Skip to main content
SpringerLink
Log in

Glutamatergic Modulators for the Treatment of Major Depressive Disorder: Metabotropic Glutamate Receptors

  • Chapter
  • First Online:
Glutamate-based Therapies for Psychiatric Disorders

Part of the book series: Milestones in Drug Therapy ((MDT))

  • 697 Accesses

Abstract

The majority of antidepressants facilitate monoamine neurotransmission within the central nervous system as their initial neurochemical processing event. These medicines do not fully serve patient needs in terms of response or remission, and suffer from some compliance issues. Among the various approaches that are being taken to discover improved therapeutics for major depressive disorders has been the targeting of the metabotropic glutamate receptors. Three major classes of mGlu receptors with a total of eight subtypes (mGlu1–8) have been considered. The bulk of data at present provides compelling evidence that mGlu5 and mGlu2/3 receptors are principal protein targets for drug discovery. These mGlu receptors have localization within primary mood circuits and are modulated by antidepressant treatment. Moreover, pharmacological blockade of mGlu5 (with MPEP, MTEP) or mGlu2/3 (with LY341495, MGS0039) receptors is associated with antidepressant-like biochemical and neurochemical changes in the mammalian brain. Small molecules that target these sites have been identified that display corresponding antidepressant-like behavioral effects. Agonist actions at mGlu2/3 receptors, demonstrated to possess anxiolytic activity in humans, might also be capable of impacting the progression of disease symptoms. Importantly, modulation of the mGlu5 and mGlu2/3 receptors impact ionotropic glutamate receptor signaling (NMDA, AMPA) that independently has been associated with mood disorders. The lack of biochemical and behavioral evidence linking other mGlu receptors to mood disorders is generally due to the absence of an appropriate arsenal of tools (e.g., selective, systemically-available compounds). However, there are data suggesting that mGlu1, mGlu7, and mGlu8 receptors might also play important roles in controlling mood. In contrast, mGlu6 receptors, with localization principally confined to retinal cells, are not likely candidate proteins. The patent and scientific literature suggests that the evaluation of these hypotheses in the clinic might be possible in the near future. With these awaited studies is the hope for new medicines for the devastating and life-threatening diseases of mood that affect large segments of the world community.

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

Access this chapter

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

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ACPD:

1-aminocyclopentane-trans-1,3R-dicarboxylic acid

ACPT-I:

(1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid

AMN082:

N,N′-dibenzyhydryl-ethane-1,2-diamine dihydrochloride

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BDNF:

Brain-derived neurotrophic factor

cAMP:

Adenosine 3′,5′-cyclic monophosphate

CNS:

Central nervous system

CPPG:

(RS)-alpha-cyclopropyl-4-phosphonophenyl glycine

DCG-IV:

((2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine)

ECT:

Electroconvulsive treatment

EMQMCM:

(3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate

FST:

Forced swim test

L-CCG-I:

(2S,1'S,2'S)-2-(carboxycyclopropyl)glycine

LY341495:

9H-xanthene-9-propanoic acid, α-amino-α-[(1S,2S)-2- carboxycyclopropyl]-(αS)-(9CI)

mGlu:

Metabotropic glutamate

MPEP:

2-methyl-6-(phenylethynyl)pyridine

MSG0039:

2-amino-3-[(3,4-dichlorophenyl)methoxy]-6-fluoro-(1R,2R,3R,5R,6R)-(9CI)

MTEP:

3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine

NBQX:

2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline

NMDA:

N-methyl-D-aspartate

PHCCC:

N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1acarboxamide

(R,S)-PPG:

(RS)-4-phosphonophenylglycine

SSRI:

Selective serotonin reuptake inhibitors

TST:

Tail suspension test

References

  1. Witkin JM, Li X (2009) New approaches to the management of major depressive disorder. In: Enna SJ, Williams M (eds) Contemporary aspects of biomedical research: biomedical issues. Advances in pharmacology, vol 57. Academic, New York, pp 347–379

    Chapter  Google Scholar 

  2. Price JL, Drevets WC (2010) Neurocircuitry of mood disorders. Neuropsychopharmacology 35:192–216

    Article  PubMed  Google Scholar 

  3. Hashimoto K (2009) Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev 61:105–123

    Article  PubMed  CAS  Google Scholar 

  4. Schoepp DD, Skolnick P (2010) Introduction. In: Skolnick P (ed) Glutamate-based therapies for psychiatric disorders. Springer, Basel

    Google Scholar 

  5. Skolnick P, Popik P, Trullas R (2010) N-Methyl-d-Aspartate (NMDA) antagonists for the treatment of depression. In: Skolnick P (ed) Glutamate-based therapies for psychiatric disorders. Springer, Basel

    Chapter  Google Scholar 

  6. Alt A, Nisenbaum ES, Bleakman D, Witkin JM (2006) A role for AMPA receptors in mood disorders. Biochem Pharmacol 71:1273–1288

    Article  PubMed  CAS  Google Scholar 

  7. Nisenbaum E, Witkin JM (2010) Positive allosteric modulation of AMPA receptors: a novel potential antidepressant therapy. In: Skolnick P (ed) Glutamate-based therapies for psychiatric disorders. Springer, Basel

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  9. Pilc A, Chaki S, Nowak G, Witkin JM (2008) Mood disorders: regulation by metabotropic glutamate receptors. Biochem Pharmacol 75:997–1006

    Article  PubMed  CAS  Google Scholar 

  10. Szabo ST, Machado-Vieira R, Yuan P, Wang Y, Wei Y, Falke C, Cirelli C, Tononi G, Manji HK, Du J (2009) Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania. Neuropharmacology 56:47–55

    Article  PubMed  CAS  Google Scholar 

  11. Valentine GW, Sanacora G (2009) Targeting glial physiology and glutamate cycling in the treatment of depression. Biochem Pharmacol 78:431–439

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Witkin JM, Eiler WJA (2006) Antagonism of metabotropic glutamate group II receptors in the potential treatment of neurological and neuropsychiatric disorders. Drug Dev Res 67:757–769

    Article  CAS  Google Scholar 

  14. Ferraguti F, Shigemoto R (2006) Metabotropic glutamate receptors. Cell Tissue Res 326:483–504

    Article  PubMed  CAS  Google Scholar 

  15. Pilc A, Legutko B (1995) The influence of prolonged antidepressant treatment on the changes in cyclic AMP accumulation induced by excitatory amino acids in rat cerebral cortical slices. NeuroReport 7:85–88

    PubMed  CAS  Google Scholar 

  16. Pilc A, Branski P, Palucha A, Tokarski K, Bijak M (1998) Antidepressant treatment influences group I of glutamate metabotropic receptors in slices from hippocampal CA1 region. Eur J Pharmacol 349:83–87

    Article  PubMed  CAS  Google Scholar 

  17. Bajkowska M, Branski P, Smialowska M, Pilc A (1995) Effect of chronic antidepressant or electroconvulsive shock treatment on mGLuR1a immunoreactivity expression in the rat hippocampus. Pol J Pharmacol 51:539–541

    Google Scholar 

  18. Smialowska M, Szewczyk B, Branski P, Wieronska JM, Palucha A, Bajkowska M, Pilc A (2002) Effect of chronic imipramine or electroconvulsive shock on the expression of mGluR1a and mGluR5a immunoreactivity in rat brain hippocampus. Neuropharmacology 42:1016–1023

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  20. Papp M, Moryl E, Willner P (1999) Pharmacological validation of the chronic mild stress model of depression. Eur J Pharmacol 296:129–136

    Article  Google Scholar 

  21. Wieronska JM, Branski P, Szewczyk B, Palucha A, Papp M, Gruca P, Moryl E, Pilc A (2001) Changes in the expression of metabotropic glutamate receptor 5 (mGluR5) in the rat hippocampus in an animal model of depression. Pol J Pharmacol 53:659–662

    PubMed  CAS  Google Scholar 

  22. Tatarczynska E, Klodzinska A, Chojnacka-Wojcik E, Palucha A, Gasparini F, Kuhn R, Pilc A (2001) Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol 132:1423–1430

    Article  PubMed  CAS  Google Scholar 

  23. Palucha A, Branski P, Szewczyk B, Wieronska JM, Klak K, Pilc A (2005) Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist. Pharmacol Biochem Behav 81:901–906

    Article  PubMed  CAS  Google Scholar 

  24. Belozertseva IV, Kos T, Popik P, Danysz W, Bespalov AY (2007) Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests. Eur Neuropsychopharmacol 17:172–179

    Article  PubMed  CAS  Google Scholar 

  25. Palucha A, Pilc A (2007) Metabotropic receptor ligands as possible anxiolytic and antidepressant agents. Pharmacol Ther 115:116–147

    Article  PubMed  CAS  Google Scholar 

  26. Li X, Need AB, Baez M, Witkin JM (2006) Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice. J Pharmacol Exp Ther 319:254–259

    Article  PubMed  CAS  Google Scholar 

  27. Pilc A, Klodzinska A, Branski P, Nowak G, Palucha A, Szewczyk B, Tatarczynska E, Chojnacka-Wojcik E, Wieronska JM (2002) Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats. Neuropharmacology 43:181–187

    Article  PubMed  CAS  Google Scholar 

  28. Pilc A et al (2010) Metabotropic approaches to anxiety. In: Skolnick P (ed) Glutamate-based therapies for psychiatric disorders. Springer, Basel

    Google Scholar 

  29. Pałucha A, Brański P, Kĺak K, Sowa M (2007) Chronic imipramine treatment reduces inhibitory properties of group II mGlu receptors without affecting their density or affinity. Pharmacol Rep 59:525–530

    PubMed  Google Scholar 

  30. Feyissa AM, Woolverton WL, Miguel-Hidalgo JJ, Wang Z, Kyle PB, Hasler G, Stockmeier CA, Iyo AH, Karolewicz B (2010) Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry 34(2):279–283

    Article  PubMed  CAS  Google Scholar 

  31. Matrisciano F, Storto M, Ngomba RT, Cappuccio I, Caricasole A, Scaccianoce S, Riozzi B, Melchiorri D, Nicoletti F (2002) Imipramine treatment up-regulates the expression and function of mGlu2/3 metabotropic glutamate receptors in the rat hippocampus. Neuropharmacology 42:1008–1015

    Article  PubMed  CAS  Google Scholar 

  32. Matrisciano F, Scaccianoce S, Del Bianco P, Panaccione I, Canudas AM, Battaglia G, Riozzi B, Ngomba RT, Molinaro G, Tatarelli R et al (2005) Metabotropic glutamate receptors and neuroadaptation to antidepressants: imipramine-induced down-regulation of beta-adrenergic receptors in mice treated with metabotropic glutamate 2/3 receptor ligands. J Neurochem 93:1345–1352

    Article  PubMed  CAS  Google Scholar 

  33. Katz MM, Tekell JL, Bowden CL, Brannan S, Houston JP, Berman N et al (2004) Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology 29:566–579

    Article  PubMed  CAS  Google Scholar 

  34. Matrisciano F, Zusso M, Panaccione I, Turriziani B, Caruso A, Iacovelli L, Noviello L, Togna G, Melchiorri D, Debetto P et al (2008) Synergism between fluoxetine and the mGlu2/3 receptor agonist, LY379268, in an in vitro model for antidepressant drug-induced neurogenesis. Neuropharmacology 54:428–437

    Article  PubMed  CAS  Google Scholar 

  35. Kawashima N, Karasawa J, Shimazaki T, Chaki S, Okuyama S, Yasuhara A, Nakazato A (2005) Neuropharmacological profiles of antagonists of group II metabotropic glutamate receptors. Neurosci Lett 378:131–134

    Article  PubMed  CAS  Google Scholar 

  36. Karasawa J, Shimazaki T, Kawashima N, Chaki S (2005) AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist. Brain Res 1042:92–98

    Article  PubMed  CAS  Google Scholar 

  37. Karasawa J, Yoshimizu T, Chaki S (2006) A metabotropic glutamate 2/3 receptor antagonist, MGS0039, increases extracellular dopamine levels in the nucleus accumbens shell. Neurosci Lett 393:127–130

    Article  PubMed  CAS  Google Scholar 

  38. Morishima Y, Miyakawa T, Furuyashiki T, Tanaka Y, Mizuma H, Nakanishi S (2005) Enhanced cocaine responsiveness and impaired motor coordination in metabotropic glutamate receptor subtype 2 knockout mice. Proc Natl Acad Sci 102:4170–4175

    Article  PubMed  CAS  Google Scholar 

  39. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O et al (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809

    Article  PubMed  CAS  Google Scholar 

  40. Duman RS, Nakagawa S, Malberg J (02001) Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology 25:836–844

    Article  PubMed  Google Scholar 

  41. Yoshimizu T, 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

    Article  PubMed  CAS  Google Scholar 

  42. Chaki S, Yoshikawa R, Hirota S, Shimazaki T, Maeda M, Kawashima N, Yoshimizu T, Yasuhara A, Sakagami K, Okuyama S et al (2004) MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuropharmacology 46:457–467

    Article  PubMed  CAS  Google Scholar 

  43. Bespalov AY, van Gaalen MM, Sukhotina IA, Wicke K, Mezler M, Schoemaker H, Gross G (2008) Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression. Eur J Pharmacol 592:96–102

    Article  PubMed  CAS  Google Scholar 

  44. Detke MJ, Rickels M, Lucki I (1995) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology 121:66–72

    Article  PubMed  CAS  Google Scholar 

  45. Kenny PJ, Gasparini F, Markou A (2003) Group II metabotropic and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors regulate the deficit in brain reward function associated with nicotine withdrawal in rats. J Pharmacol Exp Ther 306:1068–1076

    Article  PubMed  CAS  Google Scholar 

  46. Markou A, Semenova S (2010) Metabotropic glutamate receptors as targets for the treatment of drug and alcohol dependence. In: Skolnick P (ed) Glutamate-based therapies for psychiatric disorders. Springer, Basel

    Google Scholar 

  47. Yoshimizu T, Shimazaki T, Ito A, Chaki S (2006) An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats. Psychopharmacology 186:587–593

    Article  PubMed  CAS  Google Scholar 

  48. Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD (2005) Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 4:131–144

    Article  PubMed  CAS  Google Scholar 

  49. Wierońska JM, Kłak K, Pałucha A, Brański P, Pilc A (2007) Citalopram influences mGlu7, but not mGlu4 receptors' expression in the rat brain hippocampus and cortex. Brain Res 1184:88–95

    Article  PubMed  Google Scholar 

  50. Tatarczynska E, Palucha A, Szewczyk B, Chojnacka-Wojcik E, Wieronska J, Pilc A (2002) Anxiolytic- and antidepressant-like effects of group III metabotropic glutamate agonist (1S, 3R, 4S)-1-aminocyclopentane-1, 3, 4-tricarboxylic acid (ACPT-I) in rats. Pol J Pharmacol 54:707–710

    Article  PubMed  CAS  Google Scholar 

  51. Palucha A, Tatarczynska E, Branski P, Szewczyk B, Wieronska JM, Klodzinska A, Chojnacka-Wojcik E, Nowak G, Pilc A (2004) Group III mGlu receptor agonists produce anxiolytic- and antidepressant-like effects after central administration in rats. Neuropharmacology 46:151–159

    Article  PubMed  CAS  Google Scholar 

  52. Klak K, Palucha A, Branski P, Sowa M, Pilc A (2007) Combined administration of PHCCC, a positive allosteric modulator of mGlu4 receptors and ACPT-I, mGlu III receptor agonist evokes antidepressant-like effects in rats. Amino Acids 32:169–172

    Article  PubMed  CAS  Google Scholar 

  53. Cryan JF, Kelly PH, Neijt HC, Sansig G, Flor PJ, van der Putten H (2003) Antidepressant and anxiolytic-like effects in mice lacking the group III metabotropic glutamate receptor mGluR7. Eur J Neurosci 17:2409–2417

    Article  PubMed  Google Scholar 

  54. Palucha A, Klak K, Branski P, Putten H, Flor P, Pilc A (2007) Activation of the mGlu7 receptor elicits antidepressant-like effects in mice. Psychopharmacology 194:555–562

    Article  PubMed  CAS  Google Scholar 

  55. Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237

    Article  PubMed  CAS  Google Scholar 

  56. Moroni F, Cozzi A, Lombardi G, Sourtcheva S, Leonardi P, Carfi M, Pellicciari R (1998) Presynaptic mGlu(1) type receptors potentiate transmitter output in the rat cortex. Eur J Pharmacol 347:189–195

    Article  PubMed  CAS  Google Scholar 

  57. Thomas LS, Jane DE, Gasparini F, Croucher MJ (2001) Glutamate release inhibiting properties of the novel mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP): complementary in vitro and in vivo evidence. Neuropharmacology 41:523–527

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  59. Attucci S, Carla V, Mannaioni G, Moroni F (2001) Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges. Br J Pharmacol 132:799–806

    Article  PubMed  CAS  Google Scholar 

  60. Legutko B, Szewczyk B, Pomierny-Chamiolo L, Nowak G, Pilc A (2006) Effect of MPEP treatment on brain-derived neurotrophic factor gene expression. Pharmacol Rep 58:427–430

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  62. Bradbury MJ, Giracello DR, Chapman DF, Holtz G, Schaffhauser H, Rao SP et al (2003) Metabotropic glutamate receptor 5 antagonist-induced stimulation of hypothalamic–pituitary–adrenal axis activity: interaction with serotonergic systems. Neuropharmacology 44:562–572

    Article  PubMed  CAS  Google Scholar 

  63. Page ME, Szeliga P, Gasparini F, Cryan JF (2005) Blockade of the mGlu5 receptor decreases basal and stress-induced cortical norepinephrine in rodents. Psychopharmacology 179:240–246

    Article  PubMed  CAS  Google Scholar 

  64. Prikhozhan AV, Kovalev GI, Raevskii KS (1990) Effects of antidepressive agents on glutamatergic autoregulatory presynaptic mechanism in the rat cerebral cortex. Biull Eksp Biol Med 110:624–626

    Article  PubMed  CAS  Google Scholar 

  65. Golembiowska K, Dziubina A (2000) Effect of acute and chronic administration of citalopram on glutamate and aspartate release in the rat prefrontal cortex. Pol J Pharmacol 52:441–448

    Article  PubMed  CAS  Google Scholar 

  66. Bonanno G, Giambelli R, Raiteri L, Tiraboschi E, Zappettini S, Musazzi L et al (2005) Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J Neurosci 25:3270–3279

    Article  PubMed  CAS  Google Scholar 

  67. Gereau RW, Conn PJ (1995) Multiple presynaptic metabotropic glutamate receptors modulate excitatory and inhibitory synaptic transmission in hippocampal area CA1. J Neurosci 15:6879–6889

    PubMed  CAS  Google Scholar 

  68. Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK (2002) Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J Pharmacol Exp Ther 292:76–87

    Google Scholar 

  69. Lujan R, Nusser Z, Roberts JDB, Shigemoto R, Somogyi P (1996) Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur J Neurosci 8:1488–1500

    Article  PubMed  CAS  Google Scholar 

  70. Kerner JA, Standaert DG, Penney JB, Young AB, Landwehrmeyer GB (1997) Expression of group one metabotropic glutamate receptor subunit mRNAs in neurochemically identified neurons in the rat neostriatum, neocortex, and hippocampus. Mol Brain Res 48:259–269

    Article  PubMed  CAS  Google Scholar 

  71. Benquet P, Gee CE, Gerber U (2002) Two distinct signaling pathways upregulate NMDA receptor responses via two distinct metabotropic glutamate receptor subtypes. J Neurosci 22(22):9679–9686

    PubMed  CAS  Google Scholar 

  72. Ohishi H, Shigemoto R, Nakanishi S, Mizuno N (1993a) Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neuroscience 53:1009–1018

    Article  PubMed  CAS  Google Scholar 

  73. Ohishi H, Shigemoto R, Nakanishi S, Mizuno N (1993b) Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J Comp Neurol 335:252–266

    Article  PubMed  CAS  Google Scholar 

  74. Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, Flor PJ, Neki A, Abe T, Nakanishi S, Mizuno N (1997) Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J Neurosci 17:7503–7522

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

I thank the following colleagues for previous discussions that have helped shape some of the thoughts expressed here: Andrew J. Alt, David Bleakman, Shigeyuki Chaki, Gerard J. Marek, Andrzej Pilc, Gabriel Nowak, Darryle D. Schoepp, and Phil Skolnick.

Author information

Authors and Affiliations

  1. Neuroscience Discovery, Lilly Research Laboratories, Psychiatric Discovery, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN, USA

    Jeffrey M. Witkin

Authors
  1. Jeffrey M. Witkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey M. Witkin .

Editor information

Editors and Affiliations

  1. Div Pharmacotherapies & Medical Conseque, National Institute on Drug Abuse, Executive Boulevard 6001, Rockville, 20852, Maryland, USA

    Phil Skolnick

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Birkhäuser Basel

About this chapter

Cite this chapter

Witkin, J.M. (2010). Glutamatergic Modulators for the Treatment of Major Depressive Disorder: Metabotropic Glutamate Receptors. In: Skolnick, P. (eds) Glutamate-based Therapies for Psychiatric Disorders. Milestones in Drug Therapy. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0346-0241-9_4

Download citation

Publish with us

Policies and ethics

Search

Navigation