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  • Review Article
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Metabotropic glutamate receptors as novel targets for anxiety and stress disorders

Key Points

  • Anxiety disorders represent a range of conditions that include generalized anxiety, panic attacks, post-traumatic stress disorder, obsessive–compulsive syndrome and social phobias.

  • Some forms of anxiety are relatively resistant to treatment with current drugs, and furthermore, these drugs are often associated with serious side effects, such as sedation, memory impairment, ataxia, abuse potential and physical dependence. It has therefore become increasingly apparent that alternative treatment strategies are needed.

  • In general, anxiety- and stress-related illnesses are thought of as a collection of disorders that have in common excessive or inappropriate brain excitability within crucial brain circuits. As glutamate is the major excitatory neurotransmitter in the mammalian brain, it is logical that new approaches for anxiety could include drugs that modulate glutamatergic functions.

  • The metabotropic glutamate (mGlu) receptors are a novel family of class C GPCRs that comprise at least eight known subtypes. A growing body of evidence indicates that these receptors might serve as potential therapeutic targets for a variety of pathological states, including anxiety disorders.

  • In particular, as discussed in this article, group II mGlu receptors and group I mGlu receptors seem to be important in the physiological and behavioural sequelae associated with stressful stimuli.

  • Moreover, compounds selective for mGlu receptors, particularly mGlu2/3 and/or mG1u5, have proven as effective as classical anxiolytics in various animal models of anxiety without producing many of the unwanted side effects that are typical of current therapies.

  • The precise anxiolytic actions of selective mGlu receptor compounds have yet to be fully elucidated. However, a number of studies suggest that both group II mGlu receptor agonists and group I mGlu receptor antagonists might generally act to regulate neuronal hyperexcitability by direct or indirect suppression of excitatory transmission.

Abstract

Anxiety and stress disorders are the most commonly occurring of all mental illnesses, and current treatments are less than satisfactory. So, the discovery of novel approaches to treat anxiety disorders remains an important area of neuroscience research. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and G-protein-coupled metabotropic glutamate (mGlu) receptors function to regulate excitability via pre- and postsynaptic mechanisms. Various mGlu receptor subtypes, including group I (mGlu1 and mGlu5), group II (mGlu2 and mGlu3), and group III (mGlu4, mGlu7 and mGlu8) receptors, specifically modulate excitability within crucial brain structures involved in anxiety states. In addition, agonists for group II (mGlu2/3) receptors and antagonists for group I (in particular mGlu5) receptors have shown activity in animal and/or human conditions of fear, anxiety or stress. These studies indicate that metabotropic glutamate receptors are interesting new targets to treat anxiety disorders in humans.

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Figure 1: Hypothetical synapse illustrating the general synaptic localization and function of glutamatergic receptors and transporters.
Figure 2: Brain-region-dependent presynaptic inhibition of excitatory neurotransmission.
Figure 3: Effects of diazepam and LY354740 in an animal model of anxiety: fear-induced potentiated startle.
Figure 4: Anxiolytic activity of LY354740 and chlordiazepam in a mouse elevated plus maze model.
Figure 5: Potential mechanisms by which mGlu2/3 agonists act as anxiolytic agents.
Figure 6: Anxiety-like response of mGlu8 knockout mice in the elevated plus maze model.

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References

  1. Martin, P. Animal models sensitive to anti-anxiety agents. Acta Psychiatr. Scand. Suppl. 393, 74–80 (1998).

    CAS  PubMed  Google Scholar 

  2. Shekhar, A. et al. Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders. Psychopharmacology (Berl). 157, 327–339 (2001). A consensus of experts in the field of anxiety concluded that although current animal models of anxiety are useful for understanding the mechanisms that mediate fear and stress in animals and humans, they are not generally predictive of efficacy in specific diagnostic forms of anxiety in humans.

    CAS  PubMed  Google Scholar 

  3. Woods, J. H., Katz, J. L. & Winger, G. Benzodiazepines: use, abuse, and consequences. Pharmacol. Rev. 44, 151–347 (1992).

    CAS  PubMed  Google Scholar 

  4. Atack, J. R. Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Curr. Drug Targets CNS Neurol. Disord. 2, 213–232 (2003).

    CAS  PubMed  Google Scholar 

  5. Brunello, N. et al. Noradrenaline in mood and anxiety disorders: basic and clinical studies. Int. Clin. Psychopharmacol. 18, 191–202 (2003).

    PubMed  Google Scholar 

  6. Gorman, J. M. New molecular targets for antianxiety interventions. J. Clin. Psychiatry 64, 28–35 (2003).

    CAS  PubMed  Google Scholar 

  7. Kehne, J. & De Lombaert, S. Non-peptidic CRF1 receptor antagonists for the treatment of anxiety, depression and stress disorders. Curr. Drug Targets CNS Neurol. Disord. 1, 467–493 (2002).

    CAS  PubMed  Google Scholar 

  8. Holmes, A., Heilig, M., Rupniak, N. M., Steckler, T. & Griebel, G. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol. Sci. 24, 580–588 (2003).

    CAS  PubMed  Google Scholar 

  9. Vaswani, M., Linda, F. K. & Ramesh, S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 85–102 (2003).

    CAS  PubMed  Google Scholar 

  10. Clineschmidt, B. V. Restoration of shock-suppressed behavior by treatment with (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5,10-imine (MK-801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties. Drug Dev. Res. 2, 147–163 (1982).

    CAS  Google Scholar 

  11. Wiley, J. L. Behavioral pharmacology of N-methyl-D-aspartate antagonists: implications for the study and pharmacotherapy of anxiety and schizophrenia. Exp. Clin. Psychopharmacol. 5, 365–374 (1997).

    CAS  PubMed  Google Scholar 

  12. Danysz, W., Parsons, C. G., Bresnik, I. & Quack, G. Glutamate in CNS disorders. Drug News Perspec. 8, 261–277 (1996).

    Google Scholar 

  13. Parsons, C. G. et al. Modulation of NMDA receptors by glycine introduction to some basic aspects and recent developments. Amino Acids 14, 207–216 (1998).

    CAS  PubMed  Google Scholar 

  14. Schoepp, D. D. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J. Pharmacol. Exp. Ther. 299, 12–20 (2001).

    CAS  PubMed  Google Scholar 

  15. Schoepp, D. D. Novel functions for subtypes of metabotropic glutamate receptors. Neurochem. Int. 24, 439–449 (1994).

    CAS  PubMed  Google Scholar 

  16. Nakanishi, S. Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity. Neuron 13, 1031–1037 (1994).

    CAS  PubMed  Google Scholar 

  17. Pin, J. P. & Acher, F. The metabotropic glutamate receptors: structure, activation mechanism and pharmacology. Curr. Drug Targets CNS Neurol. Disord. 1, 297–317 (2002).

    CAS  PubMed  Google Scholar 

  18. Conn, P. J. & Pin, J. P. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 37, 205–237 (1997).

    CAS  PubMed  Google Scholar 

  19. Swanson, C. J. & Schoepp, D. D. A role for noradrenergic transmission in the actions of phencyclidine and the antipsychotic and antistress effects of mGlu2/3 receptor agonists. Ann. NY Acad. Sci. 1003, 309–317 (2003).

    CAS  PubMed  Google Scholar 

  20. Schoepp, D. D., Wright, R. A., Levine, L. R., Gaydos, B. & Potter, W. Z. LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress 6, 189–197 (2003). This paper demonstrated that anxiety associated with CO 2 exposure was reduced by oral administration of LY354740 in human patients with anxiety, thereby showing translation of the anxiolytic effects of LY354740 in the lactate anxiety/panic model in rats.

    CAS  PubMed  Google Scholar 

  21. Gray, J. A. Precision of the neuropsychopharmacology of anxiety: an inquiry into the functions of the septo-hippocampal system. Behav. Brain Sci. 5, 469–534 (1982).

    Google Scholar 

  22. Davis, M. The role of the amygdala in fear and anxiety. Annu. Rev. Neurosci. 15, 353–375 (1992).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Petralia, R. S., Wang, Y. X., Niedzielski, A. S. & Wenthold, R. J. The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 71, 949–976 (1996).

    CAS  PubMed  Google Scholar 

  26. Wright, R. A., Arnold, M. B., Wheeler, W. J., Ornstein, P. L. & Schoepp, D. D. [3H]LY341495 binding to group II metabotropic glutamate receptors in rat brain. J. Pharmacol. Exp. Ther. 298, 453–460 (2001).

    CAS  PubMed  Google Scholar 

  27. Cartmell, J. & Schoepp, D. D. Regulation of neurotransmitter release by metabotropic glutamate receptors. J. Neurochem. 75, 889–907 (2000).

    CAS  PubMed  Google Scholar 

  28. Anwyl, R. Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res. Brain Res. Rev. 29, 83–120 (1999).

    CAS  PubMed  Google Scholar 

  29. Tamaru, Y., Nomura, S., Mizuno, N. & Shigemoto, R. Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites. Neuroscience 106, 481–503 (2001).

    CAS  PubMed  Google Scholar 

  30. Helton, D. R., Tizzano, J. P., Monn, J. A., Schoepp, D. D. & Kallman, M. J. Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. J. Pharmacol. Exp. Ther. 284, 651–660 (1998). The novel pharmacological profile of LY354740 in animal models of anxiety is described and compared with clinically efffective agents. In particular, LY354740 had similar efficacy to a benzodiazepine in certain models, but with no evidence for CNS depression in benzodiaze-pine-sensitive models of motor function, and of learning and memory.

    CAS  PubMed  Google Scholar 

  31. Walker, D. L. & Davis, M. The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction. Pharmacol. Biochem. Behav. 71, 379–392 (2002). Report that the actions of LY354740 in the fear-potentiated startle model involves the amygdala, as intra-amygdala injections of the drug reversibly suppressed fear-potentiated startle in rats.

    CAS  PubMed  Google Scholar 

  32. Campeau, S. & Davis, M. Involvement of subcortical and cortical afferents to the lateral nucleus of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli. J. Neurosci. 15, 2312–2327 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rainnie, D. G. & Shinnick-Gallagher, P. Trans-ACPD and L-APB presynaptically inhibit excitatory glutamatergic transmission in the basolateral amygdala (BLA). Neurosci. Lett. 139, 87–91 (1992).

    CAS  PubMed  Google Scholar 

  34. Pellow, S., Chopin, P., File, S. E. & Briley, M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J. Neurosci. Methods 14, 149–167 (1985).

    CAS  PubMed  Google Scholar 

  35. Lister, R. G. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology (Berl). 92, 180–185 (1987).

    CAS  PubMed  Google Scholar 

  36. Monn, J. A. et al. Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties. J. Med. Chem. 40, 528–537 (1997). The synthesis and aspects of structure–activity of LY354740 and its isomers are described. LY354740 was a potent and stereoselective agonist for human and rat mGlu 2 and mGlu 3 receptors in vitro and the actions of LY354740 in models of anxiety showed similar stereoselectivity. The data demonstrated that LY354740 could be used to investigate the therapeutic potential mGlu 2/3 receptor activations in vivo.

    CAS  PubMed  Google Scholar 

  37. Ferris, P., Seward, E. & Dawson, G. R. Interactions between LY354740, a group II metabotropic agonist and the GABA(A)-benzodiazepine receptor complex in the rat elevated plus-maze. J. Psychopharmacol. (Oxf). 15, 76–82 (2001).

    CAS  Google Scholar 

  38. Engel, J. A., Egbe, P., Liljequist, S. & Soderpalm, B. Effects of amperozide in two animal models of anxiety. Pharmacol. Ther. 64, 429–433 (1989).

    CAS  Google Scholar 

  39. Nagatani, T. et al. Pharmacological profile of a potential anxiolytic: AP159, a new benzothieno-pyridine derivative. Psychopharmacology (Berl). 104, 432–438 (1991).

    CAS  PubMed  Google Scholar 

  40. Assie, M. B., Chopin, P., Stenger, A., Palmier, C. & Briley, M. Neuropharmacology of a new potential anxiolytic compound, F 2692, 1-(3′-trifluoromethylphenyl)-1,4-dihydro-3-amino-4-oxo-6-methylpyridazine. 1. Acute and in vitro effects. Psychopharmacology (Berl). 110, 13–18 (1993).

    CAS  PubMed  Google Scholar 

  41. Keim, S. R. & Shekhar, A. Chronic GABA dysfunction in the dorsomedial hypothalamus (DMH) of rats results in a panic-prone state that is NMDA and not non-NMDA receptor-mediated. Soc. Neurosci. Abs. 24, 1674 (1998).

    Google Scholar 

  42. Shekhar, A. & Keim, S. R. LY354740, a potent group II metabotropic glutamate receptor agonist prevents lactate-induced panic-like response in panic-prone rats. Neuropharmacology 39, 1139–1146 (2000).

    CAS  PubMed  Google Scholar 

  43. Linden, A. M., Greene, S. J., Bergeron, M. & Schoepp, D. D. Anxiolytic activity of the mGlu2/3 receptor agonist LY354740 on the elevated plus maze is associated with the suppression of stress-induced c-Fos in the hippocampus and increases in c-Fos induction in several other stress-sensitive brain regions. Neuropsychopharmacology 29, 502–513 (2004). The anxiolytic action of LY354740 in mice was associated with highly selective activation of neuronal populations in the mouse brain that included the lateral central amygdala and hippocampus, indicating that these and other associated brain regions mediate the unique pharmacology of mGlu 2/3 receptor agonists.

    CAS  PubMed  Google Scholar 

  44. Beck, C. H. M. & Fibiger, H. C. Conditioned fear-induced changes in behavior and in the expression of the immediate early gene c-fos: with and without diazepam pretreatment. J. Neurosci. 15, 709–720 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Salminen, O., Lahtinen, S. & Ahtee, L. Expression of Fos protein in various rat brain areas following acute nicotine and diazepam. Pharmacol. Biochem. Behav. 54, 241–248 (1996).

    CAS  PubMed  Google Scholar 

  46. Ryabinin, A. E., Criado, J. R., Henriksen, S. J., Bloom, F. & Wilson, M. C. Differential sensitivity of c-Fos expression in hippocampus and other brain regions to moderate and low doses of alcohol. Mol. Psychiatry 2, 32–43 (1997).

    CAS  PubMed  Google Scholar 

  47. Hitzemann, B. & Hitzemann, R. Chlorodiazepoxide-induced expression of c-Fos in the central extended amygdala and other brain regions of the C57BL/6J and DBA/2J inbred mouse strains: relationship to mechanisms of ethanol action. Alcohol. Clin. Exp. Res. 23, 1158–1172 (1999).

    CAS  PubMed  Google Scholar 

  48. Sun, N. & Cassell, M. D. Intrinsic GABAergic neurons in the rat central extended amygdala. J. Comp. Neurol. 330, 381–404 (1993).

    CAS  PubMed  Google Scholar 

  49. Sun, N., Yi, H. & Cassell, M. D. Evidence for a GABAergic interface between coritcal afferents and brainstem projection neurons in the rat central extended amygdala. J. Comp. Neurol. 340, 43–64 (1994).

    CAS  PubMed  Google Scholar 

  50. Veinante, P. & Freund-Mercier, M. -J. Intrinsic and extrinsic connections of the rat central extended amygdala: an in vivo electrophysiological study of the central amygdaloid nucleus. Brain Res. 794, 188–198 (1998).

    CAS  PubMed  Google Scholar 

  51. Olsen, R. W. Drug interactions at the GABA receptor–ionophore complex. Annu. Rev. Pharmacol. Toxicol. 22, 245–277 (1982).

    CAS  PubMed  Google Scholar 

  52. Helton, D. R., Schoepp, D. D., Monn, J. A., Tizzano, J. P. & Kallman, M. J. in Metabotropic Glutamate Receptors in Brain Function (eds. Moroni, F., Nicoletti, F. & Pellegrini-Giampietro, D. E.) 305–314 (Portland, London, 1998).

    Google Scholar 

  53. Higgins, G. A. et al. Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent. Neuropharmacology 46, 907–917 (2004).

    CAS  PubMed  Google Scholar 

  54. Moghaddam, B. & Adams, B. W. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281, 1349–1352 (1998). The potential antipsychotic actions of mGlu 2/3 receptor agonists are described in rats, and illustrate that effects in these models are linked to selective suppression of phencyclidine-induced glutamate hyperexcitability. mGlu 2/3 receptors agonists might therefore be useful for clincally testing the glutamate theory of schizophrenia in humans.

    CAS  PubMed  Google Scholar 

  55. Mohler, H., Fritschy, J. M. & Rudolph, U. A new benzodiazepine pharmacology. J. Pharmacol. Exp. Ther. 300, 2–8 (2002).

    CAS  PubMed  Google Scholar 

  56. Low, K. et al. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290, 131–134 (2000).

    CAS  PubMed  Google Scholar 

  57. Nusser, Z., Sieghart, W., Benke, D., Fritschy, J. M. & Somogyi, P. Differential synaptic localization of two major γ-aminobutyric acid type A receptor α subunits on hippocampal pyramidal cells. Proc. Natl Acad. Sci. USA 93, 11939–11944 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Fritschy, J. M., Johnson, D. K., Mohler, H. & Rudolph, U. Independent assembly and subcellular targeting of GABA(A)-receptor subtypes demonstrated in mouse hippocampal and olfactory neurons in vivo. Neurosci. Lett. 249, 99–102 (1998).

    CAS  PubMed  Google Scholar 

  59. Rudolph, U., Crestani, F. & Mohler, H. GABA(A) receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol. Sci. 22, 188–194 (2001).

    CAS  PubMed  Google Scholar 

  60. Barda, D. A. et al. SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide. Bioorg. Med. Chem. Lett. 14, 3099–3102 (2004).

    CAS  PubMed  Google Scholar 

  61. Johnson, M. P. et al. Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2- trifluoroethylsulfonyl)pyrid-3-ylmethylamine. J. Med. Chem. 46, 3189–3192 (2003). The discovery of allosteric potentiators of mGlu 2 receptors represented a new approach to finding mGlu receptor subtype-specific agents that are use-dependent and have promise for treating certain CNS disorders, including anxiety.

    CAS  PubMed  Google Scholar 

  62. Johnson, M. P. et al. Biochemical and behavioral characteristics of metabotropic glutamate 2 receptor potentiators. Psychopharmacology (Berl). (in the press).

  63. Schaffhauser, H. et al. Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2. Mol. Pharmacol. 64, 798–810 (2003).

    CAS  PubMed  Google Scholar 

  64. Romano, C. et al. Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. J. Comp. Neurol. 355, 455–469 (1995).

    CAS  PubMed  Google Scholar 

  65. Lujan, R., Roberts, J. D., Shigemoto, R., Ohishi, H. & Somogyi, P. Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1α, mGluR2 and mGluR5, relative to neurotransmitter release sites. J. Chem. Neuroanat. 13, 219–241 (1997).

    CAS  PubMed  Google Scholar 

  66. Muly, E. C., Maddox, M. & Smith, Y. Distribution of mGluR1α and mGluR5 immunolabeling in primate prefrontal cortex. J. Comp. Neurol. 467, 521–535 (2003).

    CAS  PubMed  Google Scholar 

  67. Fotuhi, M. et al. Differential localization of phosphoinositide-linked metabotropic glutamate receptor (mGluR1) and the inositol 1,4,5-trisphosphate receptor in rat brain. J. Neurosci. 13, 2001–2012 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Moroni, F. et al. Presynaptic mGlu1 type receptors potentiate transmitter output in the rat cortex. Eur. J. Pharmacol. 347, 189–195 (1998).

    CAS  PubMed  Google Scholar 

  69. Awad, H., Hubert, G. W., Smith, Y., Levey, A. I. & Conn, P. J. Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J. Neurosci. 20, 7871–7879 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Swanson, C. J., Baker, D. A., Carson, D., Worley, P. F. & Kalivas, P. W. Repeated cocaine administration attenuates group I metabotropic glutamate receptor-mediated glutamate release and behavioral activation: a potential role for Homer. J. Neurosci. 21, 9043–9052 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Kingston, A. E., Burnett, J. P., Mayne, N. G. & Lodge, D. Pharmacological analysis of 4-carboxyphenylglycine derivatives: comparison of effects on mGluR1α and mGluR5α subtypes. Neuropharmacology 34, 887–894 (1995).

    CAS  PubMed  Google Scholar 

  72. Chojnacka-Wojcik, E., Tatarczynska, E. & Pilc, A. The anxiolytic-like effect of metabotropic glutamate receptor antagonists after intrahippocampal injection in rats. Eur. J. Pharmacol. 319, 153–156 (1997).

    CAS  PubMed  Google Scholar 

  73. Testa, C. M., Standaert, D. G., Young, A. B. & Penney, J. B., Jr. Metabotropic glutamate receptor mRNA expression in the basal ganglia of the rat. J. Neurosci. 14, 3005–3018 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Koch, M. Microinjections of the metabotropic glutamate receptor agonist, trans-(+/-)-1-amino-cyclopentane-1,3-dicarboxylate (trans-ACPD) into the amygdala increase the acoustic startle response of rats. Brain Res. 629, 176–179 (1993).

    CAS  PubMed  Google Scholar 

  75. Gasparini, F. et al. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38, 1493–1503 (1999). The discovery of non-competitive antagonists for mGlu 5 receptors, such as MPEP, represents another novel approach to treating CNS disorders, and are useful pharmacological tools for studying mGlu 5 receptor functions in animal models.

    CAS  PubMed  Google Scholar 

  76. Tatarczynska, E., Klodzinska, A., Kroczka, B., Chojnacka-Wojcik, E. & Pilc, A. The antianxiety-like effects of antagonists of group I and agonists of group II and III metabotropic glutamate receptors after intrahippocampal administration. Psychopharmacology (Berl). 158, 94–99 (2001).

    CAS  PubMed  Google Scholar 

  77. Spooren, W. P., Gasparini, F., Bergmann, R. & Kuhn, R. Effects of the prototypical mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned rats. Eur. J. Pharmacol. 406, 403–410 (2000).

    CAS  PubMed  Google Scholar 

  78. Tatarczynska, E. et al. Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br. J. Pharmacol. 132, 1423–1430 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Spooren, W. P. et al. Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents. J. Pharmacol. Exp. Ther. 295, 1267–1275 (2000).

    CAS  PubMed  Google Scholar 

  80. Spooren, W. P., Schoeffter, P., Gasparini, F., Kuhn, R. & Gentsch, C. Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY314582, MPEP and NKP608). Eur. J. Pharmacol. 435, 161–170 (2002).

    CAS  PubMed  Google Scholar 

  81. Johnson, M. P., Kelly, G. & Chamberlain, M. Changes in rat serum corticosterone after treatment with metabotropic glutamate receptor agonists or antagonists. J. Neuroendocrinol. 13, 670–677 (2001).

    CAS  PubMed  Google Scholar 

  82. Brown, M. R. et al. Corticotropin-releasing factor: Effects on the sympathetic nervous system and oxygen consumption. Life Sci. 30, 207–210 (1982).

    CAS  PubMed  Google Scholar 

  83. Riedel, G., Casabona, G., Platt, B., Macphail, E. M. & Nicoletti, F. Fear conditioning-induced time- and subregion-specific increase in expression of mGlu5 receptor protein in rat hippocampus. Neuropharmacology 39, 1943–1951 (2000).

    CAS  PubMed  Google Scholar 

  84. Schulz, B. et al. The metabotropic glutamate receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks fear conditioning in rats. Neuropharmacology 41, 1–7 (2001).

    CAS  PubMed  Google Scholar 

  85. Rolls, E. T. A theory of hippocampal function in memory. Hippocampus 6, 601–620 (1996).

    CAS  PubMed  Google Scholar 

  86. Rodrigues, S. M., Bauer, E. P., Farb, C. R., Schafe, G. E. & LeDoux, J. E. The group I metabotropic glutamate receptor mGluR5 is required for fear memory formation and long-term potentiation in the lateral amygdala. J. Neurosci. 22, 5219–5229 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Bliss, T. V. & Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. Paris 232, 331–356 (1973).

    CAS  Google Scholar 

  88. Bear, M. F. & Malenka, R. C. Synaptic plasticity: LTP and LTD. Curr. Opin. Neurobiol. 4, 389–399 (1994).

    CAS  PubMed  Google Scholar 

  89. Izumi, Y., Clifford, D. B. & Zorumski, C. F. 2-Amino-3-phosphonopropionate blocks the induction and maintenance of long-term potentiation in rat hippocampal slices. Neurosci. Lett. 122, 187–190 (1991).

    CAS  PubMed  Google Scholar 

  90. Behnisch, T. & Reymann, K. G. Co-activation of metabotropic glutamate and N-methyl-D-aspartate receptors is involved in mechanisms of long-term potentiation maintenance in rat hippocampal CA1 neurons. Neuroscience 54, 37–47 (1993).

    CAS  PubMed  Google Scholar 

  91. Riedel, G., Casabona, G. & Reymann, K. G. Inhibition of long-term potentiation in the dentate gyrus of freely moving rats by the metabotropic glutamate receptor antagonist MCPG. J. Neurosci. 15, 87–98 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Wang, J. & Johnson, K. M. Regulation of striatal cyclic-3′,5′-adenosine monophosphate accumulation and GABA release by glutamate metabotropic and dopamine D1 receptors. J. Pharmacol. Exp. Ther. 275, 877–884 (1995).

    CAS  PubMed  Google Scholar 

  93. Wilsch, V. W., Behnisch, T., Jager, T., Reymann, K. G. & Balschun, D. When are class I metabotropic glutamate receptors necessary for long-term potentiation? J. Neurosci. 18, 6071–6080 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Ugolini, A., Corsi, M. & Bordi, F. Potentiation of NMDA and AMPA responses by the specific mGluR5 agonist CHPG in spinal cord motoneurons. Neuropharmacology 38, 1569–1576 (1999).

    CAS  PubMed  Google Scholar 

  95. Nielsen, K. S., Macphail, E. M. & Riedel, G. Class I mGlu receptor antagonist 1-aminoindan-1,5-dicarboxylic acid blocks contextual but not cue conditioning in rats. Eur. J. Pharmacol. 326, 105–108 (1997).

    CAS  PubMed  Google Scholar 

  96. Ohno, M. & Watanabe, S. Enhanced N-methyl-D-aspartate function reverses working memory failure induced by blockade of group I metabotropic glutamate receptors in the rat hippocampus. Neurosci. Lett. 240, 37–40 (1998).

    CAS  PubMed  Google Scholar 

  97. Semyanov, A. & Kullmann, D. M. Modulation of GABAergic signaling among interneurons by metabotropic glutamate receptors. Neuron 25, 663–672 (2000).

    CAS  PubMed  Google Scholar 

  98. Schrader, L. A. & Tasker, J. G. Modulation of multiple potassium currents by metabotropic glutamate receptors in neurons of the hypothalamic supraoptic nucleus. J. Neurophysiol. 78, 3428–3237 (1997).

    CAS  PubMed  Google Scholar 

  99. Schrader, L. A. & Tasker, J. G. Presynaptic modulation by metabotropic glutamate receptors of excitatory and inhibitory synaptic inputs to hypothalamic magnocellular neurons. J. Neurophysiol. 77, 527–536 (1997).

    CAS  PubMed  Google Scholar 

  100. Tatarczynska, E. et al. 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 (2002).

    CAS  PubMed  Google Scholar 

  101. Chojnacka-Wojcik, E., Tatarczynska, E. & Pilc, A. Anxiolytic-like effects of metabotropic glutamate antagonist (RS)-α-methylserine-O-phosphate in rats. Pol. J. Pharmacol. 48, 507–509 (1996).

    CAS  PubMed  Google Scholar 

  102. Masugi, M. et al. Metabotropic glutamate receptor subtype 7 ablation causes deficit in fear response and conditioned taste aversion. J. Neurosci. 19, 955–963 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Cryan, J. F. et al. Antidepressant and anxiolytic-like effects in mice lacking the group III metabotropic glutamate receptor mGluR7 . Eur. J. Neurosci. 17, 2409–2417 (2003).

    PubMed  Google Scholar 

  104. Linden, A. M. et al. Increased anxiety-related behavior in mice deficient for metabotropic glutamate 8 (mGlu8) receptor. Neuropharmacology 43, 251–259 (2002). Group III mGlu receptors such as mGlu 8 might also be involved in the processing of stress responses in animals and might therefore also be interesting new drug targets for anxiety.

    CAS  PubMed  Google Scholar 

  105. Belzung, C. & Griebel, G. Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav. Brain Res. 125, 141–149 (2001).

    CAS  PubMed  Google Scholar 

  106. Kilbride, J., Huang, L. Q., Rowan, M. J. & Anwyl, R. Presynaptic inhibitory action of the group II metabotropic glutamate receptor agonists, LY354740 and DCG-IV. Eur. J. Pharmacol. 356, 149–157 (1998).

    CAS  PubMed  Google Scholar 

  107. Marek, G. J., Wright, R. A., Schoepp, D. D., Monn, J. A. & Aghajanian, G. K. Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J. Pharmacol. Exp. Ther. 292, 76–87 (2000). The distribution of mGlu 2/3 -binding sites in the rat prefrontal cortex overlaps with the expression of 5-HT 2A (serotonin) receptors in that region, and at the cellular level the actions of mGlu 2/3 receptor agonists and 5-HT 2A receptor antagonists both result in suppression of thalmocortical glutamate release. The pharmacological actions in certain models of psychosis and anxiety for these two classes of agents might therefore be through this common mechamism.

    CAS  PubMed  Google Scholar 

  108. Neugebauer, V., Chen, P. S. & Willis, W. D. Groups II and III metabotropic glutamate receptors differentially modulate brief and prolonged nociception in primate STT cells. J. Neurophysiol. 84, 2998–3009 (2000).

    CAS  PubMed  Google Scholar 

  109. Tizzano, J. P., Griffey, K. I. & Schoepp, D. D. The anxiolytic action of mGlu2/3 receptor agonist, LY354740, in the fear-potentiated startle model in rats is mechanistically distinct from diazepam. Pharmacol. Biochem. Behav. 73, 367–374 (2002). Both diazepam and LY354740 reduced fear expression in fear-conditioned rats using fear-potentiated startle as a readout of behaviour. However, systemically administered LY354740, unlike diazepam, did not prevent the development of fear-learning in this model. These data indicate that the applications of LY354740 across anxiety disorders might be different from the benzodiazepines.

    CAS  PubMed  Google Scholar 

  110. Linden, A. M., Bergeron, M., Baez, M. & Schoepp, D. D. Systemic administration of the potent mGlu8 receptor agonist (S)-3,4-DCPG induces c-Fos in stress-related brain regions in wild-type, but not mGlu8 receptor knockout mice. Neuropharmacology 45, 473–483 (2003).

    CAS  PubMed  Google Scholar 

  111. Walker, D. L., Rattiner, L. M. & Davis, M. Group II metabotropic glutamate receptors within the amygdala regulate fear as assessed with potentiated startle in rats. Behav. Neurosci. 116, 1075–1083 (2002).

    CAS  PubMed  Google Scholar 

  112. Grillon, C., Cordova, J., Levine, L. R. & Morgan, C. A. Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans. Psychopharmacology (Berl). 168, 446–454 (2003). In humans, as in rats, LY354740 blocked the expression of fear-potentiated startle, without evidence of CNS depression caused by drugs such as the benzodiazepines. This shows that fear-potentiated startle can be used to assess or validate certain atypical anxiolytic agents across animal and human species.

    CAS  PubMed  Google Scholar 

  113. Klodzinska, A. et al. Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models. Neuropharmacology 38, 1831–1839 (1999).

    CAS  PubMed  Google Scholar 

  114. Benvenga, M. J., Overshiner, C. D., Monn, J. A. & Leander, J. D. Disinhibitory effects of LY354740, a new mGluR2 agonist, on behaviors suppressed by electric shock, in rats and pigeons. Drug Dev. Res. 47, 37–44 (1999).

    CAS  Google Scholar 

  115. Moore, N. A., Rees, G. & Monn, J. A. Effects of the group II metabotropic glutamate receptor agonist, LY354740 on schedule-controlled behaviour in rats. Behav. Pharmacol. 10, 319–325 (1999).

    CAS  PubMed  Google Scholar 

  116. Swanson, C. J., Perry, K. W. & Schoepp, D. D. The mGlu2/3 receptor agonist, LY354740, blocks immobilization-induced increases in noradrenaline and dopamine release in the rat medial prefrontal cortex. J. Neurochem. 88, 194–202 (2004). Stress responses that lead to enhanced release of brain monoamines can be suppressed by mGlu 2/3 receptor activation without effects on basal levels of these neurotransmitters.

    CAS  PubMed  Google Scholar 

  117. Schoepp, D. D. Case study: utility of metabotropic glutamate agonists in psychiatric illness. 5th World Congress on Stress. Abs 120 (2004).

  118. Yamanoi, K. & Ohfune, Y. Synthesis of trans and cis-α-(carboxycyclopropyl)glycines. Novel neuroinhibitory amino acids as L-glutamate analogue. Tetrahedron Lett. 29, 1181–4 (1988).

    CAS  Google Scholar 

  119. Shimamoto, K., Ishida, M., Shinozaki, H. & Ohfune, Y. Synthesis of four diastereomeric L-2-carboxycyclopropy1) glycines. Conformationally constrained L-glutamate analogues. J. Org. Chem. 56, 4167–4176 (1991).

    CAS  Google Scholar 

  120. Monn, J. A. et al. Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate: identification of a potent, highly selective, and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase. J. Med. Chem. 39, 2990–3000 (1996).

    CAS  PubMed  Google Scholar 

  121. Acher, F. C. et al. Synthesis and pharmacological characterization of aminocyclopentanetricarboxylic acids: new tools to discriminate between metabotropic glutamate receptor subtypes. J. Med. Chem. 40, 3119–3129 (1997).

    CAS  PubMed  Google Scholar 

  122. Kozikowski, A. P. et al. Synthesis and metabotropic glutamate receptor activity of a 2-aminobicyclo[3.2.0] heptane-2,5-dicarboxylic acid, a molecule possessing an extended glutamate conformation. Bioorg. Med. Chem. Lett. 8, 925–930 (1998).

    CAS  PubMed  Google Scholar 

  123. Monn, J. A. et al. Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors. J. Med. Chem. 42, 1027–1040 (1999).

    CAS  PubMed  Google Scholar 

  124. Schoepp, D. D. et al. LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. Neuropharmacology 36, 1–11 (1997). LY354740 is a potent agonist for recombinant human mGlu 2/3 receptors and selectively activates endogenous brain rat mGlu 2/3 receptors in a stereoselective manner.

    CAS  PubMed  Google Scholar 

  125. Malherbe, P. et al. Identification of essential residues involved in the glutamate binding pocket of the group II metabotropic glutamate receptor. Mol. Pharmacol. 60, 944–954 (2001).

    CAS  PubMed  Google Scholar 

  126. Kunishima, N. et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407, 971–977 (2000).

    CAS  PubMed  Google Scholar 

  127. Varney, M. A. & Suto, C. M. Discovery of subtype-selective metabotropic glutamate receptor ligands using functional HTS assays. Drug Discov. Today 1, 20–26 (2000).

    CAS  Google Scholar 

  128. Varney, M. A. et al. SIB-1757 and SIB-1893: selective, noncompetitive antagonists of metabotropic glutamate receptor type 5. J. Pharmacol. Exp. Ther. 290, 170–181 (1999). The use of high-throughput screening with functional mGlu receptor readouts led to novel subtype-selective and non-competitive mGlu 5 receptor antagonists.

    CAS  PubMed  Google Scholar 

  129. Pagano, A. et al. The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyimino-cyclopropan[b]chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors. J. Biol. Chem. 275, 33750–33758 (2000).

    CAS  PubMed  Google Scholar 

  130. Malherbe, P. et al. Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)–pyridine. Mol. Pharmacol. 64, 823–832 (2003).

    CAS  PubMed  Google Scholar 

  131. Linden, A. -M., Baez, M., Shannon, H., Bergerm, M. & Schoepp, D. D. The anxiolytic-like activity of LY354580 is absent in mGlu2 and mGlu3 knockout mice. Psychopharmacol. (in the press).

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Correspondence to Darryle D. Schoepp.

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DATABASES

Entrez Gene

mGlu1

mGlu2

mGlu3

mGlu4

mGlu5

mGlu6

mGlu7

mGlu8

Glossary

IONOTROPIC RECEPTOR

A ligand-gated ion channel receptor that modulates cell excitability.

GLYCINE SITE

The NMDA receptor is unique in that glycine (possibly D-serine) acts as a co-agonist with glutamate at a different site on the receptor complex.

ELEVATED PLUS MAZE

A commonly used anxiety test for rodents in which the animal can choose to explore an 'open' unprotected arm or a 'closed' protected arm of a cross-shaped elevated platform. Animals which are less fearful spend more time in the open arm and enter it more often.

MORRIS WATER MAZE

A learning task in which an animal is placed in a pool filled with opaque water and has to use spatial cues to find a hidden platform that is placed at a constant position.

DELAYED MATCHING TO POSITION TEST

Rats are trained to press a lever for food rewards, then trained to make either a matching or non-matching response in a task. The task consists of an illuminated lever being presented and retracted (sample stage) followed by a nose poke into the food tray, delivering two levers. For a correct matching response the animal presses the previous (sample stage) lever for a food reward; for a correct non-matching response the animal presses the other (non-sample stage) lever for a food reward.

VOGEL TEST

Also known as the conflict drinking test, this test uses water-deprived rats that are punished with an electric shock when drinking. Anxiolytic drugs increase drinking behaviour that has been suppressed under threat of shock in this test.

FOUR-PLATE TEST

A test in which the test animal is placed on a plate and allowed to explore, after which each time the animal passes from one plate to another a shock is delivered. Anxiolytic drugs reduce the fear of shock and increase the number of punished crossings.

GELLER–SEIFTER TEST

An anxiety test in which animals learn to press a lever for food, after which food is only delivered under threat of shock. Anxiolytic drugs increase lever pressing that is normally suppressed by the threat of shock punishment.

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Swanson, C., Bures, M., Johnson, M. et al. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 4, 131–144 (2005). https://doi.org/10.1038/nrd1630

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