, Volume 194, Issue 4, pp 555–562 | Cite as

Activation of the mGlu7 receptor elicits antidepressant-like effects in mice

  • Agnieszka Palucha
  • Kinga Klak
  • Piotr Branski
  • Herman van der Putten
  • Peter J. Flor
  • Andrzej Pilc
Original Investigation



Broad evidence indicates that modulation of the glutamatergic system could be an efficient way to achieve antidepressant activity. Metabotropic glutamate receptor (mGlu receptor) ligands seem to be promising agents to treat several central nervous system disorders, including psychiatric ones.


The aim of our study was to investigate potential antidepressant-like activity of the first, selective, and bio-available mGlu7 receptor agonist, AMN082 (N,N′-dibenzyhydryl-ethane-1,2-diamine dihydrochloride), in wild-type (WT) and mGlu7 receptor knock-out (KO) mice.

Materials and methods

The forced swim test (FST) and the tail suspension test (TST) in mice were used to assess antidepressant-like activity of AMN082.


We found that AMN082, administered IP, induced a dose-dependent decrease in the immobility time of WT animals in the FST and TST, suggesting antidepressant-like potency of an mGlu7 receptor agonist. Moreover, AMN082 did not change the behaviour of mGlu7 receptor KO mice compared to WT littermates in the TST, while imipramine, used as a reference control, significantly reduced their immobility, indicating an mGlu7 receptor-dependent mechanism of the antidepressant-like activity of AMN082. However, at high doses, AMN082 significantly decreased spontaneous locomotor activity of both mGlu7 receptor KO mice and WT control animals, suggesting off-target activity of AMN082 resulting in hypo-locomotion.


These results strongly suggest that activation of the mGlu7 receptor elicits antidepressant-like effects.


Antidepressant drugs AMN082 Forced swim test Locomotor activity mGlu7 receptor Tail suspension test 



This work was partially supported by Polpharma Foundation for Pharmacy and Medicine Grant No.: 34/4/2006 to A Pilc and Funds for Statutory Activity of the Institute of Pharmacology Polish Academy of Sciences.


  1. Altamura CA, Mauri MC, Ferrara A, Moro AR, D’Andrea G, Zamberlan F (1993) Plasma and platelet excitatory amino acids in psychiatric disorders. Am J Psychiatry 150:1731–1733PubMedGoogle Scholar
  2. 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 17:172–179PubMedCrossRefGoogle Scholar
  3. Bonanno G, Giambelli R, Raiteri L, Tiraboschi E, Zappettini S, Musazzi L, Raiteri M, Racagni G, Popoli M (2005) Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J Neurosci 25:3270–3279PubMedCrossRefGoogle Scholar
  4. Cartmell J, Schoepp DD (2000) Regulation of neurotransmitter release by metabotropic glutamate receptors. J Neurochem 75:889–907CrossRefGoogle Scholar
  5. Chaki S, Yoshikawa R, Hirota S, Shimazaki T, Maeda M, Kawashima N, Yoshimizu T, Yasuhara A, Sakagami K, Okuyama S, Nakanishi S, Nakazato A (2004) MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuropharmacology 46:457–467PubMedCrossRefGoogle Scholar
  6. Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237PubMedCrossRefGoogle Scholar
  7. 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 17:2409–2417PubMedCrossRefGoogle Scholar
  8. Fendt M, Schmid S, Thakker DR, Jacobson LH, Yamamoto R, Mitsukawa K, Maier R, Natt F, Hüsken D, Kelly PH, McAllister KH, Hoyer D, van der Putten H, Cryan JF, Flor PJ (2007) mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity. Mol Psychiatry (in press)Google Scholar
  9. 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 52:441–448PubMedGoogle Scholar
  10. Holmes A, Murphy DL, Crawley JN (2003) Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol Psychiatry 54:953–959PubMedCrossRefGoogle Scholar
  11. Kinoshita A, Shigemoto R, Ohishi H, van der Putten H, Mizuno N (1998) Immunohistochemical localization of metabotropic glutamate receptors, mGluR7a and mGluR7b, in the central nervous system of the adult rat and mouse: a light and electron microscopic study. J Comp Neurol 393:332–352PubMedCrossRefGoogle Scholar
  12. Klak K, Palucha A, Branski P, Sowa M, Pilc A (2007) Combined administration of PHCCC, a positive allosteric modulator of mGluR4 receptors and ACPT-I, mGlu III receptor agonist evokes antidepressant-like effects in rats. Amino Acids 32:169–172PubMedCrossRefGoogle Scholar
  13. Lira A, Zhou M, Castanon N, Ansorge MS, Gordon JA, Francis JH, Bradley-Moore M, Lira J, Underwood MD, Arango V, Kung HF, Hofer MA, Hen R, Gingrich JA (2003) Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice. Biol Psychiatry 54:960–971PubMedCrossRefGoogle Scholar
  14. Mitsukawa K, Yamamoto R, Ofner S, Nozulak J, Pescott O, Lukic S, Stoehr N, Mombereau C, Kuhn R, McAllister KH, van der Putten H, Cryan JF, Flor PJ (2005) A selective metabotropic glutamate receptor 7 agonist: activation of receptor signaling via an allosteric site modulates stress parameters in vivo. Proc Natl Acad Sci U S A 102:18712–18717PubMedCrossRefGoogle Scholar
  15. Mitsukawa K, Mombereau C, Lötscher E, Uzunov DP, van der Putten H, Flor PJ, Cryan JF (2006) Metabotropic glutamate receptor subtype 7 ablation causes dysregulation of the HPA axis and increases hippocampal BDNF protein levels: implications for stress-related psychiatric disorders. Neuropsychopharmacology 31:1112–1122PubMedGoogle Scholar
  16. Palucha A (2006) Are compounds acting at metabotropic glutamate receptors the answer to treating depression? Expert Opin Investig Drugs 15:1545–1553PubMedCrossRefGoogle Scholar
  17. Palucha A, Pilc A (2007) Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol Ther 115:116–147PubMedCrossRefGoogle Scholar
  18. Palucha A, Tatarczynska E, Branski P, Szewczyk B, Wieronska JM, Klak K, 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 46:151–159PubMedCrossRefGoogle Scholar
  19. 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 81:901–906PubMedCrossRefGoogle Scholar
  20. Paul IA, Skolnick P (2002) Glutamate and depression: clinical and preclinical studies. Ann N Y Acad Sci 1003:250–272CrossRefGoogle Scholar
  21. Pelkey KA, Lavezzari G, Racca C, Roche KW, McBain CJ (2005) mGluR7 is a metaplastic switch controlling bidirectional plasticity of feedforward inhibition. Neuron 46:89–102PubMedCrossRefGoogle Scholar
  22. Pelkey KA, Yuan X, Lavezzari G, Roche KW, McBain CJ (2006) mGluR7 undergoes rapid internalization in response to activation by the allosteric agonist AMN082. Neuropharmacology 52:108–117PubMedCrossRefGoogle Scholar
  23. 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 43:181–187PubMedCrossRefGoogle Scholar
  24. Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336PubMedGoogle Scholar
  25. Prikhozhan AV, Kovalev GI, Raevskii KS (1990) Effects of antidepressive agents on glutamatergic autoregulatory presynaptic mechanism in the rat cerebral cortex. Bull Exp Biol Med 110:624–626CrossRefGoogle Scholar
  26. Racz Z, Hamar P (2006) Can siRNA technology provide the tools for gene therapy of the future? Curr Med Chem 13:2299–2307PubMedCrossRefGoogle Scholar
  27. Ritzen A, Mathiesen JM, Thomsen C (2005) Molecular pharmacology and therapeutic prospects of metabotropic glutamate receptor allosteric modulators. Basic Clin Pharmacol Toxicol 97:202–213PubMedCrossRefGoogle Scholar
  28. Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M (2004) Specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 61:705–713PubMedCrossRefGoogle Scholar
  29. Sansig G, Bushell TJ, Clarke VRJ, Rozov A, Burnashev N, Portet C, Gasparini F, Schmutz M, Klebs K, Shigemoto R, Flor PJ, Kuhn R, Knoepfel T, Schroeder M, Hampson DR, Collett VJ, Zhang C, Duvoisin RM, Collingridge GL, van der Putten H (2001) Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7. J Neurosci 21:8734–8745PubMedGoogle Scholar
  30. Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299:12–20PubMedGoogle Scholar
  31. Stachowicz K, Chojnacka-Wojcik E, Klak K, Pilc A (2006) Anxiolytic-like effects of group III mGlu receptor agonist ACPT-I administered intrahippocampally involve GABA-A signaling. Pharmacol Rep 58:820–826PubMedGoogle Scholar
  32. Stachowicz K, Chojnacka-Wojcik E, Klak K, Pilc A (2007) Anxiolytic-like effect of group III mGlu receptor antagonist is serotonin-dependent. Neuropharmacology 52:306–312PubMedCrossRefGoogle Scholar
  33. Steru L, Chermat R, Thierry B, Simon P (1985) Tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 85:367–370CrossRefGoogle Scholar
  34. 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 132:1423–1430PubMedCrossRefGoogle Scholar
  35. Tatarczynska E, Palucha A, Szewczyk B, Chojnacka-Wojcik E, Wieronska JM, 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 54:707–710PubMedGoogle Scholar
  36. Thakker DR, Hoyer D, Schmutz M, Maier R, Natt F, Husken D, Sansig G, van der Putten H, Flor PJ, Cryan JF (2005a) mGluR7 plays a key role in the modulation of anxiety behavior: evidence from mGluR7-knockout mice and siRNA-induced knockdown in the adult mouse brain. Neuropharmacology 49:275 (abstracts)CrossRefGoogle Scholar
  37. Thakker DR, Natt F, Husken D, van der Putten H, Maier R, Hoyer D, Cryan JF (2005b) siRNA-mediated knockdown of the serotonin transporter in the adult mouse brain. Mol Psychiatry 10:782–789PubMedCrossRefGoogle Scholar
  38. Wieronska JM, Szewczyk B, Branski P, Palucha A, Pilc A (2002) Antidepressant-like effect of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist in the olfactory bulbectomized rats. Amino Acids 23:213–216PubMedCrossRefGoogle Scholar
  39. 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 (Berl) 186:587–593CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Agnieszka Palucha
    • 1
  • Kinga Klak
    • 1
  • Piotr Branski
    • 1
  • Herman van der Putten
    • 2
  • Peter J. Flor
    • 2
  • Andrzej Pilc
    • 1
    • 3
  1. 1.Department of NeurobiologyInstitute of Pharmacology Polish Academy of SciencesKrakowPoland
  2. 2.Neuroscience Research, Novartis Institutes for BioMedical ResearchNovartis Pharma AGBaselSwitzerland
  3. 3.Department of Drug Management, Collegium MedicumJagiellonian UniversityKrakowPoland

Personalised recommendations