossRefGoogle Scholar
  117. 117.
    Hashimoto K. Comments on “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. 2009;29(4):411–2 (author reply 2).PubMedCrossRefGoogle Scholar
  118. 118.
    Hashimoto K, London ED. Further characterization of [3H]ifenprodil binding to sigma receptors in rat brain. Eur J Pharmacol. 1993;236(1):159–63.PubMedCrossRefGoogle Scholar
  119. 119.
    Hashimoto K, Ishiwata K. Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals. Curr Pharm Des. 2006;12(30):3857–76.PubMedGoogle Scholar
  120. 120.
    Stahl SM. The sigma enigma: can sigma receptors provide a novel target for disorders of mood and cognition? J Clin Psychiatry. 2008;69(11):1673–4.PubMedCrossRefGoogle Scholar
  121. 121.
    Hashimoto K. Sigma-1 receptors and selective serotonin reuptake inhibitors: clinical implications of their relationship. Cent Nerv Syst Agents Med Chem. 2009;9(3):197–204.PubMedCrossRefGoogle Scholar
  122. 122.
    Ibrahim L, Diaz Granados N, Jolkovsky L, Brutsche N, Luckenbaugh DA, Herring WJ, et al. A randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J Clin Psychopharmacol. 2012;32(4):551–7.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Sanacora G. What are we learning from early-phase clinical trials with glutamate targeting medications for the treatment of major depressive disorder. JAMA Psychiatry. 2016;73(7):651–2.PubMedCrossRefGoogle Scholar
  124. 124.
    Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X. An excitatory synapse hypothesis of depression. Trends Neurosci. 2015;38(5):279–94.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. (in press).Google Scholar
  126. 126.
    Moskal JR, Kuo AG, Weiss C, Wood PL, Hanson AO, Kelso S, et al. GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-d-aspartate receptor modulator. Neuropharmacology. 2005;49(7):1077–87.PubMedCrossRefGoogle Scholar
  127. 127.
    Preskorn S, Macaluso M, Mehra DO, Zammit G, Moskal JR, Burch RM, et al. Randomized proof of concept trial of GLYX-13, an N-methyl-d-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatr Pract. 2015;21(2):140–9.PubMedCrossRefGoogle Scholar
  128. 128.
    Liu RJ, Duman C, Kato T, Hare B, Lopresto D, Bang E, et al. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Neuropsychopharmacology. 2017;42(6):1231–42.PubMedCrossRefGoogle Scholar
  129. 129.
    Chen L, Muhlhauser M, Yang CR. Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. J Neurophysiol. 2003;89(2):691–703.PubMedCrossRefGoogle Scholar
  130. 130.
    Huang CC, Wei IH, Huang CL, Chen KT, Tsai MH, Tsai P, et al. Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol Psychiatry. 2013;74(10):734–41.PubMedCrossRefGoogle Scholar
  131. 131.
    Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, et al. A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol. 2013;16(3):501–6.PubMedCrossRefGoogle Scholar
  132. 132.
    Wilhelm S, Buhlmann U, Tolin DF, Meunier SA, Pearlson GD, Reese HE, et al. Augmentation of behavior therapy with d-cycloserine for obsessive-compulsive disorder. Am J Psychiatry. 2008;165(3):335–41 (quiz 409).PubMedCrossRefGoogle Scholar
  133. 133.
    Poleszak E, Wlaź P, Szewczyk B, Wlaź A, Kasperek R, Wróbel A, et al. A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice. J Neural Transm. 2011;118(11):1535–46.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    van Berckel BN, Lipsch C, Timp S, Gispen-de Wied C, Wynne H, van Ree JM, et al. Behavioral and neuroendocrine effects of the partial NMDA agonist d-cycloserine in healthy subjects. Neuropsychopharmacology. 1997;16(5):317–24.PubMedCrossRefGoogle Scholar
  135. 135.
    Trullas R, Folio T, Young A, Miller R, Boje K, Skolnick P. 1-aminocyclopropanecarboxylates exhibit antidepressant and anxiolytic actions in animal models. Eur J Pharmacol. 1991;203(3):379–85.PubMedCrossRefGoogle Scholar
  136. 136.
    Moskal JR, Burch R, Burgdorf JS, Kroes RA, Stanton PK, Disterhoft JF, et al. GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists. Expert Opin Investig Drugs. 2014;23(2):243–54.PubMedCrossRefGoogle Scholar
  137. 137.
    Rajagopal L, Burgdorf JS, Moskal JR, Meltzer HY. GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice. Behav Brain Res. 2016;15(299):105–10.CrossRefGoogle Scholar
  138. 138.
    Shu Y, Hasenstaub A, McCormick DA. Turning on and off recurrent balanced cortical activity. Nature. 2003;423(6937):288–93.PubMedCrossRefGoogle Scholar
  139. 139.
    Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C. Interneurons of the neocortical inhibitory system. Nat Rev Neurosci. 2004;5(10):793–807.PubMedCrossRefGoogle Scholar
  140. 140.
    Williams SM, Goldman-Rakic PS, Leranth C. The synaptology of parvalbumin-immunoreactive neurons in the primate prefrontal cortex. J Comp Neurol. 1992;320(3):353–69.PubMedCrossRefGoogle Scholar
  141. 141.
    Cobb SR, Buhl EH, Halasy K, Paulsen O, Somogyi P. Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature. 1995;378(6552):75–8.PubMedCrossRefGoogle Scholar
  142. 142.
    Miles R, Toth K, Gulyas AI, Hajos N, Freund TF. Differences between somatic and dendritic inhibition in the hippocampus. Neuron. 1996;16(4):815–23.PubMedCrossRefGoogle Scholar
  143. 143.
    Cardin JA, Carlen M, Meletis K, Knoblich U, Zhang F, Deisseroth K, et al. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature. 2009;459(7247):663–7.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Sohal VS, Zhang F, Yizhar O, Deisseroth K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature. 2009;459(7247):698–702.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    de Lima AD, Morrison JH. Ultrastructural analysis of somatostatin-immunoreactive neurons and synapses in the temporal and occipital cortex of the macaque monkey. J Comp Neurol. 1989;283(2):212–27.PubMedCrossRefGoogle Scholar
  146. 146.
    Kawaguchi Y, Kubota Y. Physiological and morphological identification of somatostatin- or vasoactive intestinal polypeptide-containing cells among GABAergic cell subtypes in rat frontal cortex. J Neurosci. 1996;16(8):2701–15.PubMedCrossRefGoogle Scholar
  147. 147.
    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.PubMedCrossRefGoogle Scholar
  148. 148.
    Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA. Effects of ketamine and N-methyl-d-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience. 2003;117(3):697–706.PubMedCrossRefGoogle Scholar
  149. 149.
    Chowdhury GM, Zhang J, Thomas M, Banasr M, Ma X, Pittman B, et al. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol Psychiatry. 2017;22(1):120–6.PubMedCrossRefGoogle Scholar
  150. 150.
    Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci. 2007;27(43):11496–500.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Ling DS, Benardo LS. Recruitment of GABAA inhibition in rat neocortex is limited and not NMDA dependent. J Neurophysiol. 1995;74(6):2329–35.PubMedCrossRefGoogle Scholar
  152. 152.
    Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW, et al. NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci. 1996;16(6):2034–43.PubMedCrossRefGoogle Scholar
  153. 153.
    Hiyoshi T, Kambe D, Karasawa J, Chaki S. Involvement of glutamatergic and GABAergic transmission in MK-801-increased gamma band oscillation power in rat cortical electroencephalograms. Neuroscience. 2014;7(280):262–74.CrossRefGoogle Scholar
  154. 154.
    Jones NC, Anderson P, Rind G, Sullivan C, van den Buuse M, O’Brien TJ. Effects of aberrant gamma frequency oscillations on prepulse inhibition. Int J Neuropsychopharmacol. 2014;17(10):1671–81.PubMedCrossRefGoogle Scholar
  155. 155.
    Kocsis B. Differential role of NR2A and NR2B subunits in N-methyl-d-aspartate receptor antagonist-induced aberrant cortical gamma oscillations. Biol Psychiatry. 2012;71(11):987–95.PubMedCrossRefGoogle Scholar
  156. 156.
    Kocsis B. State-dependent increase of cortical gamma activity during REM sleep after selective blockade of NR2B subunit containing NMDA receptors. Sleep. 2012;35(7):1011–6.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Sapkota K, Mao Z, Synowicki P, Lieber D, Liu M, Ikezu T, et al. GluN2D N-methyl-d-aspartate receptor subunit contribution to the stimulation of brain activity and gamma oscillations by ketamine: implications for schizophrenia. J Pharmacol Exp Ther. 2016;356(3):702–11.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Disney AA, Reynolds JH. Expression of m1-type muscarinic acetylcholine receptors by parvalbumin-immunoreactive neurons in the primary visual cortex: a comparative study of rat, guinea pig, ferret, macaque, and human. J Comp Neurol. 2014;522(5):986–1003.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    McCormick DA, Prince DA. Two types of muscarinic response to acetylcholine in mammalian cortical neurons. Proc Nat Acad Sci USA. 1985;82(18):6344–8.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Amar M, Lucas-Meunier E, Baux G, Fossier P. Blockade of different muscarinic receptor subtypes changes the equilibrium between excitation and inhibition in rat visual cortex. Neuroscience. 2010;169(4):1610–20.PubMedCrossRefGoogle Scholar
  161. 161.
    Towers SK, Gloveli T, Traub RD, Driver JE, Engel D, Fradley R, et al. Alpha 5 subunit-containing GABAA receptors affect the dynamic range of mouse hippocampal kainate-induced gamma frequency oscillations in vitro. J Physiol. 2004;559(Pt 3):721–8.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM. Rapid antidepressant action and restoration of excitatory synaptic strength after chronic stress by negative modulators of alpha5-containing GABAA receptors. Neuropsychopharmacology. 2015;40(11):2499–509.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Carreno FR, Collins GT, Frazer A, Lodge DJ. Selective pharmacological augmentation of hippocampal activity produces a sustained antidepressant-like response without abuse-related or psychotomimetic effects. Int J Neuropsychopharmacol. 2017;20(6):504–9.  https://doi.org/10.1093/ijnp/pyx003.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Zanos P, Nelson ME, Highland JN, Krimmel SR, Georgiou P, Gould TD, et al. A negative allosteric modulator for alpha5 subunit-containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice. eNeuro. 2017;4(1).  https://doi.org/10.1523/eneuro.0285-16.2017.
  165. 165.
    Xu NZ, Ernst M, Treven M, Cerne R, Wakulchik M, Li X, et al. Negative allosteric modulation of alpha 5-containing GABAA receptors engenders antidepressant-like effects and selectively prevents age-associated hyperactivity in tau-depositing mice. Psychopharmacology. 2018.  https://doi.org/10.1007/s00213-018-4832-9
  166. 166.
    Atack JR, Maubach KA, Wafford KA, O’Connor D, Rodrigues AD, Evans DC, et al. In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)- pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA receptor alpha5 subtype-selective inverse agonist. J Pharmacol Exp Ther. 2009;331(2):470–84.PubMedCrossRefGoogle Scholar
  167. 167.
    Malherbe P, Sigel E, Baur R, Persohn E, Richards JG, Mohler H. Functional expression and sites of gene transcription of a novel alpha subunit of the GABAA receptor in rat brain. FEBS Lett. 1990;260(2):261–5.PubMedCrossRefGoogle Scholar
  168. 168.
    Lingford-Hughes A, Hume SP, Feeney A, Hirani E, Osman S, Cunningham VJ, et al. Imaging the GABA-benzodiazepine receptor subtype containing the alpha5-subunit in vivo with [11C]Ro15 4513 positron emission tomography. J Cereb Blood Flow Metab. 2002;22(7):878–89.PubMedCrossRefGoogle Scholar
  169. 169.
    Ren Z, Pribiag H, Jefferson SJ, Shorey M, Fuchs T, Stellwagen D, et al. Bidirectional homeostatic regulation of a depression-related brain state by gamma-aminobutyric acidergic deficits and ketamine treatment. Biol Psychiatry. 2016;80(6):457–68.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Shen Q, Lal R, Luellen BA, Earnheart JC, Andrews AM, Luscher B. γ-Aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression. Biol Psychiatry. 2010;68(6):512–20.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Smith KS, Rudolph U. Anxiety and depression: mouse genetics and pharmacological approaches to the role of GABA(A) receptor subtypes. Neuropharmacology. 2012;62(1):54–62.PubMedCrossRefGoogle Scholar
  172. 172.
    Fuchs T, Jefferson SJ, Hooper A, Yee P-HP, Maguire J, Luscher B. Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state. Mol Psychiatry. 2017;22(6):920–30.PubMedCrossRefGoogle Scholar
  173. 173.
    Möhler H. The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology. 2012;62(1):42–53.PubMedCrossRefGoogle Scholar
  174. 174.
    Kalueff AV, Nutt DJ. Role of GABA in anxiety and depression. Depress Anxiety. 2007;24(7):495–517.PubMedCrossRefGoogle Scholar
  175. 175.
    Klumpers UM, Veltman DJ, Drent ML, Boellaard R, Comans EF, Meynen G, et al. Reduced parahippocampal and lateral temporal GABAA-[11C]flumazenil binding in major depression: preliminary results. Eur J Nucl Med Mol Imaging. 2010;37(3):565–74.PubMedCrossRefGoogle Scholar
  176. 176.
    Sanacora G, Mason GF, Rothman DL, Krystal JH. Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry. 2002;159(4):663–5.PubMedCrossRefGoogle Scholar
  177. 177.
    Fava M, Schaefer K, Huang H, Wilson A, Iosifescu DV, Mischoulon D, et al. A post hoc analysis of the effect of nightly administration of eszopiclone and a selective serotonin reuptake inhibitor in patients with insomnia and anxious depression. J Clin Psychiatry. 2011;72(4):473–9.PubMedCrossRefGoogle Scholar
  178. 178.
    Distler MG, Plant LD, Sokoloff G, Hawk AJ, Aneas I, Wuenschell GE, et al. Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal. J Clin Invest. 2012;122(6):2306–15.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    McMurray KMJ, Ramaker MJ, Barkley-Levenson AM, Sidhu PS, Elkin PK, Reddy MK, et al. Identification of a novel, fast-acting GABAergic antidepressant. Mol Psychiatry. 2017.  https://doi.org/10.1038/mp.2017.14. (epub ahead of print).
  180. 180.
    Piantadosi SC, French BJ, Poe MM, Timic T, Markovic BD, Pabba M, et al. Sex-dependent anti-stress effect of an alpha5 subunit containing GABAA receptor positive allosteric modulator. Front Pharmacol. 2016;7:446.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Bespalov AY, van Gaalen MM, Sukhotina IA, Wicke K, Mezler M, Schoemaker H, et al. Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression. Eur J Pharmacol. 2008;592(1):96–102.PubMedCrossRefGoogle Scholar
  182. 182.
    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.PubMedCrossRefGoogle Scholar
  183. 183.
    Witkin JM, Monn JA, Schoepp DD, Li X, Overshiner C, Mitchell SN, et al. The rapidly acting antidepressant ketamine and the mGlu2/3 receptor antagonist LY341495 rapidly engage dopaminergic mood circuits. J Pharmacol Exp Ther. 2016;358(1):71–82.PubMedCrossRefGoogle Scholar
  184. 184.
    Yoshimizu T, Shimazaki T, Ito A, Chaki S. An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats. Psychopharmacology. 2006;186(4):587.PubMedCrossRefGoogle Scholar
  185. 185.
    Ohishi H, Ogawa-Meguro R, Shigemoto R, Kaneko T, Nakanishi S, Mizuno N. Immunohistochemical localization of metabotropic glutamate receptors, mGluR2 and mGluR3, in rat cerebellar cortex. Neuron. 1994;13(1):55–66.PubMedCrossRefGoogle Scholar
  186. 186.
    Petralia RS, Wang YX, Niedzielski AS, Wenthold RJ. The metabotropic glutamate receptors, MGLUR2 and MGLUR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience. 1996;71(4):949–76.PubMedCrossRefGoogle Scholar
  187. 187.
    Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, et al. Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J Neurosci. 1997;17(19):7503–22.PubMedCrossRefGoogle Scholar
  188. 188.
    Chen Y-L, Huang C-C, Hsu K-S. Time-dependent reversal of long-term potentiation by low-frequency stimulation at the hippocampal mossy fiber–CA3 synapses. J Neurosci. 2001;21(11):3705–14.PubMedCrossRefGoogle Scholar
  189. 189.
    Tzounopoulos T, Janz R, Südhof TC, Nicoll RA, Malenka RC. A role for cAMP in long-term depression at hippocampal mossy fiber synapses. Neuron. 1998;21(4):837–45.PubMedCrossRefGoogle Scholar
  190. 190.
    Ohishi H, Shigemoto R, Nakanishi S, Mizuno N. Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J Comp Neurol. 1993;335(2):252–66.PubMedCrossRefGoogle Scholar
  191. 191.
    Ciccarelli R, Sureda FX, Casabona G, Di Iorio P, Caruso A, Spinella F, et al. Opposite influence of the metabotropic glutamate receptor subtypes mGlu3 and -5 on astrocyte proliferation in culture. Glia. 1997;21(4):390–8.PubMedCrossRefGoogle Scholar
  192. 192.
    Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, et al. Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur J Neurosci. 2003;17(10):2106–18.PubMedCrossRefGoogle Scholar
  193. 193.
    Dwyer JM, Lepack AE, Duman RS. mTOR activation is required for the antidepressant effects of mGluR(2)/(3) blockade. Int J Neuropsychopharmacol. 2012;15(4):429–34.PubMedCrossRefGoogle Scholar
  194. 194.
    Koike H, Fukumoto K, Iijima M, Chaki S. Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression. Behav Brain Res. 2013;1(238):48–52.CrossRefGoogle Scholar
  195. 195.
    Fukumoto K, Iijima M, Chaki S. Serotonin-1A receptor stimulation mediates effects of a metabotropic glutamate 2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and an N-methyl-d-aspartate receptor antagonist, ketamine, in the novelty-suppressed feeding test. Psychopharmacology (Berl). 2014;231(11):2291–8.PubMedCrossRefGoogle Scholar
  196. 196.
    Dwyer JM, Lepack AE, Duman RS. mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure. J Mol Psychiatry. 2013;1(1):15.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Ago Y, Yano K, Araki R, Hiramatsu N, Kita Y, Kawasaki T, et al. Metabotropic glutamate 2/3 receptor antagonists improve behavioral and prefrontal dopaminergic alterations in the chronic corticosterone-induced depression model in mice. Neuropharmacology. 2013;65:29–38.PubMedCrossRefGoogle Scholar
  198. 198.
    Dong C, J-c Zhang, Yao W, Ren Q, Ma M, Yang C, et al. Rapid and sustained antidepressant action of the mGlu2/3 receptor antagonist MGS0039 in the social defeat stress model: comparison with ketamine. Int J Neuropsychopharmacol. 2017;20(3):228–36.PubMedGoogle Scholar
  199. 199.
    Umbricht D, Niggli M, Sanwald-Ducray P, Deptula D, Moore R, Grünbauer W, et al. Results of a double-blind placebo-controlled study of the antidepressant effects of the mGLU2 negative allosteric modulator RG1578. Eur Neuropsychopharmacol. 2015;25:S447.CrossRefGoogle Scholar
  200. 200.
    Dudek SM, Bear MF. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-d-aspartate receptor blockade. Proc Natl Acad Sci USA. 1992;89(10):4363–7.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Bliss TV, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol. 1973;232(2):331–56.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Nicoll RA, Malenka RC. Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature. 1995;377(6545):115–8.PubMedCrossRefGoogle Scholar
  203. 203.
    Alfarez DN, Joels M, Krugers HJ. Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. Eur J Neurosci. 2003;17(9):1928–34.PubMedCrossRefGoogle Scholar
  204. 204.
    Joels M, Karst H, Alfarez D, Heine VM, Qin Y, van Riel E, et al. Effects of chronic stress on structure and cell function in rat hippocampus and hypothalamus. Stress. 2004;7(4):221–31.PubMedCrossRefGoogle Scholar
  205. 205.
    Pavlides C, Nivon LG, McEwen BS. Effects of chronic stress on hippocampal long-term potentiation. Hippocampus. 2002;12(2):245–57.PubMedCrossRefGoogle Scholar
  206. 206.
    Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238–49.PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Wang M, Yang Y, Dong Z, Cao J, Xu L. NR2B-containing N-methyl-d-aspartate subtype glutamate receptors regulate the acute stress effect on hippocampal long-term potentiation/long-term depression in vivo. Neuroreport. 2006;17(12):1343–6.PubMedCrossRefGoogle Scholar
  208. 208.
    Leuner B, Shors TJ. Stress, anxiety, and dendritic spines: what are the connections? Neuroscience. 2013;22(251):108–19.CrossRefGoogle Scholar
  209. 209.
    Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci. 2013;33(40):15669–74.PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Bliss TVP, Cooke SF. Long-term potentiation and long-term depression: a clinical perspective. Clinics. 2011;66(Suppl. 1):3–17.PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Cai X, Kallarackal AJ, Kvarta MD, Goluskin S, Gaylor K, Bailey AM, et al. Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression. Nat Neurosci. 2013;16(4):464–72.PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Izumi Y, Zorumski CF. Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function. Neuropharmacology. 2014;86:273–81.PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Yao N, Skiteva O, Zhang X, Svenningsson P, Chergui K. Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit. Mol Psychiatry. 2017.  https://doi.org/10.1038/mp.2017.239. (epub ahead of print).
  214. 214.
    Moaddel R, Sanghvi M, Dossou KS, Ramamoorthy A, Green C, Bupp J, et al. The distribution and clearance of (2S,6S)-hydroxynorketamine, an active ketamine metabolite, in Wistar rats. Pharmacol Res Perspect. 2015;3(4):e00157.PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Zhang XL, Sullivan JA, Moskal JR, Stanton PK. A NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus. Neuropharmacology. 2008;55(7):1238–50.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Burgdorf J, Zhang XL, Weiss C, Matthews E, Disterhoft JF, Stanton PK, et al. The N-methyl-d-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats. Neurobiol Aging. 2011;32(4):698–706.PubMedCrossRefGoogle Scholar
  217. 217.
    Burgdorf J, Kroes RA, X-l Zhang, Gross AL, Schmidt M, Weiss C, et al. Rapastinel (GLYX-13) has therapeutic potential for the treatment of post-traumatic stress disorder: characterization of a NMDA receptor-mediated metaplasticity process in the medial prefrontal cortex of rats. Behav Brain Res. 2015;294:177–85.PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Burgdorf J, X-l Zhang, Weiss C, Gross A, Boikess SR, Kroes RA, et al. The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus. Neuroscience. 2015;308:202–11.PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    Pöschel B, Wroblewska B, Heinemann U, Manahan-Vaughan D. The metabotropic glutamate receptor mGluR3 is critically required for hippocampal long-term depression and modulates long-term potentiation in the dentate gyrus of freely moving rats. Cereb Cortex. 2005;15(9):1414–23.PubMedCrossRefGoogle Scholar
  220. 220.
    Hascup ER, Hascup KN, Stephens M, Pomerleau F, Huettl P, Gratton A, et al. Rapid microelectrode measurements and the origin and regulation of extracellular glutamate in rat prefrontal cortex. J Neurochem. 2010;115(6):1608–20.PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Chana G, Landau S, Beasley C, Everall IP, Cotter D. Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density. Biol Psychiatry. 2003;53(12):1086–98.PubMedCrossRefGoogle Scholar
  222. 222.
    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. Cereb Cortex. 2002;12(4):386–94.PubMedCrossRefGoogle Scholar
  223. 223.
    Cotter D, Mackay D, Landau S, Kerwin R, Everall I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry. 2001;58(6):545–53.PubMedCrossRefGoogle Scholar
  224. 224.
    Cotter D, Hudson L, Landau S. Evidence for orbitofrontal pathology in bipolar disorder and major depression, but not in schizophrenia. Bipolar Disord. 2005;7(4):358–69.PubMedCrossRefGoogle Scholar
  225. 225.
    Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45(9):1085–98.PubMedCrossRefGoogle Scholar
  226. 226.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Magarinos AM, McEwen BS, Flugge G, Fuchs E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci. 1996;16(10):3534–40.PubMedCrossRefGoogle Scholar
  228. 228.
    Woolley CS, Gould E, McEwen BS. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 1990;531(1–2):225–31.PubMedCrossRefGoogle Scholar
  229. 229.
    Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 1992;588(2):341–5.PubMedCrossRefGoogle Scholar
  230. 230.
    Cook SC, Wellman CL. Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J Neurobiol. 2004;60(2):236–48.PubMedCrossRefGoogle Scholar
  231. 231.
    Radley JJ, Sisti HM, Hao J, Rocher AB, McCall T, Hof PR, et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience. 2004;125(1):1–6.PubMedCrossRefGoogle Scholar
  232. 232.
    Wellman CL. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J Neurobiol. 2001;49(3):245–53.PubMedCrossRefGoogle Scholar
  233. 233.
    Goldwater DS, Pavlides C, Hunter RG, Bloss EB, Hof PR, McEwen BS, et al. Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery. Neuroscience. 2009;164(2):798–808.PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18(9):1413–7.PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry. 2009;14(8):764–73.PubMedCrossRefGoogle Scholar
  236. 236.
    Cavalleri L, Merlo Pich E, Millan MJ, Chiamulera C, Kunath T, Spano PF, et al. Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling. Mol Psychiatry. 2017.  https://doi.org/10.1038/mp.2017.241. (epub ahead of print).
  237. 237.
    Vaidya VA, Siuciak JA, Du F, Duman RS. Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. Neuroscience. 1999;89(1):157–66.PubMedCrossRefGoogle Scholar
  238. 238.
    Acosta-Pena E, Camacho-Abrego I, Melgarejo-Gutierrez M, Flores G, Drucker-Colin R, Garcia-Garcia F. Sleep deprivation induces differential morphological changes in the hippocampus and prefrontal cortex in young and old rats. Synapse. 2015;69(1):15–25.PubMedCrossRefGoogle Scholar
  239. 239.
    Opal MD, Klenotich SC, Morais M, Bessa J, Winkle J, Doukas D, et al. Serotonin 2C receptor antagonists induce fast-onset antidepressant effects. Mol Psychiatry. 2014;19(10):1106–14.PubMedCrossRefGoogle Scholar
  240. 240.
    Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338(6103):68–72.PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Derkach VA, Oh MC, Guire ES, Soderling TR. Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat Rev Neurosci. 2007;8(2):101–13.PubMedCrossRefGoogle Scholar
  242. 242.
    Henley JM, Wilkinson KA. Synaptic AMPA receptor composition in development, plasticity and disease. Nat Rev Neurosci. 2016;17(6):337–50.PubMedCrossRefGoogle Scholar
  243. 243.
    Shepherd JD, Huganir RL. The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol. 2007;23:613–43.PubMedCrossRefGoogle Scholar
  244. 244.
    Koike H, Chaki S. Requirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats. Behav Brain Res. 2014;1(271):111–5.CrossRefGoogle Scholar
  245. 245.
    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.PubMedCrossRefGoogle Scholar
  246. 246.
    Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B, et al. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology. 2013;38(9):1609–16.PubMedPubMedCentralCrossRefGoogle Scholar
  247. 247.
    Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ. Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry. 2014;29(7):419–23.PubMedCrossRefGoogle Scholar
  248. 248.
    Martin AE, Schober DA, Nikolayev A, Tolstikov VV, Anderson WH, Higgs RE, et al. Further evaluation of mechanisms associated with the antidepressant-like signature of scopolamine in mice. CNS Neurol Disord Drug Targets. 2017;16(4):492–500.PubMedCrossRefGoogle Scholar
  249. 249.
    Karasawa J, Shimazaki T, Kawashima N, Chaki S. AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist. Brain Res. 2005;1042(1):92–8.PubMedCrossRefGoogle Scholar
  250. 250.
    Wolak M, Siwek A, Szewczyk B, Poleszak E, Pilc A, Popik P, et al. Involvement of NMDA and AMPA receptors in the antidepressant-like activity of antidepressant drugs in the forced swim test. Pharmacol Rep. 2013;65(4):991–7.PubMedCrossRefGoogle Scholar
  251. 251.
    Whittington MA, Traub RD, Kopell N, Ermentrout B, Buhl EH. Inhibition-based rhythms: experimental and mathematical observations on network dynamics. Int J Psychophysiol. 2000;38(3):315–36.PubMedCrossRefGoogle Scholar
  252. 252.
    Cunningham MO, Davies CH, Buhl EH, Kopell N, Whittington MA. Gamma oscillations induced by kainate receptor activation in the entorhinal cortex in vitro. J Neurosci. 2003;23(30):9761–9.PubMedGoogle Scholar
  253. 253.
    Muthukumaraswamy SD, Shaw AD, Jackson LE, Hall J, Moran R, Saxena N. Evidence that subanesthetic doses of ketamine cause sustained disruptions of NMDA and AMPA-mediated frontoparietal connectivity in humans. J Neurosci. 2015;35(33):11694–706.PubMedPubMedCentralCrossRefGoogle Scholar
  254. 254.
    Lazarewicz MT, Ehrlichman RS, Maxwell CR, Gandal MJ, Finkel LH, Siegel SJ. Ketamine modulates theta and gamma oscillations. J Cogn Neurosci. 2010;22(7):1452–64.PubMedCrossRefGoogle Scholar
  255. 255.
    Ahnaou A, Ver Donck L, Drinkenburg WHIM. Blockade of the metabotropic glutamate (mGluR2) modulates arousal through vigilance states transitions: evidence from sleep–wake EEG in rodents. Behav Brain Res. 2014;270:56–67.PubMedCrossRefGoogle Scholar
  256. 256.
    Buzsáki G, Wang X-J. Mechanisms of gamma oscillations. Annu Rev Neurosci. 2012;35:203–25.PubMedPubMedCentralCrossRefGoogle Scholar
  257. 257.
    Kumar S, Black SJ, Hultman R, Szabo ST, DeMaio KD, Du J, et al. Cortical control of affective networks. J Neurosci. 2013;33(3):1116–29.PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Fuchikami M, Thomas A, Liu R, Wohleb ES, Land BB, DiLeone RJ, et al. Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions. Proc Nat Acad Sci. 2015;112(26):8106–11.PubMedPubMedCentralCrossRefGoogle Scholar
  259. 259.
    Nosyreva E, Szabla K, Autry AE, Ryazanov AG, Monteggia LM, Kavalali ET. Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J Neurosci. 2013;33(16):6990–7002.PubMedPubMedCentralCrossRefGoogle Scholar
  260. 260.
    Bjorkholm C, Jardemark K, Schilstrom B, Svensson TH. Ketamine-like effects of a combination of olanzapine and fluoxetine on AMPA and NMDA receptor-mediated transmission in the medial prefrontal cortex of the rat. Eur Neuropsychopharmacol. 2015;25(10):1842–7.PubMedCrossRefGoogle Scholar
  261. 261.
    El Iskandrani KS, Oosterhof CA, El Mansari M, Blier P. Impact of subanesthetic doses of ketamine on AMPA-mediated responses in rats: an in vivo electrophysiological study on monoaminergic and glutamatergic neurons. J Psychopharmacol. 2015;29(7):792–801.PubMedPubMedCentralCrossRefGoogle Scholar
  262. 262.
    Xie M, Li C, He C, Yang L, Tan G, Yan J, et al. Short-term sleep deprivation disrupts the molecular composition of ionotropic glutamate receptors in entorhinal cortex and impairs the rat spatial reference memory. Behav Brain Res. 2016;300:70–6.PubMedCrossRefGoogle Scholar
  263. 263.
    Xie M, Yan J, He C, Yang L, Tan G, Li C, et al. Short-term sleep deprivation impairs spatial working memory and modulates expression levels of ionotropic glutamate receptor subunits in hippocampus. Behav Brain Res. 2015;286:64–70.PubMedCrossRefGoogle Scholar
  264. 264.
    Zhang K, Xu T, Yuan Z, Wei Z, Yamaki VN, Huang M, et al. Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine. Sci Signal. 2016;9(458):ra123.PubMedPubMedCentralCrossRefGoogle Scholar
  265. 265.
    Lindholm JS, 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.PubMedCrossRefGoogle Scholar
  266. 266.
    Schechter LE, Ring RH, Beyer CE, Hughes ZA, Khawaja X, Malberg JE, et al. Innovative approaches for the development of antidepressant drugs: current and future strategies. NeuroRx. 2005;2(4):590–611.PubMedPubMedCentralCrossRefGoogle Scholar
  267. 267.
    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.PubMedCrossRefGoogle Scholar
  268. 268.
    Akinfiresoye L, Tizabi Y. Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR. Psychopharmacology (Berl). 2013;230(2):291–8.PubMedCrossRefGoogle Scholar
  269. 269.
    Katz LC, Shatz CJ. Synaptic activity and the construction of cortical circuits. Science. 1996;274(5290):1133–8.PubMedCrossRefGoogle Scholar
  270. 270.
    Mamounas LA, Altar CA, Blue ME, Kaplan DR, Tessarollo L, Lyons WE. BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J Neurosci. 2000;20(2):771–82.PubMedCrossRefGoogle Scholar
  271. 271.
    Poo MM. Neurotrophins as synaptic modulators. Nat Rev Neurosci. 2001;2(1):24–32.PubMedCrossRefGoogle Scholar
  272. 272.
    Pattwell SS, Bath KG, Perez-Castro R, Lee FS, Chao MV, Ninan I. The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex. J Neurosci. 2012;32(7):2410–21.PubMedPubMedCentralCrossRefGoogle Scholar
  273. 273.
    Bocchio-Chiavetto L, Bagnardi V, Zanardini R, Molteni R, Nielsen MG, Placentino A, et al. Serum and plasma BDNF levels in major depression: a replication study and meta-analyses. World J Biol Psychiatry. 2010;11(6):763–73.PubMedCrossRefGoogle Scholar
  274. 274.
    Molendijk ML, Bus BA, Spinhoven P, Penninx BW, Kenis G, Prickaerts J, et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry. 2011;16(11):1088–95.PubMedCrossRefGoogle Scholar
  275. 275.
    Karlovic D, Serretti A, Jevtovic S, Vrkic N, Seric V, Peles AM. Diagnostic accuracy of serum brain derived neurotrophic factor concentration in antidepressant naive patients with first major depression episode. J Psychiatr Res. 2013;47(2):162–7.PubMedCrossRefGoogle Scholar
  276. 276.
    Yoshida T, Ishikawa M, Niitsu T, Nakazato M, Watanabe H, Shiraishi T, et al. Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder. PLoS One. 2012;7(8):e42676.PubMedPubMedCentralCrossRefGoogle Scholar
  277. 277.
    Castren E, Antila H. Neuronal plasticity and neurotrophic factors in drug responses. Mol Psychiatry. 2017;22(8):1085–95.PubMedPubMedCentralCrossRefGoogle Scholar
  278. 278.
    Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry. 1997;54(7):597–606.PubMedCrossRefGoogle Scholar
  279. 279.
    Manji HK, Moore GJ, Rajkowska G, Chen G. Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry. 2000;5(6):578–93.PubMedCrossRefGoogle Scholar
  280. 280.
    Castren E, Voikar V, Rantamaki T. Role of neurotrophic factors in depression. Curr Opin Pharmacol. 2007;7(1):18–21.PubMedCrossRefGoogle Scholar
  281. 281.
    Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci. 1995;15(11):7539–47.PubMedCrossRefGoogle Scholar
  282. 282.
    Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003;54(1):70–5.PubMedCrossRefGoogle Scholar
  283. 283.
    Bocchio-Chiavetto L, Zanardini R, Bortolomasi M, Abate M, Segala M, Giacopuzzi M, et al. Electroconvulsive therapy (ECT) increases serum brain derived neurotrophic factor (BDNF) in drug resistant depressed patients. Eur Neuropsychopharmacol. 2006;16(8):620–4.PubMedCrossRefGoogle Scholar
  284. 284.
    Adachi M, Barrot M, Autry AE, Theobald D, Monteggia LM. Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy. Biol Psychiatry. 2008;63(7):642–9.PubMedCrossRefGoogle Scholar
  285. 285.
    Monteggia LM, Luikart B, Barrot M, Theobold D, Malkovska I, Nef S, et al. Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol Psychiatry. 2007;61(2):187–97.PubMedCrossRefGoogle Scholar
  286. 286.
    Koponen E, Rantamaki T, Voikar V, Saarelainen T, MacDonald E, Castren E. Enhanced BDNF signaling is associated with an antidepressant-like behavioral response and changes in brain monoamines. Cell Mol Neurobiol. 2005;25(6):973–80.PubMedCrossRefGoogle Scholar
  287. 287.
    Hoshaw BA, Malberg JE, Lucki I. Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Res. 2005;1037(1–2):204–8.PubMedCrossRefGoogle Scholar
  288. 288.
    Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci. 2002;22(8):3251–61.PubMedCrossRefGoogle Scholar
  289. 289.
    Schmidt HD, Duman RS. Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology. 2010;35(12):2378–91.PubMedPubMedCentralCrossRefGoogle Scholar
  290. 290.
    Taliaz D, Loya A, Gersner R, Haramati S, Chen A, Zangen A. Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. J Neurosci. 2011;31(12):4475–83.PubMedCrossRefGoogle Scholar
  291. 291.
    Rantamaki T, Hendolin P, Kankaanpaa A, Mijatovic J, Piepponen P, Domenici E, et al. Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain. Neuropsychopharmacology. 2007;32(10):2152–62.PubMedCrossRefGoogle Scholar
  292. 292.
    Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci. 2003;23(1):349–57.PubMedGoogle Scholar
  293. 293.
    Groves JO. Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry. 2007;12(12):1079–88.PubMedCrossRefGoogle Scholar
  294. 294.
    Wook Koo J, Labonte B, Engmann O, Calipari ES, Juarez B, Lorsch Z, et al. Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress-induced depressive behaviors. Biol Psychiatry. 2016;80(6):469–78.PubMedCrossRefGoogle Scholar
  295. 295.
    Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS. BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol. 2014;18(1).  https://doi.org/10.1093/ijnp/pyu033.
  296. 296.
    Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314(5796):140–3.PubMedPubMedCentralCrossRefGoogle Scholar
  297. 297.
    Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry. 2012;71(11):996–1005.PubMedCrossRefGoogle Scholar
  298. 298.
    Ghosal S, Bang E, Yue W, Hare BD, Lepack AE, Girgenti MJ, et al. Activity-dependent BDNF release is required for the rapid antidepressant actions of scopolamine. Biol Psychiatry. 2018;83(1):29–37.PubMedCrossRefGoogle Scholar
  299. 299.
    Kato T, Fogaca MV, Deyama S, Li X-Y, Fukumoto K, Duman RS. BDNF release and signaling are required for the antidepressant actions of GLYX-13. Mol Psychiatry. 2017.  https://doi.org/10.1038/mp.2017.220. (epub ahead of print).
  300. 300.
    Laje G, Lally N, Mathews D, Brutsche N, Chemerinski A, Akula N, et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol Psychiatry. 2012;72(11):e27–8.PubMedPubMedCentralCrossRefGoogle Scholar
  301. 301.
    Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM, Andreazza AC, et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(1):140–4.PubMedCrossRefGoogle Scholar
  302. 302.
    Newton SS, Collier EF, Hunsberger J, Adams D, Terwilliger R, Selvanayagam E, et al. Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J Neurosci. 2003;23(34):10841–51.PubMedGoogle Scholar
  303. 303.
    Conti B, Maier R, Barr AM, Morale MC, Lu X, Sanna PP, et al. Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine. Mol Psychiatry. 2007;12(2):167–89.PubMedCrossRefGoogle Scholar
  304. 304.
    Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM. Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry. 2003;54(7):703–9.PubMedCrossRefGoogle Scholar
  305. 305.
    Sartorius A, Hellweg R, Litzke J, Vogt M, Dormann C, Vollmayr B, et al. Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats. Pharmacopsychiatry. 2009;42(6):270–6.PubMedCrossRefGoogle Scholar
  306. 306.
    Balu DT, Hoshaw BA, Malberg JE, Rosenzweig-Lipson S, Schechter LE, Lucki I. Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res. 2008;23(1211):37–43.CrossRefGoogle Scholar
  307. 307.
    Li B, Suemaru K, Cui R, Araki H. Repeated electroconvulsive stimuli have long-lasting effects on hippocampal BDNF and decrease immobility time in the rat forced swim test. Life Sci. 2007;80(16):1539–43.PubMedCrossRefGoogle Scholar
  308. 308.
    Angelucci F, Aloe L, Jimenez-Vasquez P, Mathe AA. Electroconvulsive stimuli alter the regional concentrations of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor in adult rat brain. J ECT. 2002;18(3):138–43.PubMedCrossRefGoogle Scholar
  309. 309.
    Chen AC, Shin KH, Duman RS, Sanacora G. ECS-Induced mossy fiber sprouting and BDNF expression are attenuated by ketamine pretreatment. J ECT. 2001;17(1):27–32.PubMedCrossRefGoogle Scholar
  310. 310.
    Luo J, Min S, Wei K, Cao J, Wang B, Li P, et al. Behavioral and molecular responses to electroconvulsive shock differ between genetic and environmental rat models of depression. Psychiatry Res. 2015;226(2–3):451–60.PubMedCrossRefGoogle Scholar
  311. 311.
    Gersner R, Toth E, Isserles M, Zangen A. Site-specific antidepressant effects of repeated subconvulsive electrical stimulation: potential role of brain-derived neurotrophic factor. Biol Psychiatry. 2010;67(2):125–32.PubMedCrossRefGoogle Scholar
  312. 312.
    Vollmayr B, Faust H, Lewicka S, Henn FA. Brain-derived-neurotrophic-factor (BDNF) stress response in rats bred for learned helplessness. Mol Psychiatry. 2001;6(4):471–4.PubMedCrossRefGoogle Scholar
  313. 313.
    Fujihara H, Sei H, Morita Y, Ueta Y, Morita K. Short-term sleep disturbance enhances brain-derived neurotrophic factor gene expression in rat hippocampus by acting as internal stressor. J Mol Neurosci. 2003;21(3):223–32.PubMedCrossRefGoogle Scholar
  314. 314.
    Guo L, Guo Z, Luo X, Liang R, Yang S, Ren H, et al. Phosphodiesterase 10A inhibition attenuates sleep deprivation-induced deficits in long-term fear memory. Neurosci Lett. 2016;635:44–50.PubMedCrossRefGoogle Scholar
  315. 315.
    Guzman-Marin R, Ying Z, Suntsova N, Methippara M, Bashir T, Szymusiak R, et al. Suppression of hippocampal plasticity-related gene expression by sleep deprivation in rats. J Physiol. 2006;575(Pt 3):807–19.PubMedPubMedCentralCrossRefGoogle Scholar
  316. 316.
    Jiang Y, Zhu J. Effects of sleep deprivation on behaviors and abnormal hippocampal BDNF/miR-10B expression in rats with chronic stress depression. Int J Clin Exp Pathol. 2015;8(1):586–93.PubMedPubMedCentralGoogle Scholar
  317. 317.
    Konar A, Shah N, Singh R, Saxena N, Kaul SC, Wadhwa R, et al. Protective role of Ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain-derived cells. PLoS One. 2011;6(11):e27265.PubMedPubMedCentralCrossRefGoogle Scholar
  318. 318.
    Lee B, Sur B, Shim J, Hahm DH, Lee H. Acupuncture stimulation improves scopolamine-induced cognitive impairment via activation of cholinergic system and regulation of BDNF and CREB expressions in rats. BMC Complement Altern Med. 2014;17(14):338.CrossRefGoogle Scholar
  319. 319.
    Chen W, Cheng X, Chen J, Yi X, Nie D, Sun X, et al. Lycium barbarum polysaccharides prevent memory and neurogenesis impairments in scopolamine-treated rats. PLoS One. 2014;9(2):e88076.PubMedPubMedCentralCrossRefGoogle Scholar
  320. 320.
    Kotani S, Yamauchi T, Teramoto T, Ogura H. Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis. Chem Biol Interact. 2008;175(1–3):227–30.PubMedCrossRefGoogle Scholar
  321. 321.
    Shi Z, Chen L, Li S, Chen S, Sun X, Sun L, et al. Chronic scopolamine-injection-induced cognitive deficit on reward-directed instrumental learning in rat is associated with CREB signaling activity in the cerebral cortex and dorsal hippocampus. Psychopharmacology (Berl). 2013;230(2):245–60.PubMedCrossRefGoogle Scholar
  322. 322.
    Heo YM, Shin MS, Kim SH, Kim TW, Baek SB, Baek SS. Treadmill exercise ameliorates disturbance of spatial learning ability in scopolamine-induced amnesia rats. J Exerc Rehabil. 2014;10(3):155–61.PubMedPubMedCentralCrossRefGoogle Scholar
  323. 323.
    Weeks HR 3rd, Tadler SC, Smith KW, Iacob E, Saccoman M, White AT, et al. Antidepressant and neurocognitive effects of isoflurane anesthesia versus electroconvulsive therapy in refractory depression. PLoS One. 2013;8(7):e69809.PubMedPubMedCentralCrossRefGoogle Scholar
  324. 324.
    Langer G, Neumark J, Koinig G, Graf M, Schonbeck G. Rapid psychotherapeutic effects of anesthesia with isoflurane (ES narcotherapy) in treatment-refractory depressed patients. Neuropsychobiology. 1985;14(3):118–20.PubMedCrossRefGoogle Scholar
  325. 325.
    Langer G, Karazman R, Neumark J, Saletu B, Schonbeck G, Grunberger J, et al. Isoflurane narcotherapy in depressive patients refractory to conventional antidepressant drug treatment. A double-blind comparison with electroconvulsive treatment. Neuropsychobiology. 1995;31(4):182–94.PubMedCrossRefGoogle Scholar
  326. 326.
    Antila H, Ryazantseva M, Popova D, Sipila P, Guirado R, Kohtala S, et al. Isoflurane produces antidepressant effects and induces TrkB signaling in rodents. Sci Rep. 2017;7(1):7811.PubMedPubMedCentralCrossRefGoogle Scholar
  327. 327.
    Taha E, Gildish I, Gal-Ben-Ari S, Rosenblum K. The role of eEF2 pathway in learning and synaptic plasticity. Neurobiol Learn Mem. 2013;105:100–6.PubMedCrossRefGoogle Scholar
  328. 328.
    Chotiner JK, Khorasani H, Nairn AC, O’Dell TJ, Watson JB. Adenylyl cyclase-dependent form of chemical long-term potentiation triggers translational regulation at the elongation step. Neuroscience. 2003;116(3):743–52.PubMedCrossRefGoogle Scholar
  329. 329.
    Park S, Park JM, Kim S, Kim JA, Shepherd JD, Smith-Hicks CL, et al. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron. 2008;59(1):70–83.PubMedPubMedCentralCrossRefGoogle Scholar
  330. 330.
    Lu Y, Wang C, Xue Z, Li C, Zhang J, Zhao X, et al. PI3K/AKT/mTOR signaling-mediated neuropeptide VGF in the hippocampus of mice is involved in the rapid onset antidepressant-like effects of GLYX-13. Int J Neuropsychopharmacol. 2014;18(5).  https://doi.org/10.1093/ijnp/pyu110.
  331. 331.
    Hizli AA, Chi Y, Swanger J, Carter JH, Liao Y, Welcker M, et al. Phosphorylation of eukaryotic elongation factor 2 (eEF2) by cyclin A-cyclin-dependent kinase 2 regulates its inhibition by eEF2 kinase. Mol Cell Biol. 2013;33(3):596–604.PubMedPubMedCentralCrossRefGoogle Scholar
  332. 332.
    Knebel A, Morrice N, Cohen P. A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. EMBO J. 2001;20(16):4360–9.PubMedPubMedCentralCrossRefGoogle Scholar
  333. 333.
    Redpath NT, Foulstone EJ, Proud CG. Regulation of translation elongation factor-2 by insulin via a rapamycin-sensitive signalling pathway. EMBO J. 1996;15(9):2291–7.PubMedPubMedCentralGoogle Scholar
  334. 334.
    Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J. 2001;20(16):4370–9.PubMedPubMedCentralCrossRefGoogle Scholar
  335. 335.
    Grønli J, Dagestad G, Milde AM, Murison R, Bramham CR. Post-transcriptional effects and interactions between chronic mild stress and acute sleep deprivation: regulation of translation factor and cytoplasmic polyadenylation element-binding protein phosphorylation. Behav Brain Res. 2012;235(2):251–62.PubMedCrossRefGoogle Scholar
  336. 336.
    Reichardt LF. Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci. 2006;361(1473):1545–64.PubMedPubMedCentralCrossRefGoogle Scholar
  337. 337.
    Yoshii A, Constantine-Paton M. Post-synaptic BDNF-TrkB signaling in synapse maturation, plasticity and disease. Dev Neurobiol. 2010;70(5):304–22.PubMedPubMedCentralGoogle Scholar
  338. 338.
    Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology. 2012;62(1):35–41.PubMedCrossRefGoogle Scholar
  339. 339.
    Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926–45.PubMedCrossRefGoogle Scholar
  340. 340.
    Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 2010;33(2):67–75.PubMedCrossRefGoogle Scholar
  341. 341.
    Paul RK, Singh NS, Khadeer M, Moaddel R, Sanghvi M, Green CE, et al. (R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin (mTOR) function. Anesthesiology. 2014;121(1):149–59.PubMedPubMedCentralCrossRefGoogle Scholar
  342. 342.
    Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y, Delpire E, et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. Elife. 2014;23(3):e03581.Google Scholar
  343. 343.
    Yang C, Hu YM, Zhou ZQ, Zhang GF, Yang JJ. Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test. Ups J Med Sci. 2013;118(1):3–8.PubMedPubMedCentralCrossRefGoogle Scholar
  344. 344.
    Zhang K, Yamaki VN, Wei Z, Zheng Y, Cai X. Differential regulation of GluA1 expression by ketamine and memantine. Behav Brain Res. 2017;1(316):152–9.CrossRefGoogle Scholar
  345. 345.
    Holubova K, Kleteckova L, Skurlova M, Ricny J, Stuchlik A, Vales K. Rapamycin blocks the antidepressant effect of ketamine in task-dependent manner. Psychopharmacology (Berl). 2016;233(11):2077–97.PubMedCrossRefGoogle Scholar
  346. 346.
    Beurel E, Grieco SF, Jope RS. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther. 2015;148:114–31.PubMedCrossRefGoogle Scholar
  347. 347.
    Can A, Schulze TG, Gould TD. Molecular actions and clinical pharmacogenetics of lithium therapy. Pharmacol Biochem Behav. 2014;123:3–16.PubMedPubMedCentralCrossRefGoogle Scholar
  348. 348.
    Zhou W, Dong L, Wang N, Shi JY, Yang JJ, Zuo ZY, et al. Akt mediates GSK-3beta phosphorylation in the rat prefrontal cortex during the process of ketamine exerting rapid antidepressant actions. Neuroimmunomodulation. 2014;21(4):183–8.PubMedCrossRefGoogle Scholar
  349. 349.
    Beurel E, Grieco SF, Amadei C, Downey K, Jope RS. Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling. Bipolar Disord. 2016;18(6):473–80.PubMedPubMedCentralCrossRefGoogle Scholar
  350. 350.
    Basar K, Eren-Kocak E, Ozdemir H, Ertugrul A. Effects of acute and chronic electroconvulsive shocks on glycogen synthase kinase 3β level and phosphorylation in mice. J ECT. 2013;29(4):265–70.PubMedCrossRefGoogle Scholar
  351. 351.
    Roh MS, Kang UG, Shin SY, Lee YH, Jung HY, Juhnn YS, et al. Biphasic changes in the Ser-9 phosphorylation of glycogen synthase kinase-3beta after electroconvulsive shock in the rat brain. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(1):1–5.PubMedCrossRefGoogle Scholar
  352. 352.
    Kang UG, Roh MS, Jung JR, Shin SY, Lee YH, Park JB, et al. Activation of protein kinase B (Akt) signaling after electroconvulsive shock in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(1):41–4.PubMedCrossRefGoogle Scholar
  353. 353.
    Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry. 2018; 75(2):139–48PubMedCrossRefGoogle Scholar
  354. 354.
    Zanos P, Moaddel R, Morris PJ, Wainer IW, Albuquerque EX, Thompson SM, et al. Reply to: Antidepressant actions of ketamine versus hydroxynorketamine. Biol Psychiatry. 2017;81(8):e69–71.PubMedCrossRefGoogle Scholar
  355. 355.
    Hare BD, Ghosal S, Duman RS. Rapid acting antidepressants in chronic stress models: molecular and cellular mechanisms. Chron Stress (Thousand Oaks). 2017;1.  https://doi.org/10.1177/2470547017697317. (epub 2017 Apr 10).
  356. 356.
    Wohleb ES, Gerhard D, Thomas A, Duman RS. Molecular and cellular mechanisms of rapid-acting antidepressants ketamine and scopolamine. Curr Neuropharmacol. 2017;15(1):11–20.PubMedPubMedCentralCrossRefGoogle Scholar
  357. 357.
    Wilkinson ST, Toprak M, Turner MS, Levine SP, Katz RB, Sanacora G. A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders. Am J Psychiatry. 2017;174(7):695–6.PubMedPubMedCentralCrossRefGoogle Scholar
  358. 358.
    Sos P, Klirova M, Novak T, Kohutova B, Horacek J, Palenicek T. Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol Lett. 2013;34(4):287–93.PubMedGoogle Scholar
  359. 359.
    Hu YD, Xiang YT, Fang JX, Zu S, Sha S, Shi H, et al. Single i.v. ketamine augmentation of newly initiated escitalopram for major depression: results from a randomized, placebo-controlled 4-week study. Psychol Med. 2016;46(3):623–35.PubMedCrossRefGoogle Scholar
  360. 360.
    Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016;173(8):816–26.PubMedCrossRefGoogle Scholar
  361. 361.
    Lieberman JA, Papadakis K, Csernansky J, Litman R, Volavka J, Jia XD, et al. A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacology. 2009;34(5):1322–9.PubMedCrossRefGoogle Scholar
  362. 362.
    Smith EG, Deligiannidis KM, Ulbricht CM, Landolin CS, Patel JK, Rothschild AJ. Antidepressant augmentation using the NMDA-antagonist memantine: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2013;74(10):966–73.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PsychiatryUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Department of PsychiatryUniversity of Maryland School of MedicineBaltimoreUSA
  3. 3.Department of PharmacologyUniversity of Maryland School of MedicineBaltimoreUSA
  4. 4.Department of Anatomy and NeurobiologyUniversity of Maryland School of MedicineBaltimoreUSA
  5. 5.Department of PsychiatryYale University School of MedicineNew HavenUSA
  6. 6.Department of NeurobiologyYale University School of MedicineNew HavenUSA
  7. 7.Experimental Therapeutics and Pathophysiology Branch, Intramural Research ProgramNational Institute of Mental Health, National Institutes of HealthBethesdaUSA
  8. 8.Department of PhysiologyUniversity of Maryland School of MedicineBaltimoreUSA
  9. 9.Department of PsychiatryUniversity of Maryland School of MedicineBaltimoreUSA

Personalised recommendations