Skip to main content

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

  • Original Research Article
  • Published:

Antidepressant mechanisms: functional and molecular correlates of excitatory amino acid neurotransmission

Molecular Psychiatry volume 7, pages S15–S22 (2002)Cite this article

Abstract

Specific targeting of the serotonergic and noradrenergic systems for the development of antidepressant compounds has resulted in drugs with more favourable side-effect profiles but essentially no greater efficacy than those compounds discovered more than 40 years ago. Alternative targets are now being considered in the hope that they will have a faster onset of action and be useful for those patients currently unresponsive to conventional treatments. Excitatory amino acid neurotransmission has been attributed various roles in both normal and abnormal brain function. The N-methyl-D-aspartate receptor in particular has long been postulated to play a role in the formation of memories. Major depressive disorder is characterised by alterations in cognitive function, as well as affect. Although there is evidence that early adverse events and stress can have a causal influence on depression, the underlying neurobiology of the disorder is poorly understood. This review will document current evidence for the involvement of excitatory amino acid neurotransmission in the pathophysiology of the affective disorders. The preclinical literature suggests that both electroconvulsive stimulation and antidepressant drugs can affect hippocampal long-term potentiation and the expression of excitatory amino acid receptor subtypes. Exposing animals to stress, including the kind that produces learned helplessness, can also affect synaptic plasticity in the hippocampus. There is clinical evidence that patients with chronic depression have structural brain abnormalities, including hippocampal atrophy, and a preliminary study has shown that an N-methyl-D-aspartate receptor antagonist may have antidepressant efficacy.

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

Access options

Buy this article

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

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

Similar content being viewed by others

References

  1. Drevets WC, Price JL, Simpson JR et al. Subgenual prefrontal cortex abnormalities in mood disorders Nature 1997 386: 824–827

    Article  CAS  PubMed  Google Scholar 

  2. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW . Hippocampal atrophy in recurrent major depression Proc Natl Acad Sci U S A 1996 93: 3908–3913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shah PJ, Ebmeier KP, Glabus MF et al. Cortical grey matter reductions associated with treatment-resistant chronic unipolar depression. Controlled magnetic resonance imaging study Br J Psychiatry 1998 172: 527–532

    Article  CAS  PubMed  Google Scholar 

  4. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HI, Charney DS . Hippocampal volume reduction in major depression Am J Psychiatry 2000 157: 115–117

    Article  CAS  PubMed  Google Scholar 

  5. Benes FM, Kwok EW, Vincent SL, Todtenkopf MS . A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives Biol Psychiatry 1998 44: 88–97

    Article  CAS  PubMed  Google Scholar 

  6. Bliss TVP, Lomo T . Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetised rabbit following stimulation of the perforant path J Physiol 1973 232: 331–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Beck H, Goussakov IV, Lie A, Helmstaedter C, Elger CE . Synaptic plasticity in the human dentate gyrus J Neurosci 2000 20: 7080–7086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Collingridge GL, Kehl SJ, McLennan H . Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus J Physiol 1983 34: 33–46

    Article  Google Scholar 

  9. Bliss TVP, Collingridge GL . A synaptic model of memory: long-term potentiation in the hippocampus Nature 1993 361: 31–39

    Article  CAS  PubMed  Google Scholar 

  10. Maren S, Baudry M . Properties and mechanisms of long-term synaptic plasticity in the mammalian brain: relationships to learning and memory Neurobiol Learn Mem 1995 63: 1–18

    Article  CAS  PubMed  Google Scholar 

  11. Weeks D, Freeman CPL, Kendell RE . ECT: III: enduring cognitive deficits Br J Psychiatry 1980 137: 26–37

    Article  CAS  PubMed  Google Scholar 

  12. Lerer B, Stanley M, Keegam M, Altman H . Proactive and retroactive effects of repeated electroconvulsive shock on passive avoidance retention in rats Physiol Behav 1986 36: 471–475

    Article  CAS  PubMed  Google Scholar 

  13. Hesse GW, Teyler TJ . Reversible loss of hippocampal long-term potentiation following electroconvulsive seizures Nature 1975 264: 562–564

    Article  Google Scholar 

  14. Anwyl R, Walshe J, Rowan M . Electroconvulsive treatment reduces long-term potentiation in rat hippocampus Brain Res 1987 435: 377–379

    Article  CAS  PubMed  Google Scholar 

  15. Stewart C, Reid I . Electroconvulsive stimulation and synaptic plasticity Brain Res 1993 620: 139–141

    Article  CAS  PubMed  Google Scholar 

  16. Stewart C, Jeffery K, Reid I . LTP-like synaptic efficacy changes following electroconvulsive stimulation Neuroreport 1994 5: 1041–1044

    Article  CAS  PubMed  Google Scholar 

  17. Burnham WM, Cottrell GA, Diosy D, Racine RJ . Long-term changes in entorhinal-dentate evoked potentials induced by electroconvulsive shock seizures in rats Brain Res 1995 698: 180–184

    Article  CAS  PubMed  Google Scholar 

  18. Morris RGM, Anderson E, Lynch GS, Baudry M . Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5 Nature 1986 319: 774–776

    Article  CAS  PubMed  Google Scholar 

  19. Stewart CA, Reid IC . Ketamine prevents ECS-induced synaptic enhancement in the rat hippocampus Neurosci Lett 1994 178: 11–14

    Article  CAS  PubMed  Google Scholar 

  20. Gombos Z, Mendonça A, Cottrell GA et al. Ketamine and phenobarbital do not reduce the evoked-potential enhancement induced by electroconvulsive shock seizures in the rat Neurosci Lett 1999 275: 33–36

    Article  CAS  PubMed  Google Scholar 

  21. Lomo T . Patterns of activation in a monosynaptic cortical pathway: the perforant path input to the dentate area of the hippocampal formation Exp Brain Res 1971 12: 18–45

    CAS  PubMed  Google Scholar 

  22. Abraham WC, Goddard GV . Multiple traces of neuronal activity in the hippocampus In: Weinberger NM, McGaugh JL, Lynch G (eds) Memory Systems of the Brain Guilford: New York 1985 pp 62–76

    Google Scholar 

  23. Lynch G, Larson J, Kelso S, Barrionuevo G, Schottler F . Intracellular injections of EGTA block induction of hippocampal long-term potentiation Nature 1983 305: 719–721

    Article  CAS  PubMed  Google Scholar 

  24. Kauer JA, Malenka RC, Nicoll RA . A persistent postsynaptic modification mediates long-term potentiation in the hippocampus Neuron 1988 1: 911–917

    Article  CAS  PubMed  Google Scholar 

  25. Muller D, Lynch G . Long-term potentiation differentially affects two components of synaptic responses in hippocampus Proc Natl Acad Sci USA 1988 85: 9346–9350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Davies SN, Lester RA, Reymann KG et al. Temporally distinct pre- and post-synaptic mechanisms maintain long-term potentiation Nature 1989 338: 500–503

    Article  CAS  PubMed  Google Scholar 

  27. Tocco G, Maren S, Shors TJ, Baudry M, Thompson RF . Long-term potentiation is associated with increased [3H] AMPA binding in the rat hippocampus Brain Res 1992 573: 228–234

    Article  CAS  PubMed  Google Scholar 

  28. Naylor P, Stewart CA, Wright SR, Pearson C, Reid IC . Repeated ECS induces GluR1 mRNA but not NMDAR1A-G mRNA in the rat hippocampus Mol Brain Res 1996 35: 349–353

    Article  CAS  PubMed  Google Scholar 

  29. Wong ML, Smith MA, Licinio J et al. Differential effects of kindled and electrically induced seizures on a glutamate receptor (GluR1) gene expression Epilepsy Res 1993 14: 221–227

    Article  CAS  PubMed  Google Scholar 

  30. Reti IM, Baraban JM . Sustained increase in Narp protein expression following repeated electroconvulsive seizure Neuropsychopharmacology 2000 34: 439–443

    Article  Google Scholar 

  31. Watkins CJ, Pei Q, Newberry NR . Differential effects of electroconvulsive shock on the glutamate receptor mRNAs for NR2A, NR2B and mGluR5b Mol Brain Res 1998 61: 108–113

    Article  CAS  PubMed  Google Scholar 

  32. Sakimura K, Kutsuwada T, Ito I et al. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor-1 subunit Nature 1995 373: 151–155

    Article  CAS  PubMed  Google Scholar 

  33. Paul IA, Nowak G, Layer RT, Popik P, Skolnick P . Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments J Pharmacol Exp Ther 1994 269: 95–102

    CAS  PubMed  Google Scholar 

  34. Skolnick P . Antidepressants for the new millennium Eur J Pharmacol 1999 375: 31–40

    Article  CAS  PubMed  Google Scholar 

  35. Qian Z, Gilbert ME, Colicos MA, Kandel ER, Kuhl D . Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation Nature 1993 361: 453–457

    Article  CAS  PubMed  Google Scholar 

  36. Nibuya M, Nestler EJ, Duman RS . Chronic antidepressant administration increases the expression of cAMP Response Element Binding Protein (CREB) in rat hippocampus J Neurosci 1996 16: 2365–2372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nibuya M, Morinobu S, Duman RS . Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments J Neurosci 1995 15: 7539–7547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B . Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus Nature 1996 381: 706–709

    Article  CAS  PubMed  Google Scholar 

  39. Levine ES, Crozier RA, Black IB, Plummer MR . Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-D-aspartic acid receptor activity Proc Natl Acad Sci U S A 1998 95: 10235–10239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. O'Connor JJ, Rowan MJ, Anwyl R . Use-dependent effects of acute and chronic treatment with imipramine and buspirone on excitatory synaptic transmission in the rat hippocampus Naunyn-Schmiedeberg's Arch Pharmacol 1993 348: 158–163

    Article  CAS  Google Scholar 

  41. Massicotte G, Bernard J, Ohayon M . Chronic effects of trimipramine, an antidepressant, on hippocampal synaptic plasticity Behav Neural Biol 1993 59: 100–106

    Article  CAS  PubMed  Google Scholar 

  42. Millet Y, Ohayon M, Caulet M, Hugon N, Blanc F, Vial M . REM-sleep and learning processing: effects of antidepressants Excerpta Medica ICS 1989 899: 275

    Google Scholar 

  43. Kubota T, Jibiki I, Fukushima T, Kurokawa K, Yamaguchi N . Carbamazepine-induced blockade of induction of long-term potentiation in the perforant path-dentate gyrus pathway in chronically prepared rabbits Neurosci Lett 1994 170: 171–174

    Article  CAS  PubMed  Google Scholar 

  44. Richardson JS, Keegan DL, Bowen RC et al. Verbal learning by major depressive disorder patients during treatment with fluoxetine or amitriptyline Int Clin Psychopharmacol 1994 9: 35–40

    Article  CAS  PubMed  Google Scholar 

  45. Stewart CA, Reid IC . Repeated ECS and fluoxetine administration have equivalent effects on hippocampal synaptic plasticity Psychopharmacology 2000 148: 217–223

    Article  CAS  PubMed  Google Scholar 

  46. Abas MA, Sahakian BJ, Levy R . Neuropsychological deficits and CT scan changes in elderly depressives Psychol Med 1990 20: 507–520

    Article  CAS  PubMed  Google Scholar 

  47. Petrie RXA, Reid IC, Stewart CA . The NMDA receptor, synaptic plasticity and depressive disorder: a critical review Pharmacol Ther 2000 87: 11–25

    Article  CAS  PubMed  Google Scholar 

  48. Bernard J, Ohayon M, Massicotte G . Modulation of the AMPA receptor by phospholipase A2: effect of the antidepressant trimipramine Psychiatry Res 1994 51: 107–114

    Article  CAS  PubMed  Google Scholar 

  49. Kitamura Y, Zhao XH, Tekei M, Yonemitsu O, Nomura Y . Effects of antidepressants on the glutamatergic system in the mouse brain Neurochem Int 1991 19: 247–253

    Article  CAS  Google Scholar 

  50. Michael-Titus AT, Bains S, Jeetle J, Whelpton R . Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex_a possible mechanism of neuroprotection in major depression? Neuroscience 2000 100: 681–684

    Article  CAS  PubMed  Google Scholar 

  51. Oretti RG, Spurlock G, Buckland PR, McGuffin P . Lack of effect of antipsychotic and antidepressant drugs on glutamate receptor mRNA levels in rat brain Neurosci Lett 1994 177: 39–43

    Article  CAS  PubMed  Google Scholar 

  52. Boyer PA, Skolnick P, Fossom LH . Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNAs in mouse brain. A quantitative in situ hybridisation study J Mol Neurosci 1998 10: 219–233

    Article  CAS  PubMed  Google Scholar 

  53. Duman RS . Novel therapeutic approaches beyond the serotonin receptor Biol Psychiatry 1998 44: 324–335

    Article  CAS  PubMed  Google Scholar 

  54. Kendler KS, Karkowski LM, Prescott CA . Causal relationship between stressful life events and the onset of major depression Am J Psychiatry 1999 156: 837–841

    Article  CAS  PubMed  Google Scholar 

  55. Shors TJ, Seib TB, Levine S, Thompson RF . Inescapable versus escapable shock modulates long-term potentiation in the rat hippocampus Science 1989 244: 224–226

    Article  CAS  PubMed  Google Scholar 

  56. Staubli U, Scafidi J . Studies on long-term depression in area CA1 of the anaesthetised and freely moving rat J Neurosci 1997 17: 4820–4828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Foy MR, Stanton ME, Levine S, Thompson RF . Behavioral stress impairs long-term potentiation in rodent hippocampus Behav Neurol Biol 1987 48: 138–149

    Article  CAS  Google Scholar 

  58. Diamond DM, Bennett MC, Stevens KE, Wilson RL, Rose GM . Exposure to a novel environment interferes with the induction of hippocampal primed burst potentiation in the behaving rat Psychobiology 1990 18: 273–281

    Article  Google Scholar 

  59. Shors TJ, Thompson RF . Stress impairs synaptic LTP but does not affect paired-pulse facilitation in the stratum radiatum of the rat hippocampus Synapse 1992 11: 262–265

    Article  CAS  PubMed  Google Scholar 

  60. Diamond DM, Fleshner M, Rose GM . Psychological stress repeatedly blocks hippocampal primed burst potentiation in behaving rats Behav Brain Res 1994 62: 1–9

    Article  CAS  PubMed  Google Scholar 

  61. Kim JJ, Foy MR, Thompson RF . Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate receptor activation Proc Natl Acad Sci U S A 1996 93: 4750–4753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Xu L, Holscher C, Anwyl R et al. Glucocorticoid receptor and protein/RNA synthesis dependent mechanisms underlie the control of synaptic plasticity by stress Proc Natl Acad Sci U S A 1998 95: 3204–3208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Shors TJ, Dryver E . Effect of stress and LTP on subsequent LTP and the theta burst response in the dentate gyrus Brain Res 1994 666: 232–238

    Article  CAS  PubMed  Google Scholar 

  64. Bramham CR, Southard T, Ahlers ST, Sarvey JM . Acute cold stress leading to elevated corticosterone neither enhances synaptic efficacy nor impairs LTP in the dentate gyrus of freely moving rats Brain Res 1998 789: 245–255

    Article  CAS  PubMed  Google Scholar 

  65. Henke PG . Granule cell potentials in the dentate gyrus of the hippocampus: coping behaviour and stress ulcers in rats Behav Brain Res 1990 36: 97–103

    Article  CAS  PubMed  Google Scholar 

  66. Wilson DA, Willner J, Kurz EM, Nadel L . Early handling increases hippocampal long-term potentiation in young rats Behav Brain Res 1986 21: 223–227

    Article  CAS  PubMed  Google Scholar 

  67. Kehoe P, Hoffman JH, Austin-La France RJ, Bronzino JD . Neonatal isolation enhances dentate response to tetanisation in freely moving juvenile male rats Exp Neurol 1995 136: 89–97

    Article  CAS  PubMed  Google Scholar 

  68. Bronzino JD, Kehoe P, Austin-LaFrance RJ, Rushmore RJ, Kurdian J . Neonatal isolation alters LTP in freely moving juvenile rats: sex differences Brain Res Bull 1996 41: 175–183

    Article  CAS  PubMed  Google Scholar 

  69. Statham A, Petrie RXA, Balfour DJK, Reid IC, Stewart CA . The effects of both early life experience and repeated stress in adulthood on rat hippocampal evoked responses J Psychopharmacol 1999 13 (Suppl A): A56

    Google Scholar 

  70. Tocco G, Shors TJ, Baudry M, Thompson RF . Selective increase of AMPA binding to AMPA/quisqualate receptors in the hippocampus in response to acute stress Brain Res 1991 559: 168–171

    Article  CAS  PubMed  Google Scholar 

  71. Abraham WC, Bear MF . Metaplasticity: the plasticity of synaptic plasticity Trends Neurosci 1996 19: 126–130

    Article  CAS  PubMed  Google Scholar 

  72. Kim JJ, Yoon KS . Stress: metaplastic effects in the hippocampus Trends Neurosci 1998 21: 505–509

    Article  CAS  PubMed  Google Scholar 

  73. Maren S, Tocco G, Chavanne F, Baudry M, Thompson RF, Mitchell D . Emergence neophobia correlates with hippocampal and cortical glutamate receptor binding in rats Behav Neurol Biol 1994 62: 68–72

    Article  CAS  Google Scholar 

  74. Maren S, Patel K, Thompson RF, Mitchell D . Individual difference in emergence neophobia predict magnitude of perforant-path long-term potentiation (LTP) and plasma corticosterone in rats Psychobiology 1993 21: 2–10

    Article  Google Scholar 

  75. Pavlides C, Kimura A, Magarinos AM et al. Opposing roles of type I and type II adrenal steroid receptors in hippocampal long-term potentiation Neuroscience 1995 68: 387–394

    Article  CAS  PubMed  Google Scholar 

  76. Zhou J, Zhang F, Zhang Y . Corticosterone inhibits generation of long-term potentiation in rat hippocampal slice: involvement of brain-derived neurotrophic factor Brain Res 2000 885: 182–191

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  78. Maj J, Rogoz Z, Skuza G, Sowinska H . Effects of MK-801 and antidepressant drugs in the forced swimming test in rats Eur J Neuropsychopharmacol 1992 2: 37–41

    Article  CAS  Google Scholar 

  79. Przegalinski E, Tatarczynska E, Deren-Wesolek A, Chojnacka-Wojcik E . Antidepressant-like effects of a partial agonist atstrychnine-insensitive glycine receptor and a competitive NMDA receptor antagonist Neuropharmacology 1997 36: 31–37

    Article  CAS  PubMed  Google Scholar 

  80. Meloni D, Gambarana C, De Montis MG, Dal Pra P, Taddei I . Tagliamonte A. Dizocilpine antagonizes the effect of chronic imipramine on learned helplessness in rats Pharmacol Biochem Behav 1993 46: 423–426

    Article  CAS  PubMed  Google Scholar 

  81. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al. Antidepressant effects of ketamine in depressed patients Biol Psychiatry 2000 47: 351–354

    Article  CAS  PubMed  Google Scholar 

  82. Henke PG . Synaptic efficacy in the entorhinal-dentate pathway and stress ulcers in rats Neurosci Lett 1989 107: 110–113

    Article  CAS  PubMed  Google Scholar 

  83. Rowan MJ, Shakesby AC, Anwyl R . The 5-HT uptake enhances tianeptine reverses stress-induced block of long-term potentiation in the anaesthetised rat hippocampus Eur J Neurosci 2000 12 (Suppl 11): 388

    Google Scholar 

  84. Smith MA, Makino S, Kvetnansky R et al. Stress alters the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus J Neurosci 1995 15: 1768–1777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Dundee, Ninewells Hospital & Medical School, Dundee, DD1 9SY, UK

    C A Stewart & I C Reid

Authors
  1. C A Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I C Reid
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C A Stewart.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stewart, C., Reid, I. Antidepressant mechanisms: functional and molecular correlates of excitatory amino acid neurotransmission. Mol Psychiatry 7 (Suppl 1), S15–S22 (2002). https://doi.org/10.1038/sj.mp.4001014

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001014

Keywords

This article is cited by

Search

Advanced search

Quick links