Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter April 20, 2016

The dose makes the poison: from glutamate-mediated neurogenesis to neuronal atrophy and depression

  • Alberto Rubio-Casillas ORCID logo EMAIL logo and Alonso Fernández-Guasti


Experimental evidence has demonstrated that glutamate is an essential factor for neurogenesis, whereas another line of research postulates that excessive glutamatergic neurotransmission is associated with the pathogenesis of depression. The present review shows that such paradox can be explained within the framework of hormesis, defined as biphasic dose responses. Low glutamate levels activate adaptive stress responses that include proteins that protect neurons against more severe stress. Conversely, abnormally high levels of glutamate, resulting from increased release and/or decreased removal, cause neuronal atrophy and depression. The dysregulation of the glutamatergic transmission in depression could be underlined by several factors including a decreased inhibition (γ-aminobutyric acid or serotonin) or an increased excitation (primarily within the glutamatergic system). Experimental evidence shows that the activation of N-methyl-D-aspartate receptor (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) can exert two opposite effects on neurogenesis and neuron survival depending on the synaptic or extrasynaptic concentration. Chronic stress, which usually underlies experimental and clinical depression, enhances glutamate release. This overactivates NMDA receptors (NMDAR) and consequently impairs AMPAR activity. Various studies show that treatment with antidepressants decreases plasma glutamate levels in depressed individuals and regulates glutamate receptors by reducing NMDAR function by decreasing the expression of its subunits and by potentiating AMPAR-mediated transmission. Additionally, it has been shown that chronic treatment with antidepressants having divergent mechanisms of action (including tricyclics, selective serotonin reuptake inhibitors, and ketamine) markedly reduced depolarization-evoked glutamate release in the hippocampus. These data, taken together, suggest that the glutamatergic system could be a final common pathway for antidepressant treatments.


The authors are grateful to Dr. Erika Estrada-Camarena for her insightful comments and Dr. Bryan Phillips-Farfán for language checking.


Adesnik, H., Li, G., During, M.J., Pleasure, S.J., and Nicoll, R.A. (2008). NMDA receptors inhibit synapse unsilencing during brain development. Proc. Natl. Acad. Sci. USA 105, 5597–5602.10.1073/pnas.0800946105Search in Google Scholar

Ahmed, T., Frey, J.U., and Korz, V. (2006). Long-term effects of brief acute stress on cellular signaling and hippocampal LTP. J. Neurosci. 26, 3951–3958.10.1523/JNEUROSCI.4901-05.2006Search in Google Scholar

Akirav, I. and Richter-Levin, G. (1999). Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat. J. Neurosci. 19, 10530–10535.10.1523/JNEUROSCI.19-23-10530.1999Search in Google Scholar

Allan, S.M. and Rothwell, N.J. (2003). Inflammation in the central nervous system. Philos. Trans. R. Soc. Lond. B Biol. Sci. 358, 1669–1677.10.1098/rstb.2003.1358Search in Google Scholar

Alt, A., Nisenbaum, E.S., Bleakman, D., and Witkin, J.M. (2006). A role for AMPA receptors in mood disorders. Biochem. Pharmacol. 71, 1273–1288.10.1016/j.bcp.2005.12.022Search in Google Scholar

Altamura, C.A., Mauri, M.C., Ferrara, A., Moro, A.R., D’Andrea, G., and Zamberlan, F. (1993). Plasma and platelet excitatory amino acids in psychiatric disorders. Am. J. Psychiatry 150, 1731–1733.10.1176/ajp.150.11.1731Search in Google Scholar

Altamura, C., Maes, M., Dai, J., and Meltzer, H.Y. (1995). Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression. Eur. Neuropsychopharmacol. 5, 71–75.10.1016/0924-977X(95)00033-LSearch in Google Scholar

Anacker, C., Zunszain, P.A., Carvalho, L.A., and Pariante, C.M. (2011). The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 36, 415–425.10.1016/j.psyneuen.2010.03.007Search in Google Scholar

Autry, A.E., Adachi, M., Nosyreva, E., Na, E.S., Los, M.F., Cheng, P.F., Kavalali, E.T., and Monteggia, L.M. (2011). NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95.10.1038/nature10130Search in Google Scholar

Bai, F., Li, X., Clay, M., Lindstrom, T., and Skolnick, P. (2001). Intra- and interstrain differences in models of “behavioral despair”. Pharmacol. Biochem. Behav. 70, 187–192.10.1016/S0091-3057(01)00599-8Search in Google Scholar

Bai, F., Bergeron, M., and Nelson, D.L. (2003). Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus. Neuropharmacology 44, 1013–1021.10.1016/S0028-3908(03)00104-7Search in Google Scholar

Baker, D.A., Xi, Z.X., Shen, H., Swanson, C.J., and Kalivas, P.W. (2002). The origin and neuronal function of in vivo nonsynaptic glutamate. J. Neurosci. 22, 9134–9141.10.1523/JNEUROSCI.22-20-09134.2002Search in Google Scholar

Bambrick, L.L., Yarowsky, P.J., and Krueger, B.K. (1995). Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse. Proc. Natl. Acad. Sci. USA 92, 9692–9696.10.1073/pnas.92.21.9692Search in Google Scholar

Banasr, M., Dwyer, J.M., and Duman, R.S. (2011). Cell atrophy and loss in depression: reversal by antidepressant treatment. Curr. Opin. Cell. Biol. 23, 730–737.10.1016/ in Google Scholar

Banaudha, K. and Marini, A.M. (2000). AMPA prevents glutamate-induced neurotoxicity and apoptosis in cultured cerebellar granule cell neurons. Neurotoxicol. Res. 2, 51–61.10.1007/BF03033327Search in Google Scholar

Bano, S., Gitay, M., Ara, I., and Badawy, A. (2010). Acute effects of serotonergic antidepressants on tryptophan metabolism and corticosterone levels in rats. Pak. J. Pharm. Sci. 23, 266–272.Search in Google Scholar

Barbon, A., Popoli, M., La Via, L., Moraschi, S., Vallini, I., Tardito, D., Tiraboschi, E., Musazzi, L., Giambelli, R., Gennarelli, M., et al. (2006). Regulation of editing and expression of glutamate α-amino-propionic-acid (AMPA)/kainate receptors by antidepressant drugs. Biol. Psychiatry 59, 713–720.10.1016/j.biopsych.2005.10.018Search in Google Scholar

Barbon, A., Caracciolo, L., Orlandi, C., Musazzi, L., Mallei, A., La Via, L., Bonini, D., Mora, C., Tardito, D., Gennarelli, M., et al. (2011). Chronic antidepressant treatments induce a time-dependent up-regulation of AMPA receptor subunit protein levels. Neurochem. Int. 59, 896–905.10.1016/j.neuint.2011.07.013Search in Google Scholar

Barger, S.W., Goodwin, M.E., Porter, M.M., and Beggs, M.L. (2007). Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation. J. Neurochem. 101, 1205–1213.10.1111/j.1471-4159.2007.04487.xSearch in Google Scholar

Barry, M.F. and Ziff, E.B. (2002). Receptor trafficking and the plasticity of excitatory synapses. Curr. Opin. Neurobiol. 12, 279–286.10.1016/S0959-4388(02)00329-XSearch in Google Scholar

Baskys, A., Bayazitov, I., Fang, L., Blaabjerg, M., Poulsen, F.R., and Zimmer, J. (2005). Group I metabotropic glutamate receptors reduce excitotoxic injury and may facilitate neurogenesis. Neuropharmacology 49, 146–156.10.1016/j.neuropharm.2005.04.029Search in Google Scholar PubMed

Battaglia, G., Monn, J.A., and Schoepp, D.D. (1997). In vivo inhibition of veratridine-evoked release of striatal excitatory amino acids by the group II metabotropic glutamate receptor agonist LY354740 in rats. Neurosci. Lett. 229, 161–164.10.1016/S0304-3940(97)00442-4Search in Google Scholar

Bay-Richter, C., Linderholm, K.R., Lim, C.K., Samuelsson, M., Träskman-Bendz, L., Guillemin, G.J., Erhardt, S., and Brundin, L. (2015). A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. Brain Behav. Immun. 43, 110–117.10.1016/j.bbi.2014.07.012Search in Google Scholar

Bechtholt-Gompf, A.J., Walther, H.V., Adams, M.A., Carlezon, W.A. Jr., Ongur, D., and Cohen, B.M. (2010). Blockade of astrocytic glutamate uptake in rats induces signs of anhedonia and impaired spatial memory. Neuropsychopharmacology 35, 2049–2059.10.1038/npp.2010.74Search in Google Scholar

Behl, C., Widmann, M., Trapp, T., and Holsboer, F. (1995). 17β-Estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem. Biophys. Res. Commun. 216, 473–482.10.1006/bbrc.1995.2647Search in Google Scholar

Behl, C., Lezoualc’h, F., Trapp, T., Widmann, M., Skutella, T., and Holsboer, F. (1997). Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro. Endocrinology 138, 101–106.10.1210/endo.138.1.4835Search in Google Scholar

Berman, R.M., Cappiello, A., Anand, A., Oren, D.A., Heninger, G.R., Charney, D.S., and Krystal, J.H. (2000). Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354.10.1016/S0006-3223(99)00230-9Search in Google Scholar

Bhagwagar, Z., Wylezinska, M., Taylor, M., Jezzard, P., Matthews, P.M., and Cowen, P.J. (2004). Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor. Am. J. Psychiatry 161, 368–370.10.1176/appi.ajp.161.2.368Search in Google Scholar

Bijak, M. and Papp, M. (1995). The effect of chronic treatment with imipramine on the responsiveness of hippocampal CAI neurons to phenylephrine and serotonin in a chronic mild stress model of depression. Eur. Neuropsychopharmacol. 5, 43–48.10.1016/0924-977X(94)00132-USearch in Google Scholar

Bijak, M. and Tokarski, K. (1994). Prolonged administration of imipramine and (+)-oxaprotiline, but not citalopram, results in sensitization of the rat hippocampal CA1 neurons to serotonin ex vivo. Pol. J. Pharmacol. 46, 163–167.Search in Google Scholar

Bijak, M., Tokarski, K., Czyrak, A., Mackowiak, M., and Wedzony, K. (1996). Imipramine increases the 5-HT1A receptor-mediated inhibition of hippocampal neurons without changing the 5-HT1A receptor binding. Eur. J. Pharmacol. 305, 79–85.10.1016/0014-2999(96)00151-3Search in Google Scholar

Bjornebekk, A., Mathe, A.A., and Brene, S. (2005). The antidepressant effect of running is associated with increased hippocampal cell proliferation. Int. J. Neuropsychopharmacol. 8, 357–368.10.1017/S1461145705005122Search in Google Scholar PubMed

Bjornebekk, A., Mathe, A.A., and Brene, S. (2006). Running has differential effects on NPY, opiates, and cell proliferation in an animal model of depression and controls. Neuropsychopharmacology 31, 256–264.10.1038/sj.npp.1300820Search in Google Scholar

Block, M.L. and Hong, J.S. (2005). Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog. Neurobiol. 76, 77–98.10.1016/j.pneurobio.2005.06.004Search in Google Scholar

Boldrini, M., Santiago, A.N., Hen, R., Dwork, A.J., Rosoklija, G.B., Tamir, H., Arango, V., and John Mann, J. (2013). Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology 38, 1068–1077.10.1038/npp.2013.5Search in Google Scholar

Bonanno, G., Giambelli, R., Raiteri, L., Tiraboschi, E., Zappettini, S., Musazzi, L., Raiteri, M., Racagni, G., and Popoli, M. (2005). Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J. Neurosci. 25, 3270–3279.10.1523/JNEUROSCI.5033-04.2005Search in Google Scholar

Bowley, M.P., Drevets, W.C., Ongur, D., and Price, J.L. (2002). Low glial numbers in the amygdala in major depressive disorder. Biol. Psychiatry 52, 404–412.10.1016/S0006-3223(02)01404-XSearch in Google Scholar

Boyer, P.A., Skolnick, P., and Fossom, L.H. (1998). Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain. A quantitative in situ hybridization study. J. Mol. Neurosci. 10, 219–233.10.1007/BF02761776Search in Google Scholar

Brazel, C.Y., Nunez, J.L., Yang, Z., and Levison, S.W. (2005). Glutamate enhances survival and proliferation of neural progenitors derived from the subventricular zone. Neuroscience 131, 55–65.10.1016/j.neuroscience.2004.10.038Search in Google Scholar

Bredt, D.S. and Nicoll, R.A. (2003). AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379.10.1016/S0896-6273(03)00640-8Search in Google Scholar

Brummelte, S. and Galea, L.A. (2010). Chronic high corticosterone reduces neurogenesis in the dentate gyrus of adult male and female rats. Neuroscience 168, 680–690.10.1016/j.neuroscience.2010.04.023Search in Google Scholar PubMed

Bruno, V., Sureda, F.X., Storto, M., Casabona, G., Caruso, A., Knopfel, T., Kuhn, R., and Nicoletti, F. (1997). The neuroprotective activity of group-II metabotropic glutamate receptors requires new protein synthesis and involves a glial-neuronal signaling. J. Neurosci. 17, 1891–1897.10.1523/JNEUROSCI.17-06-01891.1997Search in Google Scholar

Bruno, V., Battaglia, G., Casabona, G., Copani, A., Caciagli, F., and Nicoletti, F. (1998). Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-β. J. Neurosci. 18, 9594–9600.10.1523/JNEUROSCI.18-23-09594.1998Search in Google Scholar

Cai, X., Kallarackal, A.J., Kvarta, M.D., Goluskin, S., Gaylor, K., Bailey, A.M., Lee, H.K., Huganir, R.L., and Thompson, S.M. (2013). Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression. Nat. Neurosci. 16, 464–472.10.1038/nn.3355Search in Google Scholar

Calabrese, E.J. (2005). Historical blunders: how toxicology got the dose-response relationship half right. Cell. Mol. Biol. 51, 643–654.Search in Google Scholar

Calabrese, E.J. (2009). Getting the dose-response wrong: why hormesis became marginalized and the threshold model accepted. Arch. Toxicol. 83, 227–247.10.1007/s00204-009-0411-5Search in Google Scholar

Calabrese, E.J. (2010). Hormesis is central to toxicology, pharmacology and risk assessment. Hum. Exp. Toxicol. 29, 249–261.10.1177/0960327109363973Search in Google Scholar

Cameron, H.A. and Gould, E. (1994). Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 61, 203–209.10.1016/0306-4522(94)90224-0Search in Google Scholar

Cameron, H.A., McEwen, B.S., and Gould, E. (1995). Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J. Neurosci. 15, 4687–4692.10.1523/JNEUROSCI.15-06-04687.1995Search in Google Scholar

Capela, J.P., Fernandes, E., Remião, F., Bastos, M.L., Meisel, A., and Carvalho, F. (2007). Ecstasy induces apoptosis via 5-HT2A-receptor stimulation in cortical neurons. Neurotoxicology 28, 868–875.10.1016/j.neuro.2007.04.005Search in Google Scholar

Carrier, N. and Kabbaj, M. (2013). Sex differences in the antidepressant-like effects of ketamine. Neuropharmacology 70, 27–34.10.1016/j.neuropharm.2012.12.009Search in Google Scholar

Chadwick, W. and Maudsley, S. (2010). The devil is in the dose: complexity of receptor systems and responses. In: Hormesis: A Revolution in Biology, Toxicology and Medicine. M.P. Mattson and E.J. Calabrese, eds. (New York: Springer).Search in Google Scholar

Chadwick, W., Magnus, T., Martin, B., Keselman, A., Mattson, M.P., and Maudsley, S. (2008). Targeting TNFα receptors for neurotherapeutics. Trends Neurosci. 31, 504–511.10.1016/j.tins.2008.07.005Search in Google Scholar

Chaturvedi, H.K., Chandra, D., and Bapna, J.S. (1999). Interaction between N-methyl-D-aspartate receptor antagonists and imipramine in shock-induced depression. Indian J. Exp. Biol. 37, 952–958.Search in Google Scholar

Cheng, B., Christakos, S., and Mattson, M.P. (1994). Tumor necrosis factors protect against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12, 139–153.10.1016/0896-6273(94)90159-7Search in Google Scholar

Choi, D.W. (1987). Ionic dependence of glutamate neurotoxicity. J. Neurosci. 7, 369–379.10.1523/JNEUROSCI.07-02-00369.1987Search in Google Scholar

Choudary, P.V., Molnar, M., Evans, S.J., Tomita, H., Li, J.Z., Vawter, M.P., Myers, R.M., Bunney, W.E. Jr., Akil, H., Watson, S.J., et al. (2005). Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc. Natl. Acad. Sci. USA 102, 15653–15658.10.1073/pnas.0507901102Search in Google Scholar

Chourbaji, S., Vogt, M.A., Fumagalli, F., Sohr, R., Frasca, A., Brandwein, C., Hörtnagl, H., Riva, M.A., Sprengel, R., and Gass, P. (2008). AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression. FASEB J. 22, 3129–3134.10.1096/fj.08-106450Search in Google Scholar

Ciccarelli, R., Di Iorio, P., Bruno, V., Battaglia, G., D’Alimonte, I., D’Onofrio, M., Nicoletti, F., and Caciagli, F. (1999). Activation of A1 adenosine and mGlu3 metabotropic glutamate receptors enhances the release of nerve growth factor and S-100 β protein from cultured astrocytes. Glia 27, 275–281.10.1002/(SICI)1098-1136(199909)27:3<275::AID-GLIA9>3.0.CO;2-0Search in Google Scholar

Cieślik, K., Sowa-Kućma, M., Ossowska, G., Legutko, B., Wolak, M., Opoka, W., and Nowak, G. (2011). Chronic unpredictable stress-induced reduction in the hippocampal brain-derived neurotrophic factor (BDNF) gene expression is antagonized by zinc treatment. Pharmacol. Rep. 63, 537–543.10.1016/S1734-1140(11)70520-5Search in Google Scholar

Conrad, C.D., Galea, L.A., Kuroda, Y., and McEwen, B.S. (1996). Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment. Behav. Neurosci. 110, 1321–1334.10.1037/0735-7044.110.6.1321Search in Google Scholar

Cordeiro, M.F., Guo, L., Luong, V., Harding, G., Wang, W., Jones, H.E., Moss, S.E., Sillito, A.M., and Fitzke, F.W. (2004). Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration. Proc. Natl. Acad. Sci. USA 101, 13352–13356.10.1073/pnas.0405479101Search in Google Scholar

Corti, C., Aldegheri, L., Somogyi, P., and Ferraguti, F. (2002). Distribution and synaptic localisation of the metabotropic glutamate receptor 4 (mGluR4) in the rodent CNS. Neuroscience 110, 403–420.10.1016/S0306-4522(01)00591-7Search in Google Scholar

Corti, C., Battaglia, G., Molinaro, G., Riozzi, B., Pittaluga, A., Corsi, M., Mugnaini, M., Nicoletti, F., and Bruno, V. (2007). The use of knock out mice unravels distinct roles for mGlu2 and mGlu3 metabotropic glutamate receptors in mechanisms of neurodegeneration/neuroprotection. J. Neurosci. 27, 8297–8308.10.1523/JNEUROSCI.1889-07.2007Search in Google Scholar

Cotter, D.R., Pariante, C.M., and Everall, I.P. (2001). Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res. Bull. 55, 585–595.10.1016/S0361-9230(01)00527-5Search in Google Scholar

Cozzi, A., Attucci, S., Peruginelli, F., Marinozzi, M., Luneia, R., Pellicciari, R., and Moroni, F. (1997). Type 2 metabotropic glutamate (mGlu) receptors tonically inhibit transmitter release in rat caudate nucleus: in vivo studies with (2S,1′S,2′S,3′R)-2-(2-carboxy-3-phenylcyclopropyl)glycine, a new potent and selective antagonist. Eur. J. Neurosci. 9, 1350–1355.10.1111/j.1460-9568.1997.tb01489.xSearch in Google Scholar

D’Onofrio, M., Cuomo, L., Battaglia, G., Ngomba, T.R., Storto, M., Kingston, A.E., Orzi, F., De Blasi, A., Di Iorio, P., Nicoletti, F., et al. (2001). Neuroprotection mediated by glial group-II metabotropic glutamate receptors requires the activation of the MAP kinase and the phosphatidylinositol-3-kinase pathways. J. Neurochem. 78, 435–445.10.1046/j.1471-4159.2001.00435.xSearch in Google Scholar

D’Suza, M.S. and Markou, A. (2010). Neural substrates of psychostimulant withdrawal-induced anhedonia. In: Behavioral Neuroscience of Drug Addiction: Current Topics in Behavioral Neuroscience 3. D.W. Self and J.K. Staley, eds. (Berlin/Heidelberg: Springer-Verlag), pp. 119–178.10.1007/7854_2009_20Search in Google Scholar

Danbolt, N.C. (2001). Glutamate uptake. Prog. Neurobiol. 65, 1–105.10.1016/S0301-0082(00)00067-8Search in Google Scholar

Danbolt, N.C., Storm-Mathisen, J., and Kanner, B. I. (1992). An [Na++K+] coupled L-glutamate transporter purified from rat brain is located in glial cell processes. Neuroscience 51, 295–310.10.1016/0306-4522(92)90316-TSearch in Google Scholar

Davis, J.B. and Maher, P. (1994). Protein kinase C activation inhibits glutamate-induced cytotoxicity in a neuronal cell line. Brain Res. 652, 169–173.10.1016/0006-8993(94)90334-4Search in Google Scholar

Deisseroth, K., Singla, S., Toda, H., Monje, M., Palmer, T.D., and Malenka, R.C. (2004). Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron 42, 535–552.10.1016/S0896-6273(04)00266-1Search in Google Scholar

Delgado, P.L., Charney, D.S., Price, L.H., Aghajanian, G.K., Landis, H., and Heninger, G.R. (1990). Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch. Gen. Psychiatry 47, 411–418.10.1001/archpsyc.1990.01810170011002Search in Google Scholar PubMed

Deutschenbaur, L., Beck, J., Kiyhankhadiv, A., Mühlhauser, M., Borgwardt, S., Walter, M., Hasler, G., Sollberger, D., and Lang, U.E. (2016). Role of calcium, glutamate and NMDA in major depression and therapeutic application. Prog. Neuropsychopharmacol. Biol. Psychiatry 64, 325–333.10.1016/j.pnpbp.2015.02.015Search in Google Scholar PubMed

Di Giorgi-Gerevini, V., Melchiorri, D., Battaglia, G., Ricci-Vitiani, L., Ciceroni, C., Busceti, C.L., Biagioni, F., Iacovelli, L., Canudas, A.M., Parati, E., et al. (2005). Endogenous activation of metabotropic glutamate receptors supports the proliferation and survival of neural progenitor cells. Cell Death Differ. 12, 1124–1133.10.1038/sj.cdd.4401639Search in Google Scholar PubMed

Dobos, N., de Vries, E.F., Kema, I.P., Patas, K., Prins, M., Nijholt, I.M., Dierckx, R.A., Korf, J., den Boer, J.A., Luiten, P.G., et al. (2012). The role of indoleamine 2,3-dioxygenase in a mouse model of neuro inflammation induced depression. J. Alzheimers Dis. 28, 905–915.10.3233/JAD-2011-111097Search in Google Scholar

Drugan, R.C., Morrow, A.L., Weizman, R., Weizman, A., Deutsch, S.I., Crawley, J.N., and Paul, S.M. (1989). Stress-induced behavioral depression in the rat is associated with a decrease in GABA receptor-mediated chloride ion flux and brain benzodiazepine receptor occupancy. Brain Res. 487, 45–51.10.1016/0006-8993(89)90938-4Search in Google Scholar

Duman, R. (2007). Neurotrophic factors in etiology and treatment of mood disorders. In: Handbook of Contemporary Neuropharmacology, D. Sibley, I. Hanin, M. Kuhar and P. Skolnick, eds. (Hoboken, NJ: Wiley), pp. 789–815.10.1002/9780470101001.hcn019Search in Google Scholar

Duman, R.S. and Aghajanian, G.K. (2012). Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68–72.10.1126/science.1222939Search in Google Scholar

During, M.J. and Spencer, D.D. (1993). Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341, 1607–1610.10.1016/0140-6736(93)90754-5Search in Google Scholar

Ebmeier, K.P., Donaghey, C., and Steele, J.D. (2006). Recent developments and current controversies in depression. Lancet 367, 153–167.10.1016/S0140-6736(06)67964-6Search in Google Scholar

Endo, Y., Nishimura, J.I., and Kimura, F. (1996). Impairment of maze learning in rats following long-term glucocorticoid treatments. Neurosci. Lett. 203, 199–202.10.1016/0304-3940(95)12296-6Search in Google Scholar

Eshel, N. and Roiser, J.P. (2010). Reward and punishment processing in depression. Biol. Psychiatry 68, 118–124.10.1016/j.biopsych.2010.01.027Search in Google Scholar PubMed

Favaron, M., Manev, H., Alho, H., Bertolino, M., Ferret, B., Guidotti, A., and Costa, E. (1988). Gangliosides prevent glutamate and kainate neurotoxicity in primary neuronal cultures of neonatal rat cerebellum and cortex. Proc. Natl. Acad. Sci. USA 85, 7351–7355.10.1073/pnas.85.19.7351Search in Google Scholar PubMed PubMed Central

Feng, Y.B., Yao, H., Man, X., Chi, L.Y., and Chi, Z.F. (2011). Effects of the group II mGlu receptor agonist 2R, 4R-APDC on dentate gyrus cell proliferation in the adult rat brain after diffuse brain injury. Neurol. Res. 33, 381–388.10.1179/016164110X12816242542733Search in Google Scholar PubMed

Feyissa, A.M., Zyga, A., Stockmeier, C.A., and Karolewicz, B. (2009). Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 70–75.10.1016/j.pnpbp.2008.10.005Search in Google Scholar

Feyissa, A.M., Woolverton, W.L., Miguel-Hidalgo, J.J., Wang, Z., Kyle, P.B., Hasler, G., Stockmeier, C.A., Iyo, A.H., and Karolewicz, B. (2010). Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 279–283.10.1016/j.pnpbp.2009.11.018Search in Google Scholar

Fischell, J., Van Dyke, A.M., Kvarta, M.D., LeGates, T.A., and Thompson, S.M. (2015). Rapid antidepressant action and restoration of excitatory synaptic strength after chronic stress by negative modulators of α5-containing GABAA receptors. Neuropsychopharmacology 40, 2499–2509.10.1038/npp.2015.112Search in Google Scholar

Fitzsimons, C.P., van Hooijdonk, L.W., Morrow, J.A., Peeters, B.W., Hamilton, N., Craighead, M., and Vreugdenhil, E. (2009). Antiglucocorticoids, neurogenesis and depression. Mini Rev. Med. Chem. 9, 249–264.10.2174/138955709787316001Search in Google Scholar

Flight, M.H. (2013). Antidepressant epigenetic action. Nat. Rev. Neurosci. 14, 226.10.1038/nrn3466Search in Google Scholar

Flugge, G. (1995). Dynamics of central nervous 5-HT1A-receptors under psychosocial stress. J. Neurosci. 15, 7132–7140.10.1523/JNEUROSCI.15-11-07132.1995Search in Google Scholar

Franceschelli, A., Sens, J., Herchick, S., Thelen, C., and Pitychoutis, P.M. (2015). Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naïve and “depressed” mice exposed to chronic mild stress. Neuroscience 290, 49–60.10.1016/j.neuroscience.2015.01.008Search in Google Scholar

Freund, T.F. and Buzsaki, G. (1996). Interneurons of the hippocampus. Hippocampus 6, 347–470.10.1002/(SICI)1098-1063(1996)6:4<347::AID-HIPO1>3.0.CO;2-ISearch in Google Scholar

Froissard, P. and Duval, D. (1994). Cytotoxic effects of glutamic acid on PC12 cells. Neurochem. Int. 24, 485–493.10.1016/0197-0186(94)90096-5Search in Google Scholar

Ghashghaei, H.T. and Barbas, H. (2002). Pathways for emotion: interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey. Neuroscience 115, 1261–1279.10.1016/S0306-4522(02)00446-3Search in Google Scholar

Gibney, S.M., Fagan, E.M., Waldron, A.M., O’Byrne, J., Connor, T.J., and Harkin, A. (2014). Inhibition of stress-induced hepatic tryptophan 2,3-dioxygenase exhibits antidepressant activity in an animal model of depressive behaviour. Int. J. Neuropsychopharmacol. 17, 917–928.10.1017/S1461145713001673Search in Google Scholar

Goeders, N.E., De Souza, E.B., and Kuhar, M.J. (1986). Benzodiazepine receptor GABA ratios: regional differences in rat brain and modulation by adrenalectomy. Eur. J. Pharmacol. 129, 363–366.10.1016/0014-2999(86)90448-6Search in Google Scholar

Gold, B.I., Bowers, M.B. Jr., Roth, R.H., and Sweeney, D.W. (1980). GABA levels in CSF of patients with psychiatric disorders. Am. J. Psychiatry 137, 362–364.10.1176/ajp.137.3.362Search in Google Scholar PubMed

Gorman, J.M. and Docherty, J.P. (2010). A hypothesized role for dendritic remodeling in the etiology of mood and anxiety disorders. J. Neuropsychiatry Clin. Neurosci. 22, 256–264.10.1176/jnp.2010.22.3.256Search in Google Scholar PubMed

Gould, E., Woolley, C.S., and McEwen, B.S. (1991). Adrenal steroids regulate postnatal development of the rat dentate gyrus: I. Effects of glucocorticoids on cell death. J. Comp. Neurol. 313, 479–485.10.1002/cne.903130308Search in Google Scholar PubMed

Gould, E., McEwen, B.S., Tanapat, P., Galea, L.A., and Fuchs, E. (1997). Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 17, 2492–2498.10.1523/JNEUROSCI.17-07-02492.1997Search in Google Scholar

Grimm, S., Luborzewski, A., Schubert, F., Merkl, A., Kronenberg, G., Colla, M., Heuser, I., and Bajbouj, M. (2012). Region-specific glutamate changes in patients with unipolar depression. J. Psychiatry Res. 46, 1059–1065.10.1016/j.jpsychires.2012.04.018Search in Google Scholar PubMed

Grote, H.E. and Hannan, A.J. (2007). Regulators of adult neurogenesis in the healthy and diseased brain. Clin. Exp. Pharmacol. Physiol. 34, 533–545.10.1111/j.1440-1681.2007.04610.xSearch in Google Scholar PubMed

Guillemin, G.J. (2012). Quinolinic acid, the inescapable neurotoxin. FEBS J. 279, 1356–1365.10.1111/j.1742-4658.2012.08485.xSearch in Google Scholar PubMed

Hall, B.J. and Ghosh, A. (2008). Regulation of AMPA receptor recruitment at developing synapses. Trends Neurosci. 31, 82–89.10.1016/j.tins.2007.11.010Search in Google Scholar PubMed

Hamidi, M., Drevets, W.C., and Price, J.L. (2004). Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol. Psychiatry 55, 563–569.10.1016/j.biopsych.2003.11.006Search in Google Scholar

Hardingham, G.E. and Bading, H. (2003). The yin and yang of NMDA receptor signalling. Trends Neurosci. 26, 81–89.10.1016/S0166-2236(02)00040-1Search in Google Scholar

Hardingham, G.E. and Bading, H. (2010). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11, 682–696.10.1038/nrn2911Search in Google Scholar PubMed PubMed Central

Hardingham, G.E., Fukunaga, Y. and Bading, H. (2002). Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414.10.1038/nn835Search in Google Scholar PubMed

Hashimoto, K., Sawa, A., and Iyo, M. (2007). Increased levels of glutamate in brains from patients with mood disorders. Biol. Psychiatry 62, 1310–1316.10.1016/j.biopsych.2007.03.017Search in Google Scholar PubMed

Hasler, G., Neumeister, A., van der Veen, J.W., Tumonis, T., Bain, E.E., Shen, J., Drevets, W.C., and Charney, D.S. (2005). Normal prefrontal γ-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy. Biol. Psychiatry 58, 969–973.10.1016/j.biopsych.2005.05.017Search in Google Scholar PubMed

Hasler, G., van der Veen, J.W., Tumonis, T., Meyers, N., Shen, J., and Drevets, W.C. (2007). Reduced prefrontal glutamate/glutamine and γ-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry 64, 193–200.10.1001/archpsyc.64.2.193Search in Google Scholar PubMed

Hayashi, T., Umemori, H., Mishina, M., and Yamamoto, T. (1999). The AMPA receptor interactions with and signals through the protein tyrosine kinase Lyn. Nature 397, 72–76.10.1038/16269Search in Google Scholar PubMed

Holden, C. (2003). Psychiatric drugs. Excited by glutamate. Science 300, 1866–1868.Search in Google Scholar

Homayoun, H. and Moghaddam, B. (2007). NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J. Neurosci. 27, 11496–11500.10.1523/JNEUROSCI.2213-07.2007Search in Google Scholar PubMed PubMed Central

Horner, H., Packan, D., and Sapolsky, R. (1990). Glucocorticoids inhibit glucose transport in cultured hippocampal neurons and glia. Neuroendocrinology 52, 57–62.10.1159/000125539Search in Google Scholar PubMed

Houzen, H., Kikuchi, S., Kanno, M., Shinpo, K., and Tashiro, K. (1997). Tumor necrosis factor enhancement of transient outward potassium currents in cultured rat cortical neurons. J. Neurosci. Res. 50, 990–999.10.1002/(SICI)1097-4547(19971215)50:6<990::AID-JNR9>3.0.CO;2-8Search in Google Scholar

Ikegaya, Y., Saito, H., and Abe, K. (1996). Dentate gyrus field potentials evoked by stimulation of the basolateral amygdaloid nucleus in anesthetized rats. Brain Res. 718, 53–60.10.1016/0006-8993(95)01465-9Search in Google Scholar

Inagaki, T., Gautreaux, C., and Luine, V. (2010). Acute estrogen treatment facilitates recognition memory consolidation and alters monoamine levels in memory-related brain areas. Horm. Behav. 58, 415–426.10.1016/j.yhbeh.2010.05.013Search in Google Scholar

Jaarsma, D., Postema, F., and Korf, J. (1992). Time course and distribution of neuronal degeneration in the dentate gyrus of rat after adrenalectomy: a silver impregnation study. Hippocampus 2, 143–150.10.1002/hipo.450020206Search in Google Scholar

Jeffcoate, W.J., Silverstone, J.T., Edwards, C.R., and Besser, G.M. (1979). Psychiatric manifestations of Cushing’s syndrome: response to lowering of plasma cortisol. Q. J. Med. 48, 465–472.Search in Google Scholar

Jensen, J.B., Schousboe, A., and Pickering, D.S. (1998). Development of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in cultured neocortical neurons visualized by cobalt staining. J. Neurosci. Res. 54, 273–281.10.1002/(SICI)1097-4547(19981015)54:2<273::AID-JNR15>3.0.CO;2-5Search in Google Scholar

Jernigan, C.S., Goswami, D.B., Austin, M.C., Iyo, A.H., Chandran, A., Stockmeier, C.A., and Karolewicz, B. (2011). The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 1774–1779.10.1016/j.pnpbp.2011.05.010Search in Google Scholar

Jiang, M., Lee, C.L., Smith, K.L., and Swann, J.W. (1998). Spine loss and other alterations of hippocampal pyramidal cell dendrites in a model of early-onset epilepsy. J. Neurosci. 18, 8356–8368.10.1523/JNEUROSCI.18-20-08356.1998Search in Google Scholar

Jiang, X., Tian, F., Mearow, K., Okagaki, P., Lipsky, R.H., and Marini, A.M. (2005). The excitoprotective effect of N-methyl-D-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. J. Neurochem. 94, 713–722.10.1111/j.1471-4159.2005.03200.xSearch in Google Scholar

Joels, M., Karst, H., Alfarez, D., Heine, V.M., Qin, Y., van Riel, E., Verkuyl, M., Lucassen, P.J., and Krugers, H.J. (2004). Effects of chronic stress on structure and cell function in rat hippocampus and hypothalamus. Stress 7, 221–231.10.1080/10253890500070005Search in Google Scholar

John, C.S., Smith, K.L., Van’t Veer, A., Gompf, H.S., Carlezon, W.A. Jr., Cohen, B.M., Öngür, D., and Bechtholt-Gompf, A.J. (2012). Blockade of astrocytic glutamate uptake in the prefrontal cortex induces anhedonia. Neuropsychopharmacology 37, 2467–2475.10.1038/npp.2012.105Search in Google Scholar

Joo, J.Y., Kim, B.W., Lee, J.S., Park, J.Y., Kim, S., Yun, Y.J., and Son, H. (2007). Activation of NMDA receptors increases proliferation and differentiation of hippocampal neural progenitor cells. J. Cell Sci. 120, 1358–1370.10.1242/jcs.002154Search in Google Scholar

Kajta, M., Domin, H., Grynkiewicz, G., and Lasoń, W. (2007). Genistein inhibits glutamate-induced apoptotic processes in primary neuron all cell cultures: an involvement of aryl hydrocarbon receptor and estrogen receptor/glycogen synthase kinase-3β intracellular signaling pathway. Neuroscience 144, 592–604.10.1016/j.neuroscience.2006.11.059Search in Google Scholar

Kajta, M., Rzemieniec, J., Litwa, E., Lasoń, W., Lenartowicz, M., Krzeptowski, W., and Wójtowicz, A.K. (2013). The key involvement of estrogen receptor β and G-protein-coupled receptor 30 in the neuroprotective action of daidzein. Neuroscience 238, 345–360.10.1016/j.neuroscience.2013.02.005Search in Google Scholar

Kalev-Zylinska, M.L., Symes, W., Young, D., and During, M.J. (2009). Knockdown and overexpression of NR1 modulates NMDA receptor function. Mol. Cell. Neurosci. 41, 383–396.10.1016/j.mcn.2009.04.003Search in Google Scholar

Kalivas, P.W. (2009). The glutamate homeostasis hypothesis of addiction. Nat. Rev. Neurosci. 10, 561–572.10.1038/nrn2515Search in Google Scholar

Kallarackal, A.J., Kvarta, M.D., Cammarata, E., Jaberi, L., Cai, X., Bailey, A.M., and Thompson, S.M. (2013). Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J. Neurosci. 33, 15669–15674.10.1523/JNEUROSCI.2588-13.2013Search in Google Scholar

Kang, I., Thompson, M.L., Heller, J., and Miller, L.G. (1991). Persistent elevation in GABAA receptor subunit mRNAs following social stress. Brain Res. Bull. 26, 809–812.10.1016/0361-9230(91)90179-NSearch in Google Scholar

Karolewicz, B., Stockmeier, C.A., and Ordway, G.A. (2005). Elevated levels of the NR2C subunit of the NMDA receptor in the locus coeruleus in depression. Neuropsychopharmacology 30, 1557–1567.10.1038/sj.npp.1300781Search in Google Scholar PubMed PubMed Central

Karolewicz, B., Feyissa, A.M., Chandran, A., Legutko, B., Ordway, G.A., Rajkowska, G., and Stockmeier, C.A. (2009). Glutamate receptors expression in postmortem brain from depressed subjects. Biol. Psychiatry, 177S.Search in Google Scholar

Kendler, K.S., Gardner, C.O., and Prescott, C.A. (2002). Toward a comprehensive developmental model for major depression in women. Am. J. Psychiatry 159, 1133–1145.10.1176/appi.ajp.159.7.1133Search in Google Scholar PubMed

Kerr, D.S., Campbell, L.W., Applegate, M.D., Brodish, A., and Landfield, P.W. (1991). Chronic stress-induced acceleration of electrophysiologic and morphometric biomarkers of hippocampal aging. J. Neurosci. 11, 1316–1324.10.1523/JNEUROSCI.11-05-01316.1991Search in Google Scholar

Kheirbek, M.A., Tannenholz, L., and Hen, R. (2012). NR2B-dependent plasticity of adult-born granule cells is necessary for context discrimination. J. Neurosci. 32, 8696–8702.10.1523/JNEUROSCI.1692-12.2012Search in Google Scholar PubMed PubMed Central

Kim, J.S., Schmid-Burgk, W., Claus, D., and Kornhuber, H.H. (1982). Increased serum glutamate in depressed patients. Arch. Psychiatr. Nervenkr. 232, 299–304.10.1007/BF00345492Search in Google Scholar PubMed

Kim, J.J., Koo, J.W., Lee, H.J., and Han, J.S. (2005). Amygdalar inactivation blocks stress-induced impairments in hippocampal long-term potentiation and spatial memory. J. Neurosci. 25, 1532–1539.10.1523/JNEUROSCI.4623-04.2005Search in Google Scholar PubMed PubMed Central

Kohli, M.A., Lucae, S., Saemann, P.G., Schmidt, M.V., Demirkan, A., Hek, K., Czamara, D., Alexander, M., Salyakina, D., Ripke, S., et al. (2011). The neuronal transporter gene SLC6A15 confers risk to major depression. Neuron 70, 252–265.10.1016/j.neuron.2011.04.005Search in Google Scholar PubMed PubMed Central

Korgaonkar, M.S., Fornito, A., Williams, L.M., and Grieve, S.M. (2014). Abnormal structural networks characterize major depressive disorder: a connectome analysis. Biol. Psychiatry 76, 567–574.10.1016/j.biopsych.2014.02.018Search in Google Scholar PubMed

Kosten, T.A., Galloway, M.P., Duman, R.S., Russell, D.S., and D’Sa, C. (2008). Repeated unpredictable stress and antidepressants differentially regulate expression of the bcl-2 family of apoptotic genes in rat cortical, hippocampal, and limbic brain structures. Neuropsychopharmacology 33, 1545–1558.10.1038/sj.npp.1301527Search in Google Scholar PubMed

Krishnan, V. and Nestler, E.J. (2008). The molecular neurobiology of depression. Nature 455, 894–902.10.1038/nature07455Search in Google Scholar PubMed PubMed Central

Kucukibrahimoglu, E., Saygin, M.Z., Caliskan, M., Kaplan, O.K., Unsal, C., and Goren, M.Z. (2009). The change in plasma GABA, glutamine and glutamate levels in fluoxetine- or S-citalopram-treated female patients with major depression. Eur. J. Clin. Pharmacol. 65, 571–577.10.1007/s00228-009-0650-7Search in Google Scholar PubMed

Kvarta, M.D., Bradbrook, K.E., Dantrassy, H.M., Bailey, A.M., and Thompson, S.M. (2015). Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses. J. Neurophysiol. 114, 1713–1724.10.1152/jn.00359.2015Search in Google Scholar PubMed PubMed Central

Lau, D., Bengtson, C.P., Buchthal, B., and Bading, H. (2015). BDNF reduces toxic extrasynaptic NMDA receptor signaling via synaptic NMDA receptors and nuclear-calcium-induced transcription of inhba/activin A. Cell Rep. 12, 1353–1366.10.1016/j.celrep.2015.07.038Search in Google Scholar PubMed

Lehre, K.P. and Danbolt, N.C. (1998). The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci. 18, 8751–8757.10.1523/JNEUROSCI.18-21-08751.1998Search in Google Scholar

Lejeune, F., Gobert, A., Rivet, J.M., and Millan, M.J. (1994). Blockade of transmission at NMDA receptors facilitates the electrical and synthetic activity of ascending serotoninergic neurones. Brain Res. 656, 427–431.10.1016/0006-8993(94)91490-7Search in Google Scholar

Li, X., Tizzano, J.P., Griffey, K., Clay, M., Lindstrom, T., and Skolnick, P. (2001). Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Neuropharmacology 40, 1028–1033.10.1016/S0028-3908(00)00194-5Search in Google Scholar

Li, X., Witkin, J.M., Need, A.B., and Skolnick, P. (2003). Enhancement of antidepressant potency by a potentiator of AMPA receptors. Cell. Mol. Neurobiol. 23, 419–430.10.1023/A:1023648923447Search in Google Scholar

Li, X.H., Liu, N.B., Zhang, M.H., Zhou, Y.L., Liao, J.W., Liu, X.Q., and Chen, H.W. (2007). Effects of chronic multiple stress on learning and memory and the expression of Fyn, BDNF, TrkB in the hippocampus of rats. Chin. Med. J. 120, 669–674.10.1097/00029330-200704020-00011Search in Google Scholar

Li, J.J., Yuan, Y.G., Hou, G., and Zhang, X.R. (2011a). Dose-related effects of venlafaxine on pCREB and brain-derived neurotrophic factor (BDNF) in the hippocampus of the rat by chronic unpredictable stress. Acta Neuropsychiatr. 23, 20–30.10.1111/j.1601-5215.2010.00512.xSearch in Google Scholar

Li, N., Liu, R.J., Dwyer, J.M., Banasr, M., Lee, B., Son, H., Li, X.Y., Aghajanian, G., and Duman, R.S. (2011b). Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol. Psychiatry 69, 754–761.10.1016/j.biopsych.2010.12.015Search in Google Scholar

Lipton, S.A. and Kater, S.B. (1989). Neurotransmitter regulation of neuronal outgrowth, plasticity and survival. Trends Neurosci. 12, 265–270.10.1016/0166-2236(89)90026-XSearch in Google Scholar

Lipton, S.A. and Nakanishi, N. (1999). Shakespeare in Love – with NMDA receptors? Nat. Med. 5, 270–271.Search in Google Scholar

Liston, C., Miller, M.M., Goldwater, D.S., Radley, J.J., Rocher, A.B., Hof, P.R., Morrison, J.H., and McEwen, B.S. (2006). Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J. Neurosci. 26, 7870–7874.10.1523/JNEUROSCI.1184-06.2006Search in Google Scholar PubMed PubMed Central

Liu, R.J. and Aghajanian, G.K. (2008). Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc. Natl. Acad. Sci. USA 105, 359–364.10.1073/pnas.0706679105Search in Google Scholar PubMed PubMed Central

Liu, X.H., Xu, H., and Barks, J.D. (1999). Tumor necrosis factor-α attenuates N-methyl-D-aspartate-mediated neurotoxicity in neonatal rat hippocampus. Brain Res. 851, 94–104.10.1016/S0006-8993(99)02126-5Search in Google Scholar

Lodge, D. (2009). The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature. Neuropharmacology 56, 6–21.10.1016/j.neuropharm.2008.08.006Search in Google Scholar

López, J.F., Chalmers, D.T., Little, K.Y., and Watson, S.J. (1998). Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol. Psychiatry 43, 547–573.10.1016/S0006-3223(97)00484-8Search in Google Scholar

Lorrain, D.S., Baccei, C.S., Bristow, L.J., Anderson, J.J., and Varney, M.A. (2003). 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 117, 697–706.10.1016/S0306-4522(02)00652-8Search in Google Scholar

Lovinger, D.M. (1991). Trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD) decreases synaptic excitation in rat striatal slices through a presynaptic action. Neurosci. Lett. 129, 17–21.10.1016/0304-3940(91)90710-BSearch in Google Scholar

Lovinger, D.M. and McCool, B.A. (1995). Metabotropic glutamate receptor-mediated presynaptic depression at corticostriatal synapses involves mGluR2 or 3. J. Neurophysiol. 73, 1076–1083.10.1152/jn.1995.73.3.1076Search in Google Scholar

Lowy, M., Gault, L., and Yamamoto, B. (1993). Adrenolectomy attenuates stress induced elevation in extracellular glutamate concentration in hippocampus. J. Neurochem. 61, 1957–1960.10.1111/j.1471-4159.1993.tb09839.xSearch in Google Scholar

Lu, W., Gray, J.A., Granger, A.J., During, M.J., and Nicoll, R.A. (2011). Potentiation of synaptic AMPA receptors induced by the deletion of NMDA receptors requires the GluA2 subunit. J. Neurophysiol. 105, 923–928.10.1152/jn.00725.2010Search in Google Scholar

Lucassen, P.J., Müller, M.B., Holsboer, F., Bauer, J., Holtrop, A., Wouda, J., Hoogendijk, W.J., De Kloet, E.R., and Swaab, D.F. (2001). Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am. J. Pathol. 158, 453–468.10.1016/S0002-9440(10)63988-0Search in Google Scholar

Lucassen, P.J., Bosch, O.J., Jousma, E., Kromer, S.A., Andrew, R., Seckl, J.R., and Neumann, I.D. (2009). Prenatal stress reduces postnatal neurogenesis in rats selectively bred for high, but not low, anxiety: possible key role of placental 11β-hydroxysteroid dehydrogenase type 2. Eur. J. Neurosci. 29, 97–103.10.1111/j.1460-9568.2008.06543.xSearch in Google Scholar PubMed

Luine, V., Villegas, M., Martinez, C., and McEwen, B.S. (1994). Repeated stress causes reversible impairments of spatial memory performance. Brain Res. 639, 167–170.10.1016/0006-8993(94)91778-7Search in Google Scholar

MacDermott, A.B., Mayer, M.L., Westbrook, G.L., Smith, S.J., and Barker, J.L. (1986). NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature 321, 519–522.10.1038/321519a0Search in Google Scholar

Maciag, D., Hughes, J., O’Dwyer, G., Pride, Y., Stockmeier, C.A., Sanacora, G., and Rajkowska, G. (2010). Reduced density of calbindin immunoreactive GABAergic neurons in the occipital cortex in major depression: relevance to neuroimaging studies. Biol. Psychiatry 67, 465–470.10.1016/j.biopsych.2009.10.027Search in Google Scholar

MacLennan, K.M., Smith, P.F., and Darlington, C.L. (1998). Adrenalectomy-induced neuronal degeneration. Prog. Neurobiol. 54, 481–498.10.1016/S0301-0082(97)00076-2Search in Google Scholar

Maeng, S., Zarate, C.A. Jr., Du, J., Schloesser, R.J., McCammon, J., Chen, G., and Manji, H.K. (2008). Cellular mechanisms underlying the antidepressant effects of ketamine: role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol. Psychiatry 63, 349–352.10.1016/j.biopsych.2007.05.028Search in Google Scholar

Maes, M., Verkerk, R., Vandoolaeghe, E., Lin, A., and Scharpe, S. (1998). Serum levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine, alanine and arginine in treatment-resistant depression: modulation by treatment with antidepressants and prediction of clinical responsivity. Acta Psychiatr. Scand. 97, 302–308.10.1111/j.1600-0447.1998.tb10004.xSearch in Google Scholar

Maes, M., Yirmyia, R., Noraberg, J., Brene, S., Hibbeln, J., Perini, G., Kubera, M., Bob, P., Lerer, B., and Maj, M. (2009). The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab. Brain Dis. 24, 27–53.10.1007/s11011-008-9118-1Search in Google Scholar

Magariños, A.M. and McEwen, B.S. (1995). Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors. Neuroscience 69, 83–88.10.1016/0306-4522(95)00256-ISearch in Google Scholar

Magariños, A.M., McEwen, B.S., Flugge, G., and Fuchs, E. (1996). Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J. Neurosci. 16, 3534–3540.10.1523/JNEUROSCI.16-10-03534.1996Search in Google Scholar

Magariños, A.M., Orchinik, M., and McEwen, B.S. (1998). Morphological changes in the hippocampal CA3 region induced by non-invasive glucocorticoid administration: a paradox. Brain Res. 809, 314–318.10.1016/S0006-8993(98)00882-8Search in Google Scholar

Magariños, A.M., Deslandes, A., and McEwen, B.S. (1999). Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress. Eur. J. Pharmacol. 371, 113–122.10.1016/S0014-2999(99)00163-6Search in Google Scholar

Malinow, R. and Malenka, R.C. (2002). AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126.10.1146/annurev.neuro.25.112701.142758Search in Google Scholar

Manganas, L.N., Zhang, X., Li, Y., Hazel, R.D., Smith, S.D., Wagshul, M.E., and Maletic-Savatic, M. (2007). Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 318, 980–985.10.1126/science.1147851Search in Google Scholar

Mao, Q., Huang, Z., and Zhong, X. (2014). Piperine reverses chronic unpredictable mild stress-induced behavioral and biochemical alterations in rats. Cell. Mol. Neurobiol. 34, 403–408.10.1007/s10571-014-0025-1Search in Google Scholar

Marini, A.M. and Paul, S.M. (1992). N-methyl-D-aspartate receptor-mediated neuroprotection in cerebellar granule cells requires new RNA and protein synthesis. Proc. Natl. Acad. Sci. USA 89, 6555–6559.10.1073/pnas.89.14.6555Search in Google Scholar

Marini, A.M., Rabin, S.J., Lipsky, R.H., and Mocchetti, L. (1998). Activity-dependent release of brain-derived neurotrophic factor underlies the neuroprotective effect of N-methyl-D-aspartate. J. Biol. Chem. 273, 29394–29349.10.1074/jbc.273.45.29394Search in Google Scholar

Marini, A.M., Ueda, Y., and June, C.H. (1999). Intracellular survival pathways against glutamate receptor agonist excitotoxicity in cultured neurons. Intracellular calcium responses. Ann. N. Y. Acad. Sci. 890, 421–437.10.1111/j.1749-6632.1999.tb08021.xSearch in Google Scholar

Marsden, W.N. (2011). Stressor-induced NMDAR dysfunction as a unifying hypothesis for the aetiology, pathogenesis and comorbidity of clinical depression. Med. Hypotheses 77, 508–528.10.1016/j.mehy.2011.06.021Search in Google Scholar

Martínez-Turrillas, R., Frechilla, D., and Del Río, J. (2002). Chronic antidepressant treatment increases the membrane expression of AMPA receptors in rat hippocampus. Neuropharmacology 43, 1230–1237.10.1016/S0028-3908(02)00299-XSearch in Google Scholar

Martínez-Turrillas, R., Del Río, J., and Frechilla, D. (2005). Sequential changes in BDNF mRNA expression and synaptic levels of AMPA receptor subunits in rat hippocampus after chronic antidepressant treatment. Neuropharmacology 49, 1178–1188.10.1016/j.neuropharm.2005.07.006Search in Google Scholar PubMed

Marx, C.E., Bradford, D.W., Hamer, R.M., Naylor, J.C., Allen, T.B., Lieberman, J.A., and Kilts, J.D. (2011). Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence. Neuroscience 191, 78–90.10.1016/j.neuroscience.2011.06.076Search in Google Scholar

Matarredona, E.R., Santiago, M., Venero, J.L., Cano, J., and Machado, A. (2001). Group II metabotropic glutamate receptor activation protects striatal dopaminergic nerve terminals against MPP+-induced neurotoxicity along with brain-derived neurotrophic factor induction. J. Neurochem. 76, 351–360.10.1046/j.1471-4159.2001.00056.xSearch in Google Scholar

Matrisciano, F., Storto, M., Ngomba, R.T., Cappuccio, I., Caricasole, A., Scaccianoce, S., Riozzi, B., Melchiorri, D., and Nicoletti, F. (2002). Imipramine treatment up-regulates the expression of mGlu2/3 metabotropic glutamate receptors in the rat hippocampus. Neuropharmacology 42, 1008–1015.10.1016/S0028-3908(02)00057-6Search in Google Scholar

Matrisciano, F., Caruso, A., Orlando, R., Marchiafava, M., Bruno, V., Battaglia, G., Gruber, S.H., Melchiorri, D., Tatarelli, R., Girardi, P., et al. (2008). Defective group-II metabotropic glutamate receptors in the hippocampus of spontaneously depressed rats. Neuropharmacology 55, 525–531.10.1016/j.neuropharm.2008.05.014Search in Google Scholar

Mattison, H.A., Popovkina, D., Kao, J.P., and Thompson, S.M. (2014). The role of glutamate in the morphological and physiological development of dendritic spines. Eur. J. Neurosci. 39, 1761–1770.10.1111/ejn.12536Search in Google Scholar

Mattson, M.P. and Calabrese, E.J. (2010). Hormesis: what it is and why it matters. In: Hormesis: A Revolution in Biology, Toxicology and Medicine. M.P. Mattson and E.J. Calabrese, eds. (New York: Springer).10.1007/978-1-60761-495-1_1Search in Google Scholar

Mattson, M.P. and Kater, S.B. (1989). Excitatory and inhibitory neurotransmitters in the generation and degeneration of hippocampal neuroarchitecture. Brain Res. 478, 337–348.10.1016/0006-8993(89)91514-XSearch in Google Scholar

Mauri, M.C., Ferrara, A., Boscati, L., Bravin, S., Zamberlan, F., Alecci, M., and Invernizzi, G. (1998). Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment. Neuropsychobiology 37, 124–129.10.1159/000026491Search in Google Scholar

McDonald, A.J. (1987). Organization of amygdaloid projections to the mediodorsal thalamus and prefrontal cortex: a fluorescence retrograde transport study in the rat. J. Comp. Neurol. 262, 46–58.10.1002/cne.902620105Search in Google Scholar

McDonald, A.J., Mascagni, F., and Guo, L. (1996). Projections of the medial and lateral prefrontal cortices to the amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat. Neuroscience 71, 55–75.10.1016/0306-4522(95)00417-3Search in Google Scholar

McDonald, J.W., Stefovska, V.G., Liu, X.Z., Shin, H., Liu, S., and Choi, D.W. (2002). Neurotrophin potentiation of iron-induced spinal cord injury. Neuroscience 115, 931–939.10.1016/S0306-4522(02)00342-1Search in Google Scholar

McEwen, B.S. (1999). Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22, 105–122.10.1146/annurev.neuro.22.1.105Search in Google Scholar

McEwen, B.S. (2000). Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology 22, 108–124.10.1016/S0893-133X(99)00129-3Search in Google Scholar

McEwen, B.S. (2003). Mood disorders and allostatic load. Biol. Psychiatry 54, 200–207.10.1016/S0006-3223(03)00177-XSearch in Google Scholar

McEwen, B.S. (2005). Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 54, 20–23.10.1016/j.metabol.2005.01.008Search in Google Scholar

McEwen, B.S. and Morrison, J.H. (2013). The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 79, 16–29.10.1016/j.neuron.2013.06.028Search in Google Scholar

McEwen, B.S., Albeck, D., Cameron, H., Chao, H.M., Gould, E., Hastings, N., Kuroda, Y., Luine, V., Magarinos, A.M., and Mckittrick, C.R. (1995). Stress and the brain: a paradoxical role for adrenal steroids. In: Vitamins and Hormones. G.D. Litwack, ed. (New York: Academic Press), pp. 371–402.10.1016/S0083-6729(08)61045-6Search in Google Scholar

McEwen, B.S., Nasca, C., and Gray, J.D. (2016). Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology 41, 3–23.10.1038/npp.2015.171Search in Google Scholar PubMed PubMed Central

McGeer, P.L. and McGeer, E.G. (2002). Local neuroinflammation and the progression of Alzheimer’s disease. J. Neurovirol. 8, 529–538.10.1080/13550280290100969Search in Google Scholar PubMed

McKernan, D.P., Dinan, T.G., and Cryan, J.F. (2009). “Killing the Blues”: a role for cellular suicide (apoptosis) in depression and the antidepressant response? Prog. Neurobiol. 88, 246–263.10.1016/j.pneurobio.2009.04.006Search in Google Scholar PubMed

McKittrick, C.R., Magarinos, A.M., Blanchard, D.C., Blanchard, R.J., and McEwen, B.S. (2000). Chronic social stress decreases binding to 5HT transporter sites and reduces dendritic arbors in CA3 of hippocampus. Synapse 36, 85–94.10.1002/(SICI)1098-2396(200005)36:2<85::AID-SYN1>3.0.CO;2-YSearch in Google Scholar

Michaels, R.L. and Rothman, S.M. (1990). Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations. J. Neurosci. 10, 283–292.10.1523/JNEUROSCI.10-01-00283.1990Search in Google Scholar

Miguel-Hidalgo, J.J., Baucom, C., Dilley, G., Overholser, J.C., Meltzer, H.Y., Stockmeier, C.A., and Rajkowska, G. (2000). Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder. Biol. Psychiatry 48, 861–873.10.1016/S0006-3223(00)00999-9Search in Google Scholar

Miguel-Hidalgo, J.J., Wei, J., Andrew, M., Overholser, J.C., Jurjus, G., Stockmeier, C.A., and Rajkowska, G. (2002). Glia pathology in the prefrontal cortex in alcohol dependence with and without depressive symptoms. Biol. Psychiatry 52, 1121–1133.10.1016/S0006-3223(02)01439-7Search in Google Scholar

Milad, M.R. and Quirk, G.J. (2002). Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74.10.1038/nature01138Search in Google Scholar

Milak, M.S., Proper, C.J., Mulhern, S.T., Parter, A.L., Kegeles, L.S., Ogden, R.T., Mao, X., Rodriguez, C.I., Oquendo, M.A., Suckow, R.F., et al. (2016). A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder. Mol. Psychiatry 21, 320–327.10.1038/mp.2015.83Search in Google Scholar

Milanese, M., Tardito, D., Musazzi, L., Treccani, G., Mallei, A., Bonifacino, T., Gabriel, C., Mocaer, E., Racagni, G., Popoli, M., et al. (2013). Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked glutamate release from hippocampal synaptosomes. BMC Neurosci. 14, 75.10.1186/1471-2202-14-75Search in Google Scholar

Miller, A.H. (2013). Conceptual confluence: the kynurenine pathway as a common target for ketamine and the convergence of the inflammation and glutamate hypotheses of depression. Neuropsychopharmacology 38, 1607–1608.10.1038/npp.2013.140Search in Google Scholar

Miller, A.L., Chaptal, C., McEwen, B.S., and Peck, E.J. Jr. (1978). Modulation of high affinity GABA uptake into hippocampal synaptosomes by glucocorticoids. Psychoneuroendocrinology 3, 155–164.10.1016/0306-4530(78)90003-3Search in Google Scholar

Miller, L.G., Greenblatt, D.J., Barnhill, J.G., Thompson, M.L., and Shaderh, R.I. (1988). Modulation of benzodiazepine receptor binding in mouse brain by adrenalectomy and steroid replacement. Brain Res. 446, 314–320.10.1016/0006-8993(88)90890-6Search in Google Scholar

Miller, A.H., Maletic, V., and Raison, C.L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741.10.1016/j.biopsych.2008.11.029Search in Google Scholar

Miller, O.H., Moran, J.T., and Hall, B.J. (2016). Two cellular hypotheses explaining the initiation of ketamine’s antidepressant actions: direct inhibition and disinhibition. Neuropharmacology 100, 17–26.10.1016/j.neuropharm.2015.07.028Search in Google Scholar

Mirescu, C. and Gould, E. (2006). Stress and adult neurogenesis. Hippocampus 16, 233–238.10.1002/hipo.20155Search in Google Scholar

Mitani, H., Shirayama, Y., Yamada, T., Maeda, K., Ashby, C.R. Jr., and Kawahara, R. (2006). Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 1155–1158.10.1016/j.pnpbp.2006.03.036Search in Google Scholar

Moghaddam, B. (1993). Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J. Neurochem. 60, 1650–1657.10.1111/j.1471-4159.1993.tb13387.xSearch in Google Scholar

Moghaddam, B. (2002). Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders. Biol. Psychiatry 51, 775–787.10.1016/S0006-3223(01)01362-2Search in Google Scholar

Moghaddam, B., Bolinao, M.L., Stein-Behrens, B., and Sapolsky, R. (1994). Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res. 655, 251–254.10.1016/0006-8993(94)91622-5Search in Google Scholar

Moghaddam, B., Adams, B., Verma, A., and Daly, D. (1997). 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. 17, 2921–2927.10.1523/JNEUROSCI.17-08-02921.1997Search in Google Scholar

Morgan, M.A. and LeDoux, J.E. (1995). Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats. Behav. Neurosci. 109, 681–688.10.1037/0735-7044.109.4.681Search in Google Scholar

Müller, N. (2014). Immunology of major depression. Neuroimmunomodulation 21, 123–130.10.1159/000356540Search in Google Scholar PubMed

Müller, N. and Schwarz, M.J. (2007). The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol. Psychiatry 12, 988–1000.10.1038/ in Google Scholar

Müller, H.K., Wegener, G., Liebenberg, N., Zarate, C.A. Jr., Popoli, M., and Elfving, B. (2013). Ketamine regulates the presynaptic release machinery in the hippocampus. J. Psychiatry Res. 47, 892–899.10.1016/j.jpsychires.2013.03.008Search in Google Scholar

Murakami, S., Imbe, H., Morikawa, Y., Kubo, C., and Senba, E. (2005). Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly. Neurosci. Res. 53, 129–139.10.1016/j.neures.2005.06.008Search in Google Scholar

Murakami, G., Nakamura, M., Takita, M., Ishida, Y., Ueki, T., and Nakahara, D. (2015). Brain rewarding stimulation reduces extracellular glutamate through glial modulation in medial prefrontal cortex of rats. Neuropsychopharmacology 40, 2686–2695.10.1038/npp.2015.115Search in Google Scholar

Murphy, T.H., Miyamoto, M., Sastre, A., Schnaar, R.L., and Coyle, J.T. (1989). Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron 2, 1547–1558.10.1016/0896-6273(89)90043-3Search in Google Scholar

Musazzi, L., Milanese, M., Farisello, P., Zappettini, S., Tardito, D., Barbiero, V.S., Bonifacino, T., Mallei, A., Baldelli, P., Racagni, G., et al. (2010). Acute stress increases depolarization-evoked glutamate release in the rat prefrontal/frontal cortex: the dampening action of antidepressants. PLoS One 5, e8566.10.1371/journal.pone.0008566Search in Google Scholar

Musazzi, L., Racagni, G., and Popoli, M. (2011). Stress, glucocorticoids and glutamate release: effects of antidepressant drugs. Neurochem. Int. 59, 138–149.10.1016/j.neuint.2011.05.002Search in Google Scholar

Musazzi, L., Treccani, G., and Popoli, M. (2015). Functional and structural remodeling of glutamate synapses in prefrontal and frontal cortex induced by behavioral stress. Front. Psychiatry 6, 60.10.3389/fpsyt.2015.00060Search in Google Scholar

Myint, A.M. and Kim, Y.K. (2003). Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med. Hypotheses 61, 519–525.10.1016/S0306-9877(03)00207-XSearch in Google Scholar

Nacher, J., Rosell, D.R., Alonso-Llosa, G., and McEwen, B.S. (2001). NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur. J. Neurosci. 13, 512–520.10.1046/j.0953-816x.2000.01424.xSearch in Google Scholar PubMed

Nair, A., Vadodaria, K.C., Banerjee, S.B., Benekareddy, M., Dias, B.G., Duman, R.S., Vaidya, V.A. (2007). Stressor-specific regulation of distinct brain-derived neurotrophic factor transcripts and cyclic AMP response element-binding protein expression in the postnatal and adult rat hippocampus. Neuropsychopharmacology 32, 1504–1519.10.1038/sj.npp.1301276Search in Google Scholar

Nakamura, T., Gu, Z., and Lipton, S.A. (2007). Contribution of glutamatergic signaling to nitrosative stress-induced protein misfolding in normal brain aging and neurodegenerative diseases. Aging Cell 6, 351–359.10.1111/j.1474-9726.2007.00284.xSearch in Google Scholar

Nasca, C., Xenos, D., Barone, Y., Caruso, A., Scaccianoce, S., Matrisciano, F., Battaglia, G., Mathé, A.A., Pittaluga, A., Lionetto, L., et al. (2013). L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc. Natl. Acad. Sci. USA 110, 4804–4809.10.1073/pnas.1216100110Search in Google Scholar

Nasca, C., Bigio, B., Zelli, D., Nicoletti, F., and McEwen, B.S. (2015). Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility. Mol. Psychiatry 20, 755–763.10.1038/mp.2014.96Search in Google Scholar

Nava, N., Treccani, G., Liebenberg, N., Chen, F., Popoli, M., Wegener, G., and Nyengaard, J.R. (2015). Chronic desipramine prevents acute stress-induced reorganization of medial prefrontal cortex architecture by blocking glutamate vesicle accumulation and excitatory synapse increase. Int. J. Neuropsychopharmacol. 18, 1–11.10.1093/ijnp/pyu085Search in Google Scholar

Nestler, E.J. and Carlezon, W.A. Jr. (2006). The mesolimbic dopamine reward circuit in depression. Biol. Psychiatry 59, 1151–1159.10.1016/j.biopsych.2005.09.018Search in Google Scholar

Newpher, T.M. and Ehlers, M.D. (2008). Glutamate receptor dynamics in dendritic microdomains. Neuron 58, 472–497.10.1016/j.neuron.2008.04.030Search in Google Scholar

Nieuwenhuys, R. (1994). The neocortex. An overview of its evolutionary development, structural organization and synaptology. Anat. Embryol. (Berl.) 190, 307–337.Search in Google Scholar

Nowak, G., Trullas, R., Layer, R.T., Skolnick, P., and Paul, I.A. (1993). Adaptive changes in the N-methyl-D-aspartate receptor complex after chronic treatment with imipramine and 1 aminocyclopropanecarboxylic acid. J. Pharmacol. Exp. Ther. 265, 1380–1386.Search in Google Scholar

O’Connor, J.C., Lawson, M.A., André, C., Moreau, M., Lestage, J., Castanon, N., Kelley, K.W., and Dantzer, R. (2009). Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol. Psychiatry 14, 511–522.10.1038/ in Google Scholar

Ongur, D., Drevets, W.C., and Price, J.L. (1998). Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc. Natl. Acad. Sci. USA 95, 13290–13295.10.1073/pnas.95.22.13290Search in Google Scholar

Orchinik, M., Weiland, N.G., and McEwen, B.S. (1995). Chronic exposure to stress levels of corticosterone alters GABAA receptor subunit mRNA levels in rat hippocampus. Mol. Brain Res. 34, 29–37.10.1016/0169-328X(95)00118-CSearch in Google Scholar

Orchinik, M., Carroll, S.S., Li, Y.H., McEwen, B.S., and Weiland, N.G. (2001). Heterogeneity of hippocampal GABAA receptors: regulation by corticosterone. J. Neurosci. 21, 330–339.10.1523/JNEUROSCI.21-01-00330.2001Search in Google Scholar

Overstreet, D.H. (1993). The Flinders sensitive line rats: a genetic animal model of depression. Neurosci. Biobehav. Rev. 17, 51–68.10.1097/00008877-199204001-00115Search in Google Scholar

Palmer, T.D., Takahashi, J., and Gage, F.H. (1997). The adult rat hippocampus contains primordial neural stem cells. Mol. Cell. Neurosci. 8, 389–404.10.1006/mcne.1996.0595Search in Google Scholar

Papp, M. and Moryl, E. (1993). New evidence for the antidepressant activity of MK-801, a non-competitive antagonist of NMDA receptors. Pol. J. Pharmacol. 45, 549–553.Search in Google Scholar

Paul, I.A. and Skolnick, P. (2003). Glutamate and depression: clinical and preclinical studies. Ann. N. Y. Acad. Sci. 1003, 250–272.10.1196/annals.1300.016Search in Google Scholar

Paul, I.A., Nowak, G., Layer, R.T., Popik, P., and Skolnick, P. (1994). Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. J. Pharmacol. Exp. Ther. 269, 95–102.Search in Google Scholar

Pérez-Arellano, I., Carmona-Alvarez, F., Martínez, A.I., Rodríguez-Díaz, J., and Cervera, J. (2010). Pyrroline-5-carboxylate synthase and proline biosynthesis: from osmotolerance to rare metabolic disease. Protein Sci. 19, 372–382.10.1002/pro.340Search in Google Scholar

Pérez-Gómez, A. and Tasker, R.A. (2014). Enhanced mossy fiber sprouting and synapse formation in organotypic hippocampal cultures following transient domoic acid excitotoxicity. Neurotoxicol. Res. 25, 402–410.10.1007/s12640-013-9450-zSearch in Google Scholar

Pérez-Rodríguez, R., Oliván, A.M., Roncero, C., Morón-Oset, J., González, M.P., and Oset-Gasque, M.J. (2014). Glutamate triggers neurosecretion and apoptosis in bovine chromaffin cells through a mechanism involving NO production by neuronal NO synthase activation. Free Radic. Biol. Med. 69, 390–402.10.1016/j.freeradbiomed.2014.01.029Search in Google Scholar

Petrie, R.X., Reid, I.C., and Stewart, C.A. (2000). The N-methyl-D-aspartate receptor, synaptic plasticity, and depressive disorder. A critical review. Pharmacol. Ther. 87, 11–25.10.1016/S0163-7258(00)00063-2Search in Google Scholar

Petrovich, G.D., Canteras, N.S., and Swanson, L.W. (2001). Combinatorial amygdalar inputs to hippocampal domains and hypothalamic behavior systems. Brain Res. Rev. 38, 247–289.10.1016/S0165-0173(01)00080-7Search in Google Scholar

Phillips, R.G. and LeDoux, J.E. (1992). Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285.10.1037/0735-7044.106.2.274Search in Google Scholar

Pilc, A., Wierońska, J.M., and Skolnick, P. (2013). Glutamate-based antidepressants: preclinical psychopharmacology. Biol. Psychiatry 73, 1125–1132.10.1016/j.biopsych.2013.01.021Search in Google Scholar

Pin, J.P. and Duvoisin, R. (1995). The metabotropic glutamate receptors: structure and functions. Neuropharmacology 34, 1–26.10.1016/0028-3908(94)00129-GSearch in Google Scholar

Pitman, D.L., Ottenweller, J.E., and Natelson, B.H. (1988). Plasma corticosterone levels during repeated presentation of two intensities of restraint stress: chronic stress and habituation. Physiol. Behav. 43, 47–55.10.1016/0031-9384(88)90097-2Search in Google Scholar

Pittaluga, A., Raiteri, L., Longordo, F., Luccini, E., Barbiero, V.S., Racagni, G., Popoli, M., and Raiteri, M. (2007). Antidepressant treatments and function of glutamate ionotropic receptors mediating amine release in hippocampus. Neuropharmacology 53, 27–36.10.1016/j.neuropharm.2007.04.006Search in Google Scholar PubMed

Pittenger, C. and Duman, R.S. (2008). Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33, 88–109.10.1038/sj.npp.1301574Search in Google Scholar PubMed

Popoli, M., Gennarelli, M., and Racagni, G. (2002). Modulation of synaptic plasticity by stress and antidepressants. Bipolar Disord. 4, 166–182.10.1034/j.1399-5618.2002.01159.xSearch in Google Scholar PubMed

Popoli, M., Yan, Z., McEwen, B.S., and Sanacora, G. (2012). The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 13, 22–37.10.1038/nrn3138Search in Google Scholar PubMed PubMed Central

Price, J.L. and Drevets, W.C. (2010). Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192–216.10.1038/npp.2009.104Search in Google Scholar PubMed PubMed Central

Price, R.B., Shungu, D.C., Mao, X., Nestadt, P., Kelly, C., Collins, K.A., Murrough, J.W., Charney, D.S., and Mathew, S.J. (2009). Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: relationship to treatment resistance in major depressive disorder. Biol. Psychiatry 65, 792–800.10.1016/j.biopsych.2008.10.025Search in Google Scholar PubMed PubMed Central

Quarton, G., Clark, L., Cobb, S., and Bauer, W. (1955). Mental disturbances associated with ACTH and cortisone: a review of explanatory hypotheses. Medicine (Baltimore) 34, 13–50.10.1097/00005792-195502000-00002Search in Google Scholar PubMed

Quirarte, G.L., de la Teja, I.S., Casillas, M., Serafin, N., Prado-Alcalá, R.A., and Roozendaal, B. (2009). Corticosterone infused into the dorsal striatum selectively enhances memory consolidation of cued water-maze training. Learn. Mem. 16, 586–589.10.1101/lm.1493609Search in Google Scholar

Quirk, G.J., Likhtik, E., Pelletier, J.G., and Pare, D. (2003). Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J. Neurosci. 23, 8800–8807.10.1523/JNEUROSCI.23-25-08800.2003Search in Google Scholar

Racagni, G. and Popoli, M. (2008). Cellular and molecular mechanisms in the long-term action of antidepressants. Dialogues Clin. Neurosci. 10, 385–400.10.31887/DCNS.2008.10.4/gracagniSearch in Google Scholar

Radecki, D.T., Brown, L.M., Martinez, J., and Teyler, T.J. (2005). BDNF protects against stress-induced impairments in spatial learning and memory and LTP. Hippocampus 15, 246–253.10.1002/hipo.20048Search in Google Scholar

Radley, J.J., Rocher, A.B., Janssen, W.G., Hof, P.R., McEwen, B.S., and Morrison, J.H. (2005). Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress. Exp. Neurol. 196, 199–203.10.1016/j.expneurol.2005.07.008Search in Google Scholar

Radley, J.J., Rocher, A.B., Miller, M., Janssen, W.G., Liston, C., Hof, P.R., McEwen, B.S., and Morrison, J.H. (2006). Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb. Cortex 16, 313–320.10.1093/cercor/bhi104Search in Google Scholar

Radley, J.J., Rocher, A.B., Rodriguez, A., Ehlenberger, D.B., Dammann, M., McEwen, B.S., Morrison, J.H., Wearne, S.L., and Hof, P.R. (2008). Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J. Comp. Neurol. 507, 1141–1150.10.1002/cne.21588Search in Google Scholar

Rajkowska, G. (2000). Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol. Psychiatry 48, 766–777.10.1016/S0006-3223(00)00950-1Search in Google Scholar

Rajkowska, G., Miguel-Hidalgo, J.J., Wei, J., Dilley, G., Pittman, S.D., Meltzer, H.Y., Overholser, J.C., Roth, B.L., and Stockmeier, C.A. (1999). Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol. Psychiatry 45, 1085–1098.10.1016/S0006-3223(99)00041-4Search in Google Scholar

Rajkowska, G., Halaris, A., and Selemon, L.D. (2001). Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol. Psychiatry. 49, 741–752.10.1016/S0006-3223(01)01080-0Search in Google Scholar

Ravindran, J., Shuaib, A., Ijaz, S., Galazka, P., Waqar, T., Ishaqzay, R., Miyashita, H., and Liu, L. (1994). High extracellular GABA levels in hippocampus – as a mechanism of neuronal protection in cerebral ischemia in adrenalectomized gerbils. Neurosci. Lett. 176, 209–211.10.1016/0304-3940(94)90084-1Search in Google Scholar

Ren, J., Li, X., Zhang, X., Li, M., Wang, Y., and Ma, Y. (2013). The effects of intra-hippocampal microinfusion of D-cycloserine on fear extinction, and the expression of NMDA receptor subunit NR2B and neurogenesis in the hippocampus in rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 44, 257–264.10.1016/j.pnpbp.2013.02.017Search in Google Scholar

Ressler, K.J. and Mayberg, H.S. (2007). Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat. Neurosci. 10, 1116–1124.10.1038/nn1944Search in Google Scholar

Richardson, M.P., Strange, B.A., and Dolan, R.J. (2004). Encoding of emotional memories depends on amygdala and hippocampus and their interactions. Nat. Neurosci. 7, 278–285.10.1038/nn1190Search in Google Scholar

Rosenberg, P.A. and Aizenman, E. (1989). Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci. Lett. 103, 162–168.10.1016/0304-3940(89)90569-7Search in Google Scholar

Rosenberg, P.A., Amin, S., and Leitner, M. (1992). Glutamate uptake disguises neurotoxic potency of glutamate agonists in cerebral cortex in dissociated cell culture. J. Neurosci. 12, 56–61.10.1523/JNEUROSCI.12-01-00056.1992Search in Google Scholar

Russo, S.J. and Charney, D.S. (2013). Next generation antidepressants. Proc. Natl. Acad. Sci. USA 110, 4441–4442.10.1073/pnas.1301593110Search in Google Scholar PubMed PubMed Central

Sairanen, M., Lucas, G., Ernfors, P., Castren, M., and Castren, E. (2005). Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J. Neurosci. 25, 1089–1094.10.1523/JNEUROSCI.3741-04.2005Search in Google Scholar PubMed PubMed Central

Sanacora, G. (2010). Cortical inhibition, γ-aminobutyric acid, and major depression: there is plenty of smoke but is there fire? Biol. Psychiatry 67, 397–398.10.1016/j.biopsych.2010.01.003Search in Google Scholar PubMed

Sanacora, G. and Saricicek, A. (2007). GABAergic contributions to the pathophysiology of depression and the mechanism of antidepressant action. CNS Neurol. Disord. Drug Targets 6, 127–140.10.2174/187152707780363294Search in Google Scholar PubMed

Sanacora, G., Mason, G.F., Rothman, D.L., Behar, K.L., Hyder, F., Petroff, O.A., Berman, R.M., Charney, D.S., and Krystal, J.H. (1999). Reduced cortical γ-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry 56, 1043–1047.10.1001/archpsyc.56.11.1043Search in Google Scholar

Sanacora, G., Mason, G.F., Rothman, D.L., and Krystal, J.H. (2002). Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am. J. Psychiatry 159, 663–665.10.1176/appi.ajp.159.4.663Search in Google Scholar

Sanacora, G., Gueorguieva, R., Epperson, C.N., Wu, Y.T., Appel, M., Rothman, D.L., Krystal, J.H., and Mason, G.F. (2004). Subtype-specific alterations of γ-aminobutyric acid and glutamate in patients with major depression. Arch. Gen. Psychiatry. 61, 705–713.10.1001/archpsyc.61.7.705Search in Google Scholar

Sanacora, G., Zarate, C.A., Krystal, J.H., and Manji, H.K. (2008). Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat. Rev. Drug Discov. 7, 426–437.10.1038/nrd2462Search in Google Scholar

Sanacora, G., Treccani, G., and Popoli, M. (2012). Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62, 63–77.10.1016/j.neuropharm.2011.07.036Search in Google Scholar

Santarelli, S., Namendorf, C., Anderzhanova, E., Gerlach, T., Bedenk, B., Kaltwasser, S., Wagner, K., Labermaier, C., Reichel, J., Drgonova, J., et al. (2015). The amino acid transporter SLC6A15 is a regulator of hippocampal neurochemistry and behavior. J. Psychiatry Res. 68, 261–269.10.1016/j.jpsychires.2015.07.012Search in Google Scholar

Sapolsky, R.M. (1985). A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults. J. Neurosci. 5, 1227–1231.10.1523/JNEUROSCI.05-05-01228.1985Search in Google Scholar

Sapolsky, R.M. (2000). The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol. Psychiatry 48, 755–765.10.1016/S0006-3223(00)00971-9Search in Google Scholar

Sapolsky, R.M. and Pulsinelli, W.A. (1985). Glucocorticoids potentiate ischemic injury to neurones: therapeutic implications. Science 229, 1397–1399.10.1126/science.4035356Search in Google Scholar PubMed

Schiepers, O.J., Wichers, M.C., and Maes, M. (2005). Cytokines and major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 201–217.10.1016/j.pnpbp.2004.11.003Search in Google Scholar PubMed

Schlett, K. (2006). Glutamate as a modulator of embryonic and adult neurogenesis. Curr. Top. Med. Chem. 6, 949–960.10.2174/156802606777323665Search in Google Scholar

Schuhmacher, A., Lennertz, L., Wagner, M., Höfels, S., Pfeiffer, U., Guttenthaler, V., Maier, W., Zobel, A., and Mössner, R. (2013). A variant of the neuronal amino acid transporter SLC6A15 is associated with ACTH and cortisol responses and cognitive performance in unipolar depression. Int. J. Neuropsychopharmacol. 16, 83–90.10.1017/S1461145712000223Search in Google Scholar

Sha, S., Qu, W.J., Li, L., Lu, Z.H., Chen, L., Yu, W.F., and Chen, L. (2013). σ-1 Receptor knockout impairs neurogenesis in dentate gyrus of adult hippocampus via down-regulation of NMDA receptors. CNS Neurosci. Ther. 19, 705–713.10.1111/cns.12129Search in Google Scholar

Sharma, S., Darland, D., Lei, S., Rakoczy, S., and Brown-Borg, H.M. (2012). NMDA and kainate receptor expression, long-term potentiation, and neurogenesis in the hippocampus of long-lived Ames dwarf mice. Age (Dordr.) 34, 609–620.10.1007/s11357-011-9253-1Search in Google Scholar

Sharon, D., Vorobiov, D., and Dascal, N. (1997). Positive and negative coupling of the metabotropic glutamate receptors to a G protein-activated K+ channel, GIRK, in Xenopus oocytes. J. Gen. Physiol. 109, 477–490.10.1085/jgp.109.4.477Search in Google Scholar

Sheardown, M.J., Nielsen, E.O., Hansen, A.J., Jacobsen, P., and Honore, T. (1990). 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)quinoxaline: a neuroprotectant for cerebral ischemia. Science 247, 571–574.10.1126/science.2154034Search in Google Scholar

Shepherd, J.D. and Huganir, R.L. (2007). The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu. Rev. Cell. Dev. Biol. 23, 613–643.10.1146/annurev.cellbio.23.090506.123516Search in Google Scholar

Skolnick, P. (1999). Antidepressants for the new millennium. Eur. J. Pharmacol. 375, 31–40.10.1016/S0014-2999(99)00330-1Search in Google Scholar

Skolnick, P. (2008). AMPA receptors: a target for novel antidepressants? Biol. Psychiatry 63, 347–348.10.1016/j.biopsych.2007.10.011Search in Google Scholar PubMed

Skolnick, P., Layer, R.T., Popik, P., Nowak, G., Paul, I.A., and Trullas, R. (1996). Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 29, 23–26.10.1055/s-2007-979537Search in Google Scholar PubMed

Skolnick, P., Legutko, B., Li, X., and Bymaster, F.P. (2001). Current perspectives on the development of non-biogenic amine-based antidepressants. Pharmacol. Res. 43, 411–422.10.1006/phrs.2000.0806Search in Google Scholar

Skolnick, P., Popik, P., and Trullas, R. (2009). Glutamate-based antidepressants: 20 years on. Trends Pharmacol. Sci. 30, 563–569.10.1016/ in Google Scholar

Snyder, J.S., Soumier, A., Brewer, M., Pickel, J., and Cameron, H.A. (2011). Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476, 458–461.10.1038/nature10287Search in Google Scholar

Song, H., Kempermann, G., Overstreet, Wadiche L., Zhao, C., Schinder, A.F., and Bischofberger, J. (2005). New neurons in the adult mammalian brain: synaptogenesis and functional integration. J. Neurosci. 25, 10366–10368.10.1523/JNEUROSCI.3452-05.2005Search in Google Scholar

Soriano, F.X., Papadia, S., Hofmann, F., Hardingham, N.R., Bading, H., and Hardingham, G.E. (2006). Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability. J. Neurosci. 26, 4509–4518.10.1523/JNEUROSCI.0455-06.2006Search in Google Scholar

Sousa, N., Cerqueira, J.J., and Almeida, O.F. (2008). Corticosteroid receptors and neuroplasticity. Brain Res. Rev. 57, 561–570.10.1016/j.brainresrev.2007.06.007Search in Google Scholar

Sterner, E.Y. and Kalynchuk, L.E. (2010). Behavioral and neurobiological consequences of prolonged glucocorticoid exposure in rats: relevance to depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 777–790.10.1016/j.pnpbp.2010.03.005Search in Google Scholar

Stone, T.W. and Perkins, M.N. (1981). Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur. J. Pharmacol. 72, 411–412.10.1016/0014-2999(81)90587-2Search in Google Scholar

Streeter, C.C., Hennen, J., Ke, Y., Jensen, J.E., Sarid-Segal, O., Nassar, L.E., Knapp, C., Meyer, A.A., Kwak, T., Renshaw, P.F., et al. (2005). Prefrontal GABA levels in cocaine-dependent subjects increase with pramipexole and venlafaxine treatment. Psychopharmacology 182, 516–526.10.1007/s00213-005-0121-5Search in Google Scholar PubMed

Strom, J.A., Theodorsson, A., and Theodorsson, E. (2011). Hormesis and female sex hormones. Pharmaceuticals (Basel) 4, 726–740.10.3390/ph4050726Search in Google Scholar PubMed PubMed Central

Su, X.W., Li, X.Y., Banasr, M., Koo, J.W., Shahid, M., Henry, B., and Duman, R.S. (2009). Chronic treatment with AMPA receptor potentiator Org 26576 increases neuronal cell proliferation and survival in adult rodent hippocampus. Psychopharmacology (Berl.) 206, 215–222.10.1007/s00213-009-1598-0Search in Google Scholar

Sublette, M.E. and Postolache, T.T. (2012). Neuroinflammation and depression: the role of indoleamine 2,3-dioxygenase (IDO) as a molecular pathway. Psychosom. Med. 74, 668–272.10.1097/PSY.0b013e318268de9fSearch in Google Scholar

Südhof, T.C. (2004). The synaptic vesicle cycle. Annu. Rev. Neurosci. 27, 509–547.10.1146/annurev.neuro.26.041002.131412Search in Google Scholar

Suppiramaniam, V., Bahr, B.A., Sinnarajah, S., Owens, K., Rogers, G., Yilma, S., and Vodyanoy, V. (2001). Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors. Synapse 40, 154–158.10.1002/syn.1037Search in Google Scholar

Swaab, D.F., Bao, A.M., and Lucassen, P.J. (2005). The stress system in the human brain in depression and neurodegeneration. Ageing Res. Rev. 4, 141–194.10.1016/j.arr.2005.03.003Search in Google Scholar

Tanaka, M. and Sokabe, M. (2013). Bidirectional modulatory effect of 17β-estradiol on NMDA receptors via ERα and ERβ in the dentate gyrus of juvenile male rats. Neuropharmacology 75, 262–273.10.1016/j.neuropharm.2013.07.029Search in Google Scholar

Tanapat, P., Galea, L.A., and Gould, E. (1998). Stress inhibits the proliferation of granule cell precursors in the developing dentate gyrus. Int. J. Dev. Neurosci. 16, 235–239.10.1016/S0736-5748(98)00029-XSearch in Google Scholar

Taylor, M.A. and Fink, M. (2008). Restoring melancholia in the classification of mood disorders. J. Affect. Disord. 105, 1–14.10.1016/j.jad.2007.05.023Search in Google Scholar PubMed

Thakker-Varia, S., Behnke, J., Dooin, D., Dlal, V., Thakkar, K., Khadim, F., Wilson, E., Palmieri, A., Antila, H., Rantamaki, T., et al. (2014). VGF (TLQP-62)-induced neurogenesis targets early phase neural progenitor cells in the adult hippocampus and requires glutamate and BDNF signaling. Stem Cell Res. 12, 762–777.10.1016/j.scr.2014.03.005Search in Google Scholar PubMed PubMed Central

Thompson, S.M., Kallarackal, A.J., Kvarta, M.D., Van Dyke, A.M., LeGates, T.A., and Cai, X. (2015). An excitatory synapse hypothesis of depression. Trends Neurosci. 38, 279–294.10.1016/j.tins.2015.03.003Search in Google Scholar PubMed PubMed Central

Tokuda, K., Izumi, Y., and Zorumski, C.F. (2011). Ethanol enhances neurosteroidogenesis in hippocampal pyramidal neurons by paradoxical NMDA receptor activation. J. Neurosci. 31, 9905–9909.10.1523/JNEUROSCI.1660-11.2011Search in Google Scholar

Trullas, R. and Skolnick, P. (1990). Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur. J. Pharmacol. 185, 1–10.10.1016/0014-2999(90)90204-JSearch in Google Scholar

Tuor, U.I. (1997). Glucocorticoids and the prevention of hypoxic-ischemic brain damage. Neurosci Biobehav Rev. 21, 175–179.10.1016/S0149-7634(96)00007-3Search in Google Scholar

Turrin, N.P. and Rivest, S. (2006). Tumor necrosis factor α but not interleukin-1β mediates neuroprotection in response to acute nitric oxide excitotoxicity. J. Neurosci. 26, 143–151.10.1523/JNEUROSCI.4032-05.2006Search in Google Scholar PubMed PubMed Central

Ultanir, S.K., Kim, J.E., Hall, B.J., Deerinck, T., Ellisman, M., and Ghosh, A. (2007). Regulation of spine morphology and spine density by NMDA receptor signaling in vivo. Proc. Natl. Acad. Sci. USA 104, 19553–19558.10.1073/pnas.0704031104Search in Google Scholar PubMed PubMed Central

Underwood, M.D., Kassir, S.A., Bakalian, M.J., Galfalvy, H., Mann, J.J., and Arango, V. (2012). Neuron density and serotonin receptor binding in prefrontal cortex in suicide. Int. J. Neuropsychopharmacol. 15, 435–447.10.1017/S1461145711000691Search in Google Scholar PubMed PubMed Central

Vásquez, C.E., Riener, R., Reynolds, E., and Britton, G.B. (2014). NMDA receptor dysregulation in chronic state: a possible mechanism underlying depression with BDNF downregulation. Neurochem. Int. 79, 88–97.10.1016/j.neuint.2014.09.007Search in Google Scholar PubMed

Vega-Rivera, N.M., Fernández-Guasti, A., Ramírez-Rodríguez, G., and Estrada-Camarena, E. (2014). Forced swim and chronic variable stress reduced hippocampal cell survival in OVX female rats. Behav. Brain Res. 270, 248–255.10.1016/j.bbr.2014.05.033Search in Google Scholar PubMed

Vega-Rivera, N.M., Fernández-Guasti, A., Ramírez-Rodríguez, G., and Estrada-Camarena, E. (2015). Effect of sub-optimal doses of fluoxetine plus estradiol on antidepressant-like behavior and hippocampal neurogenesis in ovariectomized rats. Psychoneuroendocrinology 57, 113–124.10.1016/j.psyneuen.2015.03.022Search in Google Scholar PubMed

Verkhratsky, A., Rodríguez, J.J., and Steardo, L. (2014). Astrogliopathology: a central element of neuropsychiatric diseases? Neuroscientist 20, 576–588.10.1177/1073858413510208Search in Google Scholar PubMed

Voss, O.P., Milne, S., Sharkey, J., O’Neill, M.J., and McCulloch, J. (2007). Molecular mechanisms of neurite growth with AMPA receptor potentiation. Neuropharmacology 52, 590–597.10.1016/j.neuropharm.2006.09.001Search in Google Scholar

Vyas, A., Bernal, S., and Chattarji, S. (2003). Effects of chronic stress on dendritic arborization in the central and extended amygdala. Brain Res. 965, 290–294.10.1016/S0006-8993(02)04162-8Search in Google Scholar

Wang, J.L. (2005). Work stress as a risk factor for major depressive episode(s). Psychol. Med. 35, 865–871.10.1017/S0033291704003241Search in Google Scholar

Wang, Y., Huang, Y., Zhao, L., Li, Y., and Zheng, J. (2014). Glutaminase 1 is essential for the differentiation, proliferation, and survival of human neural progenitor cells. Stem Cells Dev. 23, 2782–2790.10.1089/scd.2014.0022Search in Google Scholar

Wąsik, A., Kajta, M., Lenda, T., and Antkiewicz-Michaluk, L. (2014). Concentration-dependent opposite effects of 1-benzyl-1,2,3,4-tetrahydroisoquinoline on markers of apoptosis: in vitro and ex vivo studies. Neurotoxicol. Res. 25, 90–99.10.1007/s12640-013-9436-xSearch in Google Scholar

Watanabe, Y., Gould, E., and McEwen, B.S. (1992). Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 588, 341–345.10.1016/0006-8993(92)91597-8Search in Google Scholar

Watkins, J.C. (2000). L-glutamate as a central neurotransmitter: looking back. Biochem. Soc. Trans. 28, 297–309.10.1042/bst0280297Search in Google Scholar

Webster, M.J., Knable, M.B., Johnston-Wilson, N., Nagata, K., Inagaki, M., and Yolken, R.H. (2001). Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. Brain Behav. Immun. 15, 388–400.10.1006/brbi.2001.0646Search in Google Scholar

Wedzony, K., Mackowiak, M., Czyrak, A., Fijal, K., and Michalska, B. (1997). Single doses of MK-801, a non-competitive antagonist of NMDA receptors, increase the number of 5-HT1A serotonin receptors in the rat brain. Brain Res. 756, 84–91.10.1016/S0006-8993(97)00159-5Search in Google Scholar

Wei, T., Chen, C., Hou, J., Xin, W., and Mori, A. (2000). Nitric oxide induces oxidative stress and apoptosis in neuronal cells. Biochim. Biophys. Acta 1498, 72–79.10.1016/S0167-4889(00)00078-1Search in Google Scholar

Weizman, A., Weizman, R., Kook, K.A., Vocci, F., Deutsch, S.I., and Paul, S.M. (1990). Adrenalectomy prevents the stress-induced decrease in in vivo [3H]Ro15-1788 binding to GABAA benzodiazepine receptors in the mouse. Brain Res. 519, 347–350.10.1016/0006-8993(90)90100-PSearch in Google Scholar

Whitney, N.P., Peng, H., Erdmann, N.B., Tian, C., Monaghan, D.T., and Zheng, J.C. (2008). Calcium-permeable AMPA receptors containing Q/R-unedited GluR2 direct human neural progenitor cell differentiation to neurons. FASEB J. 22, 2888–2900.10.1096/fj.07-104661Search in Google Scholar

Wierońska, J.M., Legutko, B., Dudys, D., and Pilc, A. (2008). Olfactory bulbectomy and amitriptyline treatment influences mGlu receptors expression in the mouse brain hippocampus. Pharmacol. Rep. 60, 844–855.Search in Google Scholar

Wierońska, J.M., Stachowicz, K., Nowak, G., and Pilc, A. (2011). The loss of glutamate-GABA harmony in anxiety disorders. In: Anxiety Disorders, Prof. Vladimir Kalinin, ed. (InTech), ISBN: 978-953-307-592-1, DOI: 10.5772/19919.10.5772/19919Search in Google Scholar

Willner, P. (2005). Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52, 90–110.10.1159/000087097Search in Google Scholar

Wilson, M.A. and Biscardi, R. (1994). Sex differences in GABA/benzodiazepine receptor changes and corticosterone release after acute stress in rats. Exp. Brain Res. 101, 97–306.10.1007/BF00228750Search in Google Scholar

Wingenfeld, K., Schulz, M., Damkroeger, A., Rose, M., and Driessen, M. (2009). Elevated diurnal salivary cortisol in nurses is associated with burnout but not with vital exhaustion. Psychoneuroendocrinology 34, 1144–1151.10.1016/j.psyneuen.2009.02.015Search in Google Scholar

Wong, E.Y. and Herbert, J. (2005). Roles of mineralocorticoid and glucocorticoid receptors in the regulation of progenitor proliferation in the adult hippocampus. Eur. J. Neurosci. 22, 785–792.10.1111/j.1460-9568.2005.04277.xSearch in Google Scholar

Woolley, C.S., Gould, E., and McEwen, B.S. (1990). Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 531, 225–231.10.1016/0006-8993(90)90778-ASearch in Google Scholar

Wu, X. and Castrén, E. (2009). Co-treatment with diazepam prevents the effects of fluoxetine on the proliferation and survival of hippocampal dentate granule cells. Biol. Psychiatry 66, 5–8.10.1016/j.biopsych.2009.01.023Search in Google Scholar PubMed

Xiao, X.L., Ma, D.L., Wu, J., and Tang, F.R. (2013). Metabotropic glutamate receptor 5 (mGluR5) regulates proliferation and differentiation of neuronal progenitors in the developmental hippocampus. Brain Res. 1493, 1–12.10.1016/j.brainres.2012.11.015Search in Google Scholar PubMed

Xu, H., Chen, Z., He, J., Haimanot, S., Li, X., Dyck, L., and Li, X.M. (2006). Synergetic effects of quetiapine and venlafaxine in preventing the chronic restraint stress-induced decrease in cell proliferation and BDNF expression in rat hippocampus. Hippocampus 16, 551–559.10.1002/hipo.20184Search in Google Scholar

Yamamoto, B. and Reagan, L.P. (2006). The glutamatergic system in neuronal plasticity and vulnerability in mood disorders. Neuropsychol. Dis. Treat. 2, 7–14.Search in Google Scholar

Ye, Y., Wang, G., Wang, H., and Wang, X. (2011). Brain-derived neurotrophic factor (BDNF) infusion restored astrocytic plasticity in the hippocampus of a rat model of depression. Neurosci. Lett. 503, 15–19.10.1016/j.neulet.2011.07.055Search in Google Scholar

Yilmaz, A., Schulz, D., Aksoy, A., and Canbeyli, R. (2002). Prolonged effect of an anesthetic dose of ketamine on behavioral despair. Pharmacol. Biochem. Behav. 71, 341–334.10.1016/S0091-3057(01)00693-1Search in Google Scholar

Yoshimizu, T. and Chaki, S. (2004). Increased cell proliferation in the adult mouse hippocampus following chronic administration of group II metabotropic glutamate receptor antagonist, MGS0039. Biochem. Biophys. Res. Commun. 315, 493–496.10.1016/j.bbrc.2004.01.073Search in Google Scholar PubMed

Yuen, E.Y., Wei, J., Liu, W., Zhong, P., Li, X., and Yan, Z. (2012). Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron 73, 962–977.10.1016/j.neuron.2011.12.033Search in Google Scholar PubMed PubMed Central

Zarate, C.A. Jr. and Manji, H.K. (2008). The role of AMPA receptor modulation in the treatment of neuropsychiatric diseases. Exp. Neurol. 211, 7–10.10.1016/j.expneurol.2008.01.011Search in Google Scholar PubMed PubMed Central

Zarate, C.A., Quiroz, J., Payne, J., and Manji, H.K. (2002). Modulators of the glutamatergic system: implications for the development of improved therapeutics in mood disorders. Psychopharmacol. Bull. 36, 35–83.Search in Google Scholar

Zarate, C.A. Jr., Singh, J.B., Carlson, P.J., Brutsche, N.E., Ameli, R., Luckenbaugh, D.A., Charney, D.S., and Manji, H.K. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856–864.10.1001/archpsyc.63.8.856Search in Google Scholar PubMed

Zhang, Y.M., Lu, X.F., and Bhavnani, B.R. (2003). Equine estrogens differentially inhibit DNA fragmentation induced by glutamate in neuronal cells by modulation of regulatory proteins involved in programmed cell death. BMC Neurosci. 4, 32.10.1186/1471-2202-4-32Search in Google Scholar PubMed PubMed Central

Zhang, R., Peng, Z., Wang, H., Xue, F., Chen, Y., Wang, Y., Wang, H., and Tan, Q. (2014). Gastrodin ameliorates depressive-like behaviors and up-regulates the expression of BDNF in the hippocampus and hippocampal-derived astrocyte of rats. Neurochem. Res. 39, 172–179.10.1007/s11064-013-1203-0Search in Google Scholar PubMed

Zhang, Z., Ma, W., Wang, L., Gong, H., Tian, Y., Zhang, J., Liu, J., Lu, H., Chen, X., and Liu, Y. (2015). Activation of type 4 metabotropic glutamate receptor attenuates oxidative stress-induced death of neural stem cells with inhibition of JNK and p38 MAPK signaling. Stem Cells Dev. 24, 2709–2722.10.1089/scd.2015.0067Search in Google Scholar PubMed PubMed Central

Zhou, J.Z., Zhang, Y.X., and Zhou, J.H. (1999). Neurotoxic effect of corticosterone on primary cultured hippocampal neurons and its relationship with excitatory amino acids. Chin. J. Pharmacol. Toxicol. 13, 161–167.Search in Google Scholar

Zhou, J., Zhang, F., and Zhang, Y. (2000). Corticosterone inhibits generation of long-term potentiation in rat hippocampal slice: involvement of brain-derived neurotrophic factor. Brain Res. 885, 182–191.10.1016/S0006-8993(00)02934-6Search in Google Scholar

Zimmer, E.R., Torrez, V.R., Kalinine, E., Augustin, M.C., Zenki, K.C., Almeida, R.F., Hansel, G., Muller, A.P., Souza, D.O., Machado-Vieira, R., et al. (2015). Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with anxiety-like phenotype. Front. Cell Neurosci. 9, 219.10.3389/fncel.2015.00219Search in Google Scholar PubMed PubMed Central

Zorumski, C.F., Paul, S.M., Izumi, Y., Covey, D.F., and Mennerick, S. (2013). Neurosteroids, stress and depression: potential therapeutic opportunities. Neurosci. Biobehav. Rev. 37, 109–122.10.1016/j.neubiorev.2012.10.005Search in Google Scholar PubMed PubMed Central

Received: 2015-12-2
Accepted: 2016-3-4
Published Online: 2016-4-20
Published in Print: 2016-8-1

©2016 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 4.3.2024 from
Scroll to top button