Metabotropic glutamate receptors: Their therapeutic potential in anxiety

Current Topics in Behavioral Neurosciences

Volumn 2, Issue , 2010, Pages 391-413

  Spooren, Will ^a   Lesage, Anne ^b   Lavreysen, Hilde ^b   Gasparini, Fabrizio ^c   Steckler, Thomas ^b  

^a Hoffmann La Roche   (Switzerland)

^b CNS Neurosciences Pharmaceutical Research and Early Development   (Belgium)

^c NOVARTIS PHARMA AG   (Switzerland)

Author keywords

Allosteric; Anxiety; Glutamate; Metabotropic; Orthosteric; Receptors

Indexed keywords

2 CYCLOPROPYL 5 [1 (2 FLUORO 3 PYRIDINYL) 5 METHYL 1H 1,2,3 TRIAZOL 4 YL] 2,3 DIHYDRO 1H ISOINDOL 1 ONE; 2 METHYL 6 (2 PHENYLVINYL)PYRIDINE; 3 ETHYL 2 METHYLQUINOLIN 6 YL CIS 4 METHOXYCYCLOHEXYL KETONE; 3,4 DIHYDRO 2H PYRANO[2,3] B QUINOLIN 7 YLCIS 4 METHOXYCYCLOHEXYL KETONE; 4 [1 (2 FLUOROPYRIDINE 3 YL) 5 METHYL 1H 1,2,3 TRIAZOL 4 YL] N ISOPROPYL N METHYL 3,6 DIHYDROPYRIDINE 1 [2H]CARBOXAMIDE; 6 METHYL 2 PHENYLAZO 3 PYRIDINOL; 9 DIMETHYLAMINO 3 (N HEXAMETHYLENEIMINYL) 3H 5 THIA 1,3,6 TRIAZAFLUOREN 4 ONE; A 841720; ADX 10059; AMN 082; BAY 36 7620; DIAZEPAM; EGLUMETAD; FENOBAM; JNJ 16259685; JNJ 16567083; LORAZEPAM; LY 487379; LY487379; METABOTROPIC RECEPTOR; METABOTROPIC RECEPTOR 1; METABOTROPIC RECEPTOR 2; METABOTROPIC RECEPTOR 3; METABOTROPIC RECEPTOR 4; METABOTROPIC RECEPTOR 5; METABOTROPIC RECEPTOR 6; METABOTROPIC RECEPTOR 7; METABOTROPIC RECEPTOR 8; METABOTROPIC RECEPTOR AGONIST; METABOTROPIC RECEPTOR ANTAGONIST; PAROXETINE; TALAGLUMETAD; UNCLASSIFIED DRUG; UNINDEXED DRUG; 6 METHYL 2 (PHENYLETHYNYL)PYRIDINE; 6-METHYL-2-(PHENYLETHYNYL)PYRIDINE; 7 (HYDROXYIMINO)CYCLOPROPAN(B)CHROMEN 1A CARBXOYLIC ACID ETHYL ESTER; 7-(HYDROXYIMINO)CYCLOPROPAN(B)CHROMEN-1A-CARBXOYLIC ACID ETHYL ESTER; ANXIOLYTIC AGENT; CHROMONE DERIVATIVE; LIGAND GATED ION CHANNEL; PHENAZOPYRIDINE; PYRIDINE DERIVATIVE;

AMYGDALOID NUCLEUS; ANXIETY DISORDER; ARTICLE; BASAL GANGLION; BRAIN REGION; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG INDICATION; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG TARGETING; GENERALIZED ANXIETY DISORDER; HIPPOCAMPUS; HUMAN; IC 50; LIMBIC CORTEX; NONHUMAN; OLFACTORY BULB; PANIC; PERIAQUEDUCTAL GRAY MATTER; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; RECEPTOR BLOCKING; SYNAPTIC TRANSMISSION; TISSUE DISTRIBUTION; ANIMAL; BRAIN; CLASSIFICATION; DRUG ANTAGONISM; DRUG EFFECT; METABOLISM; REVIEW; TREATMENT OUTCOME;

ANIMALS; ANTI-ANXIETY AGENTS; ANXIETY DISORDERS; BRAIN; CHROMONES; HUMANS; LIGAND-GATED ION CHANNELS; PHENAZOPYRIDINE; PYRIDINES; RECEPTORS, METABOTROPIC GLUTAMATE; SYNAPTIC TRANSMISSION; TREATMENT OUTCOME;

EID: 84862865362     PISSN: 18663370     EISSN: 18663389     Source Type: Book Series    
DOI: 10.1007/7854_2010_36     Document Type: Article

References (132)

1. Aiba A, Chen C, Herrup K, Rosenmund C, Stevens CF, Tonegawa S (1994) Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice. Cell 79:365-375
2. Anwyl R (2009) Metabotropic glutamate receptor-dependent long-term potentiation. Neuropharmacology 56:735-740
3. Battaglia G, Bruno V, Pisani A, Centonze D, Vincenza M, Calabresi P, Nicoletti F (2001) Selective blockade of type-1 metabotropic glutamate receptors induces neuroprotection by enhancing gabaergic transmission. Mol Cell Neurosci 17:1071-1083
4. Battaglia G, Busceti CL, Molinaro G, Biagioni F, Traficante A, Nicoletti F, Bruno V (2006) Pharmacological activation of mGlu4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. J Neurosci 26:7222-7229
5. Beqollari D, Kammermeier PJ (2008) The mGlu(4) receptor allosteric modulator N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide acts as a direct agonist at mGlu(6) receptors. Eur J Pharmacol 589:49-52
6. Bergink V, Westernberg HGM (2005) Metabotropic glutamate II receptor agonists in panic disorder: a double blind clinical trial with LY354740. Int Clin Psychopharmacol 20:291-293
7. Bittencourt AS, Carobrez AP, Zamprogno LP, Tufik S, Schenberg LC (2004) Organization of single components of defensive behaviors within distinct columns of periaqueductal gray matter of the rat: role of N-methyl-D-aspartic acid glutamate receptors. Neuroscience 125:74-89
8. Bordi F (1996) Reduced long-term potentiation in the dentate gyrus of mGlu1 receptor-mutant mice in vivo. Eur J Pharmacol 301:R15-R16
9. Bradley SR, Levey AI, Hersch SM, Conn PJ (1996) Immunocytochemical localization of group III metabotropic glutamate receptors in the hippocampus with subtype-specific antibodies. J Neurosci 16:2044-2056
10. Bradley SR, Standaert DG, Rhodes KJ, Rees HD, Testa CM, Levey AI, Conn PJ (1999) Immunohistochemical localization of subtype 4a metabotropic glutamate receptors in the rat and mouse basal ganglia. J Comp Neurol 407:33-46
11. Brauner-Osborne H, Slok FA, Skjaerbaek N, Ebert B, Sekiyama N, Nakanishi S, Krogsgaard-Larsen P (1996) A new highly selective metabotropic excitatory amino acid agonist: 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid. J Med Chem 39:3188-3194
12. Brauner-Osborne H, Wellendorph P, Jensen AA (2007) Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. Curr Drug Targets 8:169-184
13. Bushell TJ, Sansig G, Collett VJ, van der Putten H, Collingridge GL (2002) Altered short-term synaptic plasticity in mice lacking the metabotropic glutamate receptor mGlu7. Scientific World J 2:730-737
14. Callaerts-Vegh Z, Beckers T, Ball SM, Baeyens F, Callaerts PF, Cryan JF, Molnar E, D'Hooge R (2006) Concomitant deficits in working memory and fear extinction are functionally dissociated from reduced anxiety in metabotropic glutamate receptor 7-deficient mice. J Neurosci 26:6573-6582
15. Carroll FY, Stolle A, Beart PM, Voerste A, Brabet I, Muller F, Joly C, Antonicek H, Bockaert J, Müller T, Pin JP, Prézeau L (2001) BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol Pharmacol 59:965-973
16. Chaudhari N, Landin MA, Roper SD (2000) A Metabotropic glutamate receptor variant functions as a taste receptor. Nat Neurosci 3:113-119
17. Chojnacka-Wojcik E, Tatarczynska E, Pilc A (1996) Anxiolytic-like effects of metabotropic glutamate antagonist (RS)-alpha-methylserine-O-phosphate in rats. Pol J Pharmacol 48: 507-509
18. Conquet F, Bashir ZI, Davies CH, Daniel H, Ferraguti F, Bordi F, Franz-Bacon K, Reggiani A, Matarese V, Condé F, Collingridge GL, Crépel F (1994) Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1. Nature 372:237-243
19. Corti C, Restituito S, Rimland JM, Brabet I, Corsi M, Pin JP, Ferraguti F (1998) Cloning and characterization of alternative mRNA forms for the rat metabotropic glutamate receptors mGluR7 and mGluR8. Eur J Neurosci 10:3629-3641
20. Corti C, Battaglia G, Molinaro G, Riozzi B, Pittaluga A, Corsi M, Mugnaini M, Nicoletti F, Bruno V (2007) The use of knock-out mice unravels distinct roles for mGlu2 and mGlu3 metabotropic glutamate receptors in mechanisms of neurodegeneration/neuroprotection. J Neurosci 27:8297-8308
21. Cozzi A, Meli E, Carlà V, Pellicciari R, Moroni F, Pellegrini-Giampietro DE (2002) Metabotropic glutamate 1 (mGlu1) receptor antagonists enhance GABAergic neurotransmission: a mechanism for the attenuation of post-ischemic injury and epileptiform activity? Neuropharmacology 43:119-130
22. 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
23. De Colle C, Bessis AS, Bockaert J, Acher F, Pin JP (2000) Pharmacological characterization of the rat metabotropic glutamate receptor type 8a revealed strong similarities and slight differences with the type 4a receptor. Eur J Pharmacol 394:17-26
24. Dingledine R, Conn PJ (2000) Peripheral glutamate receptors: molecular biology and role in taste sensation. J Nutr 130(4 Suppl):1039S-1042S
25. Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tolleson GD (2008) Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology 33:1603-1610
26. Duvoisin RM, Zhang C, Ramonell K (1995) A novel metabotropic glutamate receptor expressed in the retina and olfactory bulb. J Neurosci 15:3075-3083
27. Duvoisin RM, Zhang C, Pfankuch TF, O'Connor H, Gayet-Primo J, Quraishi S, Raber J (2005) Increased measures of anxiety and weight gain in mice lacking the group III metabotropic glutamate receptor mGluR8. Eur J Neurosci 22:425-436
28. El-Kouhen O, Lehto SG, Pan JB, Chang R, Baker SJ, Zhong C, Hollingsworth PR, Mikusa JP, Cronin EA, Chu KL, McGaraughty SP, Uchic ME, Miller LN, Rodell NM, Patel M, Bhatia P, Mezler M, Kolasa T, Zheng GZ, Fox GB, Stewart AO, Decker MW, Moreland RB, Brioni JD, Honore P (2006) Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist. Br J Pharmacol 149:761-774
29. Engers DW, Niswender CM, Weaver CD, Jadhav S, Menon UN, Zamorano R, Conn PJ, Lindsley CW, Hopkins CR (2009) Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs). J Med Chem 52:4115-4118
30. Engin E, Treit D (2008) The effects of intra-cerebral drug infusions on animals' unconditioned fear reactions: a systematic review. Prog Neuropsychopharmacol Biol Psychiatry 32:1399-1419
31. Fell MJ, Svensson KA, Johnson BG, Schoepp DD (2008) Evidence for the role of mGlu2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist LY404039. J Pharmacol Exp Ther 326:209-217
32. Fendt M, Schmid S, Thakker DR, Jacobson LH, Yamamoto R, Mitsukawa K, Maier R, Natt F, Husken D, Kelly PH, McAllister KH, Hoyer D, van der Putten H, Cryan JF, Flor PJ (2008) mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity. Mol Psychiatry 13:970-979
33. Ferraguti F, Shigemoto R (2006) Metabotropic glutamate receptors. Cell Tissue Res 326:483-504
34. Ferris P, Seward E, Dawson GR (2001) Interactions between LY354740, a group II metabotropic agonist and the GABA(A)-benzodiazepine receptor complex in the rat elevated plus-maze. J Psychopharmacol 15:76-82
35. Friedman CTH, Davis JL, Ciccone PE, Rubin RT (1980) Phase II double-blind controlled study of a new anxiolytic, fenobam (McN-3377) vs placebo. Curr Ther Res 27:144-151
36. Galici R, Jones CK, Hemstapat K, Nong Y, Echemendia NG, Williams LC, de Paulis T, Conn PJ (2006) Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor dubtype 2, has antipsychotic-and anxiolytic-like effects in mice. J Pharmacol Exp Ther 318:173-185
37. Gasparini F, Spooren W(2007) Allosteric modulators for mGlu receptors. Curr Neuropharmacol 5 (3):187-194
38. Gasparini F, Bilbe G, Gomez-Mancilla B, Spooren W (2008) mGluR5 antagonists: discovery, characterization and drug development. Curr Opin Drug Discov Devel 11(5):655-665
39. Gil-Sanz C, Delgado-Garci{dotless}́a JM, Fairén A, Gruart A (2008) Involvement of the mGluR1 receptor in hippocampal synaptic plasticity and associative learning in behaving mice. Cereb Cortex 18:1653-1663
40. Goldberg ME, Salama AI, Patel JB, Malick JB (1983) Novel non-benzodiazepine anxiolytics. Neuropharmacology 22(12B):1499-1504
41. Gravius A, Pietraszak M, Schäfer D, Schmidt WJ, DanyszW (2005) Effects of mGlu1 and mGlu5 receptor antagonists on negatively reinforced learning. Behav Pharmacol 16:113-121
42. Gravius A, Barberi C, Schäfer D, Schmidt WJ, Danysz W(2006) The role of group I metabotropic glutamate receptors in acquisition and expression of contextual and auditory fear conditioning in rats-a comparison. Neuropharmacology 51:1146-1155
43. Grillon C, Cordova J, Levine LR, Morgan CA III (2003) Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans. Psychopharmacology 168:446-454
44. Han G, Hampson DR (1999) Ligand binding to the amino-terminal domain of the mGluR4 subtype of metabotropic glutamate receptor. J Biol Chem 274:10008-10013
45. Heidinger V, Manzerra P, Wang ZQ, Strasser U, Yu S-P, Choi DW, Behrens MM (2002) Metabotropic glutamate receptor 1-induced upregulation of NMDA receptor current: mediation through the Pyk2/Src-family kinase pathway in cortical neurons. J Neurosci 22:5452-5461
46. Hoang CJ, Hay M (2001) Expression of metabotropic glutamate receptors in nodose ganglia and the nucleus of the solitary tract. Am J Physiol Heart Circ Physiol 281:457-462
47. Holscher C, Schmid S, Pilz PK, Sansig G, van der Putten H, Plappert CF (2004) Lack of the metabotropic glutamate receptor subtype 7 selectively impairs short-term working memory but not long-term memory. Behav Brain Res 154:473-481
48. Holscher C, Schmid S, Pilz PK, Sansig G, van der Putten H, Plappert CF (2005) Lack of the metabotropic glutamate receptor subtype 7 selectively modulates Theta rhythm and working memory. Learn Mem 12:450-455
49. Hsia AY, Salin PA, Castillo PE, Aiba A, Abeliovich A, Tonegawa S, Nicoll RA (1995) Evidence against a role for metabotropic glutamate receptors in mossy fiber LTP: the use of mutant mice and pharmacological antagonists. Neuropharmacology 34:1567-1572
50. Jaeschke G, Wettstein J, Nordquist R, Spooren W (2008) mGlu5 receptor antagonists and their therapeutic potential. Expert Opin Ther Patents 18(2):123-142
51. Janssens N, Lesage AS (2001) Glutamate receptor subunit expression in primary neuronal and secondary glial cultures. J Neurochem 77(6):1457-1474
52. Johnson MP, Baez M, Jagdmann GE Jr, Britton TC, Large TH, Callagaro DO, Tizzano JP, Monn JA, Schoepp DD (2003) 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-3ylmethylamine. J Med Chem 46:3189-3192
53. Johnson PL, Lowry CA, Truitt W, Shekhar A (2008) Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic. J Psychopharmacol 22:642-652
54. Kellner M, Muhtz C, Stark K, Yassouridis A, Arlt J, Wiedemann K (2005) Effects of a metabotropic glutamate2/3 receptor agonist (LY544344/LY354740) on panic anxiety induced by cholecystokinin tetrapeptide in healthy humans: preliminary results. Psychopharmacology 179:310-315
55. Kim J, Lee S, Park H, Song B, Hong I, Geum D, Shin K, Choi S (2007) Blockade of amygdala metabotropic glutamate receptor subtype 1 impairs fear extinction. Biochem Biophys Res Commun 355:188-193
56. 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 393:332-352
57. Klodzinska A, Tatarczynska E, Stachowicz K, Chojnacka-Wojcik E (2004) The anxiolytic-like activity of aida (1-aminoindan-1, 5-dicarboxylic acid), an mGlu1 receptor antagonist. J Physiol Pharmacol 55:113-126
58. Kotlinska J, Bochenski M (2008) The influence of various glutamate receptors antagonists on anxiety-like effect of ethanol withdrawal in a plus-maze test in rats. Eur J Pharmacol 598: 57-63
59. Lapierre YD, Oyewumi LK (1982) Fenobam: another Anxiolytic? Curr Ther Res 31:95-101
60. Lavreysen H, Janssen C, Bischoff F, Langlois X, Leysen JE, Lesage ASJ (2003) [3H]R214127: a novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists. Mol Pharmacol 63:1082-1093
61. Lavreysen H, Nóbrega Pereira S, Leysen JE, Langlois X, Lesage ASJ (2004a) Metabotropic glutamate 1 receptor distribution and occupancy in the rat brain: a quantitative autoradiographic study using [3H]R214127. Neuropharmacology 46:609-619
62. Lavreysen H, Wouters R, Bischoff F, Nóbrega Pereira S, Langlois X, Blokland S, Somers M, Dillen L, Lesage ASJ (2004b) JNJ16259685, a highly potent, selective ans systemically active mGlu1 receptor antagonist. Neuropharmacology 47:961-972
63. Lesage ASJ, Steckler T (2010). Metabotropic glutamate mGlu1 receptor stimulation and blockade: therapeutic opportunities in psychiatric illness. Eur J Pharmacol (in press)
64. 2challenge in patients diagnosed with panic disorders. Neuropharmacology 43:294-295
65. Lima VCF, Molchanov ML, Aguiar DC, Campos AC, Silveira Guimaraes F (2008) Modulation of defensive responses and anxiety-like behaviors by group I metabotropic glutamate receptors located in the dorsolateral periaqueductal gray. Prog Neuropsychopharmacol Biol Psychiatry 32:178-185
66. Linden AM, Johnson BG, Peters SC, Shannon HE, Tian M, Wang Y, Yu JL, Koster A, Baez M, Schoepp DD (2002) Increased anxiety-related behavior in mice deficient for metabotropic glutamate 8 (mGlu8) receptor. Neuropharmacology 43:251-259
67. Linden AM, Bergeron M, Baez M, Schoepp DD (2003) Systemic administration of the potent mGlu8 receptor agonist (S)-3, 4-DCPG induces c-Fos in stress-related brain regions in wildtype, but not mGlu8 receptor knockout mice. Neuropharmacology 45:473-483
68. Linden AM, Greene SJ, Bergeron M, Schoepp DD (2004) Anxolytic ativity of the mGlu/3 receptor aonist LY354740 on the elevated plus aze is associated with 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
69. Linden AM, Shannon H, Baez M, Yu J, Koester A, Schoepp DD (2005) Anxiolytic activity of the mGlu2/3 receptor agonist LY354740 on the elevated plus maze test is disrupted in metabotropic glutamate 2 and 3 knockout mice. Psychopharmacology 179:284-291
70. Maciejak P, Lehner M, Turzynska D, Szyndler J, Bidzinski A, Taracha E, Sobolewska A, Walkowiak J, Skórzewska A, Wislowska A, Hamed A, Plaznik A (2008) The opposite role of hippocampal mGluR1 in fear conditioning in kindled and non-kindled rats. Brain Res 1187:184-193
71. MajM, Bruno V, Dragic Z, Yamamoto R, Battaglia G, InderbitzinW, StoehrN, Stein T, Gasparini F, Vranesic I (2003) (-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection. Neuropharmacology 45:895-906
72. Marino MJ, Williams DL Jr, O'Brien JA, Valenti O, McDonald TP, Clements MK, Wang R, DiLella AG, Hess JF, Kinney GG, Conn PJ (2003) Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment. Proc Natl Acad Sci USA 100:13668-13673
73. Masu M, Iwakabe H, Tagawa Y, Miyoshi T, Yamashita M, Fukuda Y, Sasaki H, Hiroi K, Nakamura Y, Shigemoto R (1995) Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene. Cell 80:757-765
74. Michelson D, Levine LR, Dellva MA, Mesters P, Schoepp DD, Dunayevich D, Tollefson GD (2005) Clinical studies with mGluR2/3 agonists: LY354740 compared with placebo in patients with generalized anxiety disorder. Neuropharmacology 49:257
75. 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 USA 102:18712-18717
76. 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 31:1112-1122
77. Monn JA, Valli MJ, Massey SM, Wright RA, Salhoff CR, Johnson BG et al (1997) 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
78. Nadlewska A, Car H, Wisniewska RJ, Wisniewski K (2003) Influence of aida on certain behaviors in rats subjected to experimental hypoxia. Pol J Pharmacol 55:171-180
79. Nakajima Y, Iwakabe H, Akazawa C, Nawa H, Shigemoto R, Mizuno N, Nakanishi S (1993) Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for L-2-amino-4-phosphonobutyrate. J Biol Chem 268:11868-11873
80. Navarro JF, De Castro V, Marti{dotless}́n-López M (2008) JNJ16259685, a selective mGlu1 antagonist, suppresses isolation-induced aggression in male mice. Eur J Pharmacol 586:217-220
81. Nielsen KS, Macphail EM, Riedel G (1997) 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
82. Niswender C, Johnson KA, Weaver CD, Jones CK, Xiang Z, Luo Q, Rodriguez AL, Marlo JE, de Paulis T, Thompson AD, Days EL, Nalywajko T, Austin CA, Baxter Williams M, Ayala JE, Williams R, Lindsley CW, Conn PJ (2008) Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol Pharmacol 74:1345-1358
83. 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 46:151-159
84. Patel JB, Martin C, Malick JB (1982) Differential antagonism of the anticonflict effects of typical and atypical anxiolytics. Eur J Pharmacol 86(2):295-298
85. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, AvedisovaAS, BardensteinLM, Gurovich IY, MorozovaMA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 13:1102-1107
86. Pecknold JC, McClure DJ, Appeltauer L, Wrzesinski L, Allan TJ (1982) Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study. Clin Psychopharmacol 2(2):129-133
87. Pellegrini-Giampietro DE, Peruginelli F, Meli E, Cozzi A, Albani-Torregrossa S, Pellicciari R, Moroni F (1999) Protection with metabotropic glutamate 1 receptor antagonists in models of ischemic neuronal death: time-course and mechanisms. Neuropharmacology 38:1607-1619
88. Priolo E, Libri V, Lopilato R, David E, Nappi G, Nisticò G (1991) Panic-like attack induced by microinfusion into the locus coeruleus of antagonists and inverse agonists at GABAA-receptors in rodents. Funct Neurol 6:393-403
89. Porter RHP, Jaeschke G, Spooren W et al (2005) Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther 315:711-721
90. Robbins MJ, Starr KR, Honey A, Soffin EM, Rourke C, Jones GA, Kelly FM, Strum J, Melarange RA, Harris AJ, Rocheville M, Rupniak T, Murdock PR, Jones DN, Kew JN, Maycox PR (2007) Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia. Brain Res 1152:215-227
91. Rorick-Kehn LM, Hart JC, McKinzie DL (2005) Pharmacological characterization of stressinduced hyperthermia in DBA/2 mice using metabotropic and ionotropic glutamate receptor ligands. Psychopharmacology 183:226-240
92. Rorick-Kehn LM, Perkins EJ, Knitowski KM, Hart JC, Johnson BG, Schoepp DD, McKinzie DL (2006) Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344. J Pharmacol Exp Ther 316:905-913
93. Rorick-Kehn LM, Johnson BG, Knitowski KM, Salhoff CR, Witkin JM, Perry KW, Griffey KI, Tizzano JP, Monn JA, McKinzie DL, Schoepp DD (2007) In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders. Psychopharmacology 193:121-136
94. Salt TE, Binns KE (2000) Contributions of mGlu1 and mGlu5 receptors to interactions with Nmethyl-D-aspartate receptor-mediated responses and nociceptive sensory responses of rat thalamic neurons. Neuroscience 100:375-380
95. Sansig G, Bushell TJ, Clarke VR, 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 21:8734-8745
96. Satow A, Maehara S, Ise S, Hikichi H, Fukushima M, Suzuki G, Kimura T, Tanaka T, Ito S, Kawamoto H, Ohta H (2008) Pharmacological effects of the metabotropic glutamate receptor 1 antagonist compared with those of the metabotropic glutamate receptor 5 antagonist and metabotropic glutamate receptor 2/3 agonist in rodents: detailed investigations with a selective allosteric metabotropic glutamate receptor 1 antagonist, FTIDC [4-[1-(2-Fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-Nisopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide]. J Pharmacol Exp Ther 326:577-586
97. Saugstad JA, Kinzie JM, Shinohara MM, Segerson TP, Westbrook GL (1997) Cloning and expression of rat metabotropic glutamate receptor 8 reveals a distinct pharmacological profile. Mol Pharmacol 51:119-125
98. Schlumberger C, Schafer D, Barberi C, More L, Nagel J, Pietraszek M, Schmidt WJ, Danysz W (2009) Effects of a metabotropic glutamate receptor group II agonist LY354740 in animal models of positive schizophrenia symptoms and cognition. Behav Pharmacol 20:56-66
99. Schmid S, Fendt M (2006) Effects of the mGluR8 agonist (S)-3, 4-DCPG in the lateral amygdala on acquisition/expression of fear-potentiated startle, synaptic transmission, and plasticity. Neuropharmacology 50:154-164
100. Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. Pharmacol Exp Ther 299(1):12-20
101. Schoepp DD, Conn PJ (2002) Metabotropic glutamate receptors. Pharmacol Biochem Behav 74 (1):255-256
102. Schoepp DD, Wright RA, Levine LR, Gaydos B, Potter WZ (2003) LY354740, A mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress 6:189-197
103. Shekhar A, Keim SR (2000) LY354740, a potent group II metabotropic glutamate receptor agonist prevents lactate-induced panic-like response in panic-prone rats. Neuropharmacology 39:1139-1146
104. Shigemoto R, Mizuno N (2000) Metabotropic glutamate receptors-immunocytochemical and in situ hybridization analysis. In: Ottersen OP, Storm-Mathisen J (eds) Handbook of chemical neuroanatomy. Elsevier Science, Amsterdam, pp 63-98
105. Shigemoto R, Nakanishi S, Mizuno N (1992) Distribution of the mRNA for a metabotropic glutamate receptor (mGluR1) in the central nervous system: an in situ hybridization study in adult and developing rat. J Comp Neurol 322:121-135
106. 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
107. Silva AJ (2003) Molecular and cellular cognitive studies of the role of synaptic plasticity in memory. J Neurobiol 54:224-237
108. Simonyi A, Ngomba RT, Storto M, Catania MV, Miller LA, Youngs B, DiGiorgi-Gerevini V, Nicoletti F, Sun GY (2005) Expression of groups I and II metabotropic glutamate receptors in the rat brain during aging. Brain Res 1043:95-106
109. Simonyi A, Serfozo P, Shelat PB, Dopheide MM, Coulibaly AP, Schachtman TR (2007) Differential roles of hippocampal metabotropic glutamate receptors 1 and 5 in inhibitory avoidance learning. Neurobiol Learn Mem 88:305-311
110. Spooren W, Gasparini F (2004) mGlu5 receptor antagonists: a novel class of anxiolytics? Drug News Perspect 17(4):251-257
111. Spooren W, Ballard T, Gasparini F, Amalric M, Mutel V, Schreiber R (2003) Insight into the function of group I and group II metabotropic glutamate (mGlu) receptors: behavioural characterization and implications for the treatment of CNS disorders. Behav Pharmacol 14:257-277
112. Spooren WP, Gasparini F, van der Putten H, Koller M, Nakanishi S, Kuhn R (2000) Lack of effect of LY314582 (a group 2 metabotropic glutamate receptor agonist) on phencyclidine-induced locomotor activity in metabotropic glutamate receptor 2 knockout mice. Eur J Pharmacol 397 (1):R1-R2
113. Spooren WP, Schoeffter P, Gasparini F, Kuhn R, Gentsch C (2002) Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY354740, MPEP and NKP608). Eur J Pharmacol 435:161-170
114. Stachowicz K, Klak K, Pilc A, Chojnacka-Wojcik E (2005) Lack of the antianxiety-like effect of (S)-3, 4-DCPG, an mGlu8 receptor agonist, after central administration in rats. Pharmacol Rep 57:856-860
115. Asignaling. Pharmacol Rep 58: 820-826
116. Steckler T, Lavreysen H, Oliveira AM, Aerts N, Van Craenendonck H, Prickaerts J, Megens A, Lesage ASJ (2005) Effects of mGlu1 receptor blockade on anxiety-related behaviour in the rat lick suppression test. Psychopharmacology 179:198-206
117. Suzuki G, Kimura T, Satow A, Kaneko N, Fukuda J, Hikichi H, Sakai N, Maehara S, Kawagoe-Takaki H, Hata M, Azuma T, Ito S, Kawamoto H, Ohta H (2007a) Pharmacological characterization of a new, orally active and potent allosteric metabotropic glutamate receptor 1 antagonist, 4-[1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1, 2, 3-triazol-4-yl]-N-isopropyl-N-methyl-3, 6-dihydropyridine-1(2H)-carboxamide (FTIDC). J Pharmacol Exp Ther 321:1144-1153
118. Suzuki G, Tsukamoto N, Fushiki H, Kawagishi A, NakamuraM, Kurihara H, Mitsuya M, Ohkubo M, Ohta H (2007b) In vitro pharmacological characterization of novel isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists. J Pharm Exp Ther 323:147-156
119. 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
120. Tatarczynska E, Klodzinska A, Kroczka B, Chojnacka-Wojcik E, Pilc A (2001) The antianxietylike effects of antagonists of group I and agonists of group II and III metabotropic glutamate receptors after intrahippocampal administration. Psychopharmacology 158:94-99
121. Testa CM, Standaert DG, Young AB, Penney JB Jr (1994) Metabotropic glutamate receptor mRNA expression in the basal ganglia of the rat. J Neurosci 14:3005-3018
122. Tizzano JP, Griffey KI, Schoepp DD (2002) the anxiolytic action of mGlu2/3 receptor agonist, LY354740, in the fear-potentiated startle model in rats is mechanistically distingt from diazepam. Pharmacol Biochem Behav 73:367-374
123. Thomas NK, Wright RA, Howson PA, Kingston AE, Schoepp DD, Jane DE (2001) (S)-3, 4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord. Neuropharmacology 40:311-318
124. Tong Q, Kirchgessner AL (2003) Localization and function of metabotropic glutamate receptor 8 in the enteric nervous system. Am J Physiol Gastrointest Liver Physiol 285:G992-G1003
125. Tong Q, Ouedraogo R, Kirchgessner AL (2002) Localization and function of group III metabotropic glutamate receptors in rat pancreatic islets. Am J Physiol Endocrinol Metab 282:1324-1333
126. Varty GB, Grilli M, Forlani A, Fredduzzi S, Grzelak ME, Guthrie DH, Hodgson RA, Lu SX, Nicolussi E, Pond AJ, Parker EM, Hunter JC, Higgins GA, Reggiani A, Bertorelli R (2005) The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles. Psychopharmacology 179:207-217
127. Walker DL, Rattiner LM, Davis M (2002) Group II metabotropic glutamate receptors within the amygdale regulate fear as assessed with potentiated startle in rats. Behav Neurosci 116:1075-1083
128. Witkin JM, Marekm GJ, Johnson BG, Schoepp DD (2007) Metabotropic glutamate receptors in the control of mood disorders. CNS Neurol Disord Drug Targets 6:87-100
129. Woolley ML, Pemberton DJ, Bate S, Corti C, Jones DNC (2008) The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity. Psychopharmacology 196:431-440
130. Wright RA, Arnold MB, Wheeler WJ, Ornstein PL, Schoepp DD (2000) Binding of [3H](2 S, 10S, 20S)-2-(9-xanthylmethyl)-2-(20-carboxycyclopropyl) glycine ([3H]LY341495) to cell membranes expressing recombinant human group III metabotropic glutamate receptor subtypes. Naunyn Schmiedebergs Arch Pharmacol 362:546-554
131. Wu WN, McKown LA, O'Neill PJ (1995) In vitro and in vivo metabolism of the antianxiolytic agent fenobam in the rat. J Pharm Sci 84(2):185-189
132. Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR Jr, Schoepp DD, Belagaje RM (1998) Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells. Mol Brain Res 53:88-97