Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
CNS Drugs
Published in: CNS Drugs 8/2010

01-08-2010 | Review Article

Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists

Authors: Dr John H. Krystal, Sanjay J. Mathew, D. Cyril D’Souza, Amir Garakani, Handan Gunduz-Bruce, Dennis S. Charney

Published in: CNS Drugs | Issue 8/2010

Login to get access

Abstract

Drugs acting at metabotropic glutamate receptors (mGluRs) are among the most promising agents under development for the treatment of psychiatric disorders. The research in this area is at a relatively early stage, as there are no drugs acting at mGluRs that have been approved for the treatment of any psychiatric disorder. However, in the areas of schizophrenia, anxiety disorders and mood disorders, research conducted in animal models appears to translate well into efficacy in human laboratory-based models of psychopathology and in preliminary clinical trials. Further, the genes coding for mGluRs are implicated in the risk for a growing number of psychiatric disorders. This review highlights the best studied mGluR strategies for psychiatry, based on human molecular genetics, studies in animal models and preliminary clinical trials. It describes the potential value of mGluR2 and mGluR5 agonists and positive allosteric modulators for the treatment of schizophrenia. It also reviews evidence that group II mGluR agonists and positive allosteric modulators as well as group I mGluR antagonists might also treat anxiety disorders and some forms of depression, while mGluR2 and group I mGluR antagonists (particularly mGluR5 antagonists) might have antidepressant properties. This review also links growing insights into the role of glutamate in the pathophysiology of these disorders to hypothesized mGluR-related treatment mechanisms.
Literature
1.
Schoepp DD, Conn PJ. Metabotropic glutamate receptors. Pharmacol Biochem Behav 2002; 74(1): 255–6PubMedCrossRef
2.
Moghaddam B. Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology (Berl) 2004; 174(1): 39–44CrossRef
3.
Krystal JH, Petrakis IL, Mason G, et al. N-methyl-D-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability. Pharmacol Ther 2003; 99(1): 79–94PubMedCrossRef
4.
Krystal JH, Moghaddam B. Contributions of glutamate and GABA systems to the neurobiology and treatment of schizophrenia. In: Hirsch S, Weinberger D, editors. Schizophrenia. 3rd ed. Oxford (UK): Blackwell Science, 2010
5.
Chambers AC, Bremner JD, Moghaddam B, et al. Glutamate and post-traumatic stress disorder: toward a neurobiology of dissociation. Semin Clin Neuropsychiatry 1999; 4(4): 274–81PubMed
6.
Sanacora G, Zarate CAJ, Krystal JH, et al. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Rev: Drug Discov 2008; 7(5): 426–37CrossRef
7.
Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 2004; 9(11): 984–97, 979PubMedCrossRef
8.
Gupta DS, McCullumsmith RE, Beneyto M, et al. Meta-botropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia. Synapse 2005; 57(3): 123–31PubMedCrossRef
9.
Ohnuma T, Augood SJ, Arai H, et al. Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. Brain Res Mol Brain Res 1998; 56(1-2): 207–17PubMedCrossRef
10.
Sartorius LJ, Weinberger DR, Hyde TM, et al. Expression of a GRM3 splice variant is increased in the dorsolateral prefrontal cortex of individuals carrying a schizophrenia risk SNP. Neuropsychopharmacology 2008; 33(11): 2626–34PubMedCrossRef
11.
Corti C, Crepaldi L, Mion S, et al. Altered dimerization of metabotropic glutamate receptor 3 in schizophrenia. Biol Psychiatry 2007; 62(7): 747–55PubMedCrossRef
12.
Tkachev D, Mimmack ML, Huffaker SJ, et al. Further evidence for altered myelin biosynthesis and glutamatergic dysfunction in schizophrenia. Int J Neuropsychopharmacol 2007; 10(4): 557–63PubMedCrossRef
13.
Gonzalez-Maeso J, Ang RL, Yuen T, et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 2008; 452(7183): 93–7PubMedCrossRef
14.
Richardson-Burns SM, Haroutunian V, Davis KL, et al. Metabotropic glutamate receptor mRNA expression in the schizophrenic thalamus. Biol Psychiatry 2000; 47(1): 22–8PubMedCrossRef
15.
Crook JM, Akil M, Law BC, et al. Comparative analysis of group II metabotropic glutamate receptor immunoreactivity in Brodmann’s area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects. Mol Psychiatry 2002; 7(2): 157–64PubMedCrossRef
16.
Pietraszek M, Gravius A, Schafer D, et al. mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition. Neuropharmacology 2005; 49(1): 73–85PubMedCrossRef
17.
Maeda J, Suhara T, Okauchi T, et al. Different roles of group I and group II metabotropic glutamate receptors on phencyclidine-induced dopamine release in the rat prefrontal cortex. Neurosci Lett 2003; 336(3): 171–4PubMedCrossRef
18.
Chan MH, Chiu PH, Sou JH, et al. Attenuation of ketamine-evoked behavioral responses by mGluR5 positive modulators in mice. Psychopharmacology (Berl) 2008; 198(1): 141–8CrossRef
19.
Lecourtier L, Homayoun H, Tamagnan G, et al. Positive allosteric modulation of metabotropic glutamate 5 (mGlu5) receptors reverses N-methyl-D-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex. Biol Psychiatry 2007; 62(7): 739–46PubMedCrossRef
20.
Homayoun H, Stefani MR, Adams BW, et al. Functional interaction between NMDA and mGlu5 receptors: effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology 2004; 29(7): 1259–69PubMedCrossRef
21.
Pietraszek M, Rogoz Z, Wolfarth S, et al. Opposite influence of MPEP, an mGluR5 antagonist, on the locomotor hyperactivity induced by PCP and amphetamine. J Physiol Pharmacol 2004; 55(3): 587–93PubMed
22.
Campbell UC, Lalwani K, Hernandez L, et al. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats. Psychopharmacology (Berl) 2004; 175(3): 310–8CrossRef
23.
Imre G, Salomons A, Jongsma M, et al. Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat. Pharmacol Biochem Behav 2006; 84(3): 392–9PubMedCrossRef
24.
Moghaddam B, Adams BW. Reversal of phencyclidine ef-fects by a group II metabotropic glutamate receptor agonist in rats. Science 1998; 281(5381): 1349–52PubMedCrossRef
25.
Woolley ML, Pemberton DJ, Bate S, et al. The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity. Psychopharmacology (Berl) 2008; 196(3): 431–40CrossRef
26.
Rorick-Kehn LM, Johnson BG, Knitowski KM, et al. In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders. Psychopharmacology (Berl) 2007; 193(1): 121–36CrossRef
27.
Cartmell J, Monn JA, Schoepp DD. The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J Pharmacol Exp Ther 1999; 291(1): 161–70PubMed
28.
Cartmell J, Monn JA, Schoepp DD. Attenuation of specific PCP-evoked behaviors by the potent mGlu2/3 receptor agonist, LY379268 and comparison with the atypical antipsychotic, clozapine. Psychopharmacology (Berl) 2000; 148(4): 423–9CrossRef
29.
Fell MJ, Johnson BG, Svensson KA, et al. Evidence for the role of mGlu2 not mGlu3 receptors in the pre-clinical antipsychotic pharmacology of the mGlu2/3 receptor agonist LY 404039. J Pharmacol Exp Ther 2008; 326(1): 209–17PubMedCrossRef
30.
Homayoun H, Jackson ME, Moghaddam B. Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats. J Neurophysiol 2005; 93(4): 1989–2001PubMedCrossRef
31.
Clark M, Johnson BG, Wright RA, et al. Effects of the mGlu2/3 receptor agonist LY379268 on motor activity in phencyclidine-sensitized rats. Pharmacol Biochem Behav 2002; 73(2): 339–46PubMedCrossRef
32.
Harich S, Gross G, Bespalov A. Stimulation of the metabotropic glutamate 2/3 receptor attenuates social novelty discrimination deficits induced by neonatal phencyclidine treatment. Psychopharmacology (Berl) 2007; 192(4): 511–9CrossRef
33.
Schreiber R, Lowe D, Voerste A, et al. LY354740 affects startle responding but not sensorimotor gating or discriminative effects of phencyclidine. Eur J Pharmacol 2000; 388(2): R3–4PubMedCrossRef
34.
Olszewski RT, Wegorzewska MM, Monteiro AC, et al. Phencyclidine and dizocilpine induced behaviors reduced by N-acetylaspartylglutamate peptidase inhibition via metabotropic glutamate receptors. Biol Psychiatry 2008; 63(1): 86–91PubMedCrossRef
35.
Baker DA, Madayag A, Kristiansen LV, et al. Contribution of cystine-glutamate antiporters to the psychotomimetic effects of phencyclidine. Neuropsychopharmacology 2008; 33(7): 1760–72PubMedCrossRef
36.
Robbins MJ, Starr KR, Honey A, et al. Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia. Brain Res 2007; 1152: 215–27PubMedCrossRef
37.
Benneyworth MA, Xiang Z, Smith RL, et al. A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Mol Pharmacol 2007; 72(2): 477–84PubMedCrossRef
38.
Marek GJ, Wright RA, Schoepp DD, et al. Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J Pharmacol Exp Ther 2000; 292(1): 76–87PubMed
39.
Galici R, Echemendia NG, Rodriguez AL, et al. A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors has effects similar to an orthosteric mGlu2/3 receptor agonist in mouse models predictive of antipsychotic activity. J Pharmacol Exp Ther 2005; 315(3): 1181–7PubMedCrossRef
40.
Kinney GG, O’Brien JA, Lemaire W, et al. A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. J Pharmacol Exp Ther 2005; 313(1): 199–206PubMedCrossRef
41.
Homayoun H, Moghaddam B. Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs. Proc Natl Acad Sci U S A 2008; 105(46): 18041–6PubMedCrossRef
42.
Cartmell J, Monn JA, Schoepp DD. The mGlu(2/3) receptor agonist LY379268 selectively blocks amphetamine ambulations and rearing. Eur J Pharmacol 2000; 400(2-3): 221–4PubMedCrossRef
43.
van Berckel BN, Kegeles LS, Waterhouse R, et al. Modulation of amphetamine-induced dopamine release by group II metabotropic glutamate receptor agonist LY354740 in non-human primates studied with positron emission tomography. Neuropsychopharmacology 2006; 31(5): 967–77PubMedCrossRef
44.
Homayoun H, Moghaddam B. Bursting of prefrontal cor-tex neurons in awake rats is regulated by metabotropic glutamate 5 (mGlu5) receptors: rate-dependent influence and interaction with NMDA receptors. Cereb Cortex 2006; 16(1): 93–105PubMedCrossRef
45.
Devon RS, Anderson S, Teague PW, et al. The genomic organisation of the metabotropic glutamate receptor subtype 5 gene, and its association with schizophrenia. Mol Psychiatry 2001; 6(3): 311–4PubMedCrossRef
46.
Tu JC, Xiao B, Naisbitt S, et al. Coupling of mGluR/ Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 1999; 23(3): 583–92PubMedCrossRef
47.
Gauthier J, Champagne N, Lafreniere RG, et al. De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci U S A 2010; 107: 7863–8PubMedCrossRef
48.
Luccini E, Musante V, Neri E, et al. Functional interactions between presynaptic NMDA receptors and metabotropic glutamate receptors co-expressed on rat and human noradrenergic terminals. Br J Pharmacol 2007; 151(7): 1087–94PubMedCrossRef
49.
Choe ES, Shin EH, Wang JQ. Regulation of phosphorylation of NMDA receptor NR1 subunits in the rat neostriatum by group I metabotropic glutamate receptors in vivo. Neurosci Lett 2006; 394(3): 246–51PubMedCrossRef
50.
Awad H, Hubert GW, Smith Y, et al. Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci 2000; 20(21): 7871–9PubMed
51.
Bruno V, Copani A, Knopfel T, et al. Activation of metabotropic glutamate receptors coupled to inositol phospholipid hydrolysis amplifies NMDA-induced neuronal degeneration in cultured cortical cells. Neurophar-macology 1995; 34(8): 1089–98CrossRef
52.
Jia Z, Lu Y, Henderson J, et al. Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR 5. Learn Mem 1998; 5(4-5): 331–43PubMed
53.
Pisani A, Gubellini P, Bonsi P, et al. Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons. Neuroscience 2001; 106(3): 579–87PubMedCrossRef
54.
Alagarsamy S, Marino MJ, Rouse ST, et al. Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems. Nat Neurosci 1999; 2(3): 234–40PubMedCrossRef
55.
Ugolini A, Corsi M, Bordi F. Potentiation of NMDA and AMPA responses by the specific mGluR5 agonist CHPG in spinal cord motoneurons. Neuropharmacology 1999; 38(10): 1569–76PubMedCrossRef
56.
Pietraszek M, Nagel J, Gravius A, et al. The role of group I metabotropic glutamate receptors in schizophrenia. Amino Acids 2007; 32(2): 173–8PubMedCrossRef
57.
Pilowsky LS, Bressan RA, Stone JM, et al. First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry 2006; 11(2): 118–9PubMedCrossRef
58.
Javitt DC. Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. Int Rev Neurobiol 2007; 78: 69–108PubMedCrossRef
59.
Kristiansen LV, Huerta I, Beneyto M, et al. NMDA receptors and schizophrenia. Curr Opin Pharmacol 2007; 7(1): 48–55PubMedCrossRef
60.
Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 1995; 52(12): 998–1007PubMedCrossRef
61.
Koros E, Rosenbrock H, Birk G, et al. The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, induces social isolation in rats. Neuropsychopharmacology 2007; 32(3): 562–76PubMedCrossRef
62.
Brody SA, Conquet F, Geyer MA. Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice. Psychopharmacology (Berl) 2004; 172(2): 187–95CrossRef
63.
Conn PJ, Lindsley CW, Jones CK. Activation of metabo-tropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol Sci 2009; 30(1): 25–31PubMedCrossRef
64.
Rodriguez AL, Williams R. Recent progress in the development of allosteric modulators of mGluR 5. Curr Opin Drug Discov Devel 2007; 10(6): 715–22PubMed
65.
Harrison PJ, Lyon L, Sartorius LJ, et al. The group II metabotropic glutamate receptor 3 (mGluR3, mGlu3, GRM3): expression, function and involvement in schizophrenia. J Psychopharmacol 2008; 22(3): 308–22PubMedCrossRef
66.
Joo A, Shibata H, Ninomiya H, et al. Structure and polymorphisms of the human metabotropic glutamate receptor type 2 gene (GRM2): analysis of association with schizophrenia. Mol Psychiatry 2001; 6(2): 186–92PubMedCrossRef
67.
Marti SB, Cichon S, Propping P, et al. Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population. Am J Med Genet 2002; 114(1): 46–50PubMedCrossRef
68.
Fujii Y, Shibata H, Kikuta R, et al. Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia. Psychiatr Genet 2003; 13(2): 71–6PubMed
69.
Egan MF, Straub RE, Goldberg TE, et al. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc Natl Acad Sci U S A 2004; 101(34): 12604–9PubMedCrossRef
70.
Chen Q, He G, Chen Q, et al. A case-control study of the relationship between the metabotropic glutamate receptor 3 gene and schizophrenia in the Chinese population. Schizophr Res 2005; 73(1): 21–6PubMedCrossRef
71.
Norton N, Williams HJ, Dwyer S, et al. No evidence for association between polymorphisms in GRM3 and schizophrenia. BMC Psychiatry 2005; 5: 23PubMedCrossRef
72.
Tochigi M, Suga M, Ohashi J, et al. No association between the metabotropic glutamate receptor type 3 gene (GRM3) and schizophrenia in a Japanese population. Schizophr Res 2006; 88(1-3): 260–4PubMedCrossRef
73.
Albalushi T, Horiuchi Y, Ishiguro H, et al. Replication study and meta-analysis of the genetic association of GRM3 gene polymorphisms with schizophrenia in a large Japanese case-control population. Am J Med Genet B Neuropsychiatr Genet 2008; 147(3): 392–6PubMed
74.
Bishop JR, Wang K, Moline J, et al. Association analysis of the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia. Psychiatr Genet 2007; 17(6): 358PubMedCrossRef
75.
Schwab SG, Plummer C, Albus M, et al. DNA sequence variants in the metabotropic glutamate receptor 3 and risk to schizophrenia: an association study. Psychiatr Genet 2008; 18(1): 25–30PubMedCrossRef
76.
Ohtsuki T, Toru M, Arinami T. Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia. Psychiatr Genet 2001; 11(2): 79–83PubMedCrossRef
77.
Bray NJ, Williams NM, Bowen T, et al. No evidence for association between a non-synonymous polymorphism in the gene encoding human metabotropic glutamate receptor 7 and schizophrenia. Psychiatr Genet 2000; 10(2): 83–6PubMedCrossRef
78.
Bolonna AA, Kerwin RW, Munro J, et al. Polymorphisms in the genes for mGluR types 7 and 8: association studies with schizophrenia. Schizophr Res 2001; 47(1): 99–103PubMedCrossRef
79.
Ohtsuki T, Koga M, Ishiguro H, et al. A polymorphism of the metabotropic glutamate receptor mGluR7 (GRM7) gene is associated with schizophrenia. Schizophr Res 2008; 101(1-3): 9–16PubMedCrossRef
80.
Takaki H, Kikuta R, Shibata H, et al. Positive associations of polymorphisms in the metabotropic glutamate receptor type 8 gene (GRM8) with schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2004; 128(1): 6–14CrossRef
81.
Marenco S, Steele SU, Egan MF, et al. Effect of metabotropic glutamate receptor 3 genotype on N-acetylas-partate measures in the dorsolateral prefrontal cortex. Am J Psychiatry 2006; 163(4): 740–2PubMedCrossRef
82.
Bishop JR, Ellingrod VL, Moline J, et al. Association between the polymorphic GRM3 gene and negative symptom improvement during olanzapine treatment. Schizophr Res 2005; 77(2-3): 253–60PubMedCrossRef
83.
Wroblewska B, Wroblewski JT, Pshenichkin S, et al. N-acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J Neurochem 1997; 69(1): 174–81PubMedCrossRef
84.
Bergeron R, Imamura Y, Frangioni JV, et al. Endogenous N-acetylaspartylglutamate reduced NMDA receptor-dependent current neurotransmission in the CA1 area of the hippocampus. J Neurochem 2007; 100(2): 346–57PubMedCrossRef
85.
Tsai G, Passani LA, Slusher BS, et al. Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. Arch Gen Psychiatry 1995; 52(10): 829–36PubMedCrossRef
86.
Ghose S, Weickert CS, Colvin SM, et al. Glutamate car-boxypeptidase II gene expression in the human frontal and temporal lobe in schizophrenia. Neuropsycho-pharmacology 2004; 29(1): 117–25CrossRef
87.
Krystal JH, D’Souza DC, Mathalon D, et al. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology 2003; 169: 215–33PubMedCrossRef
88.
Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 2007; 13(9): 1102–7PubMedCrossRef
89.
Moghaddam B, Adams B, Verma A, et al. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 1997; 17(8): 2921–7PubMed
90.
Dursun SM, Deakin JF. Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. J Psychopharmacol 2001; 15(4): 297–301PubMedCrossRef
91.
Post RM. Comparative pharmacology of bipolar disorder and schizophrenia. Schizophr Res 1999; 39(2): 153–8; discussion 163PubMedCrossRef
92.
Tiihonen J, Halonen P, Wahlbeck K, et al. Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychiatry 2005; 66(8): 1012–5PubMedCrossRef
93.
Large CH, Webster EL, Goff DC. The potential role of lamotrigine in schizophrenia. Psychopharmacology (Berl) 2005; 181(3): 415–36CrossRef
94.
Anand A, Charney DS, Cappiello A, et al. Lamotrigine attenuates ketamine effects in humans: support for hyperglutamatergic effects of NMDA antagonists. Arch Gen Psychiatry 2000; 57: 270–6PubMedCrossRef
95.
Gozzi A, Large CH, Schwarz A, et al. Differential effects of antipsychotic and glutamatergic agents on the phMRI response to phencyclidine. Neuropsychopharmacology 2008; 33(7): 1690–703PubMedCrossRef
96.
Brody SA, Geyer MA, Large CH. Lamotrigine prevents ketamine but not amphetamine-induced deficits in prepulse inhibition in mice. Psychopharmacology (Berl) 2003; 169(3-4): 240–6CrossRef
97.
Farber NB, Newcomer JW, Olney JW. Lamotrigine prevents NMDA antagonist neurotoxicity. Schizophr Res 1999; 36 (1-3): 308
98.
Idris NF, Repeto P, Neill JC, et al. Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and D-amphetamine in the rat. Psychopharmacology (Berl) 2005; 179(2): 336–48CrossRef
99.
Kremer I, Vass A, Gorelik I, et al. Placebo-controlled trial of lamotrigine added to conventional and atypical anti-psychotics in schizophrenia. Biol Psychiatry 2004; 56(6): 441–6PubMedCrossRef
100.
Tiihonen J, Hallikainen T, Ryynänen O-P, et al. Lamo-trigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Biol Psychiatry 2003; 54: 1–6CrossRef
101.
Goff DC, Keefe R, Citrome L, et al. Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol 2007; 27(6): 582–9PubMedCrossRef
102.
Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 1998; 281: 1349–52PubMedCrossRef
103.
Swanson CJ, Schoepp DD. The group II metabotropic glutamate receptor agonist (−)-2-oxa-4-amino-bicyclo [3.1.0.]hexane-4,6-dicarboxylate (LY379268) and clozapine reverse phencyclidine-induced behaviors in monoamine-depleted rats. J Pharmacol Exp Ther 2002; 303(3): 919–27PubMedCrossRef
104.
Krystal JH, Abi-Saab W, Perry E, et al. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, in healthy human subjects. Psychopharmacology 2005; 179(1): 303–9PubMedCrossRef
105.
106.
Baker DA, Xi ZX, Shen H, et al. The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci 2002; 22(20): 9134–41PubMed
107.
Berk M, Copolov D, Dean O, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia: a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008; 64(5): 361–8PubMedCrossRef
108.
Lavoie S, Murray MM, Deppen P, et al. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology 2008; 33(9): 2187–99PubMedCrossRef
109.
Olszewski RT, Bukhari N, Zhou J, et al. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J Neurochem 2004; 89(4): 876–85PubMedCrossRef
110.
Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comor-bidity Survey. Arch Gen Psychiatry 1994; 51(1): 8–19PubMedCrossRef
111.
112.
Mathew SJ, Price RB, Charney DS. Recent advances in the neurobiology of anxiety disorders: implications for novel therapeutics. Am J Med Genet C Semin Med Genet 2008; 14C: 89–98
113.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association, 2000
114.
Andrade L, Eaton WW, Chilcoat H. Lifetime comorbidity of panic attacks and major depression in a population-based study: symptom profiles. Br J Psychiatry 1994; 165(3): 363–9PubMedCrossRef
115.
Beekman AT, de Beurs E, van Balkom AJ, et al. Anxiety and depression in later life: co-occurrence and communality of risk factors. Am J Psychiatry 2000; 157(1): 89–95PubMed
116.
Judd LL, Kessler RC, Paulus MP, et al. Comorbidity as a fundamental feature of generalized anxiety disorders: results from the National Comorbidity Study (NCS). Acta Psychiatr Scand Suppl 1998; 393: 6–11PubMedCrossRef
117.
Glantz MD, Anthony JC, Berglund PA, et al. Mental disorders as risk factors for later substance dependence: estimates of optimal prevention and treatment benefits. Psychol Med 2009; 39(8): 1365–77PubMedCrossRef
118.
Robinson J, Sareen J, Cox BJ, et al. Self-medication of anxiety disorders with alcohol and drugs: results from a nationally representative sample. J Anxiety Disord 2009; 23(1): 38–45PubMedCrossRef
119.
Hasin DS, Stinson FS, Ogburn E, et al. Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry 2007; 64(7): 830–42PubMedCrossRef
120.
Howland RH, Rush AJ, Wisniewski SR, et al. Concurrent anxiety and substance use disorders among outpatients with major depression: clinical features and effect on treatment outcome. Drug Alcohol Depend 2009; 99(1–3): 248–60PubMedCrossRef
121.
Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry 2008; 165(3): 342–51PubMedCrossRef
122.
Swanson CJ, Bures M, Johnson MP, et al. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 2005; 4(2): 131–44PubMedCrossRef
123.
Moghaddam B. Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders. Biol Psychiatry 2002; 51(10): 775–87PubMedCrossRef
124.
Phan KL, Fitzgerald DA, Cortese BM, et al. Anterior cin-gulate neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla. Neuroreport 2005; 16(2): 183–6PubMedCrossRef
125.
Pollack MH, Jensen JE, Simon NM, et al. High-field MRS study of GABA, glutamate and glutamine in social anxiety disorder: response to treatment with levetiracetam. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32(3): 739–43PubMedCrossRef
126.
Pittenger C, Coric V, Banasr M, et al. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs 2008; 22(9): 761–86PubMedCrossRef
127.
Mathew SJ, Amiel JM, Coplan JD, et al. Open-label trial of riluzole in generalized anxiety disorder. Am J Psychiatry 2005; 162(12): 2379–81PubMedCrossRef
128.
Mathew SJ, Price RB, Mao X, et al. Hippocampal N-acetylaspartate concentration and response to riluzole in generalized anxiety disorder. Biol Psychiatry 2008; 63(9): 891–8PubMedCrossRef
129.
Van Ameringen M, Mancini C, Pipe B, et al. An open trial of topiramate in the treatment of generalized social phobia. J Clin Psychiatry 2004; 65(12): 1674–8PubMedCrossRef
130.
Tassone DM, Boyce E, Guyer J, et al. Pregabalin: a novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clin Ther 2007; 29(1): 26–48PubMedCrossRef
131.
Krystal JH, Tolin DF, Sanacora G, et al. Neuroplasticity as a target for the pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia. Drug Discov Today 2009; 14: 690–7PubMedCrossRef
132.
Davis M, Ressler K, Rothbaum BO, et al. Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry 2006; 60: 369–75PubMedCrossRef
133.
Norberg MM, Krystal JH, Tolin DF, et al. A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biol Psychiatry 2008; 63: 1118–26PubMedCrossRef
134.
Ressler KJ, Rothbaum BO, Tannenbaum L, et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 2004; 61: 1136–44PubMedCrossRef
135.
Camodeca N, Breakwell NA, Rowan MJ, et al. Induction of LTD by activation of group I mGluR in the dentate gyrusin vitro. Neuropharmacology 1999; 38: 1597–606PubMedCrossRef
136.
Popkirov SG, Manahan-Vaughan D. Involvement of the metabotropic glutamate receptor mGluR5 in NMDA receptor-dependent, learning-facilitated long-term depression in CA1 synapses. Cereb Cortex. Epub 2010 Jun 4
137.
Sung KW, Choi S, Lovinger DM, et al. Activation of group I mGluRs is necessary for induction of long-term depression at striatal synapses. J Neurolphysiol 2001; 86: 2405–12
138.
Ballard TM, Woolley ML, Prinssen E, et al. The effect of the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison. Psychopharmacology (Berl) 2005; 179(1): 218–29CrossRef
139.
Busse CS, Brodkin J, Tattersall D, et al. The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in rodent models of anxiety. Neuropsychopharmacology 2004; 29(11): 1971–9PubMedCrossRef
140.
Porter RH, Jaeschke G, Spooren W, et al. Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther 2005; 315(2): 711–21PubMedCrossRef
141.
Pecknold JC, McClure DJ, Appeltauer L, et al. Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study. J Clin Psychopharmacol 1982; 2(2): 129–33PubMedCrossRef
142.
Mitsukawa K, Mombereau C, Lotscher E, et al. 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 2006; 31(6): 1112–22PubMed
143.
Fendt M, Schmid S, Thakker DR, et al. mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity. Mol Psychiatry 2008; 13(10): 970–9PubMedCrossRef
144.
Schoepp DD, Wright RA, Levine LR, et al. LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress 2003; 6(3): 189–97PubMedCrossRef
145.
Linden AM, Greene SJ, Bergeron M, et al. 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 2004; 29(3): 502–13PubMedCrossRef
146.
Nordquist RE, Steckler T, Wettstein JG, et al. Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety. Psychopharmacology (Berl) 2008; 199(3): 389–402CrossRef
147.
Pietraszek M, Sukhanov I, Maciejak P, et al. Anxiolytic-like effects of mGlu1 and mGlu5 receptor antagonists in rats. Eur J Pharmacol 2005; 514(1): 25–34PubMedCrossRef
148.
Steckler T, Lavreysen H, Oliveira AM, et al. Effects of mGlu1 receptor blockade on anxiety-related behaviour in the rat lick suppression test. Psychopharmacology (Berl) 2005; 179(1): 198–206CrossRef
149.
Rorick-Kehn LM, Hart JC, McKinzie DL. Pharmacological characterization of stress-induced hyperthermia in DBA/2 mice using metabotropic and ionotropic glutamate receptor ligands. Psychopharmacology (Berl) 2005; 183(2): 226–40CrossRef
150.
Varty GB, Grilli M, Forlani A, et al. 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 (Berl) 2005; 179(1): 207–17CrossRef
151.
Satow A, Maehara S, Ise S, et al. 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]-N-isopropyl-N-methy l-3,6-dihydropyridine-1(2H)-carboxamide]. J Pharmacol Exp Ther 2008; 326(2): 577–86PubMedCrossRef
152.
Klodzinska A, Tatarczynska E, Stachowicz K, et al. The anxiolytic-like activity of AIDA (1-aminoindan-1,5-dicarboxylic acid), an mGLu 1 receptor antagonist. J Physiol Pharmacol 2004; 55 (1 Pt 1): 113–26PubMed
153.
Lima VC, Molchanov ML, Aguiar DC, et al. Modulation of defensive responses and anxiety-like behaviors by group I metabotropic glutamate receptors located in the dorsolateral periaqueductal gray. Prog Neuropsycho-pharmacol Biol Psychiatry 2008; 32(1): 178–85
154.
Brodkin J, Bradbury M, Busse C, et al. Reduced stress-induced hyperthermia in mGluR5 knockout mice. Eur J Neurosci 2002; 16(11): 2241–4PubMedCrossRef
155.
Klodzinska A, Tatarczynska E, Chojnacka-Wojcik E, et al. Anxiolytic-like effects of MTEP, a potent and selective mGlu5 receptor agonist does not involve GABA(A) signaling. Neuropharmacology 2004; 47(3): 342–50PubMedCrossRef
156.
Molina-Hernandez M, Tellez-Alcantara NP, Perez-Garcia J, et al. Estrus variation in anticonflict-like effects of the mGlu5 receptor antagonist MTEP, microinjected into lateral septal nuclei of female Wistar rats. Pharmacol Biochem Behav 2006; 84(3): 385–91PubMedCrossRef
157.
Nordquist RE, Durkin S, Jaeschke G, et al. Stress-induced hyperthermia: effects of acute and repeated dosing of MPEP. Eur J Pharmacol 2007; 568(1–3): 199–202PubMedCrossRef
158.
Spooren WP, Schoeffter P, Gasparini F, et al. Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY314582, MPEP and NKP608). Eur J Pharmacol 2002; 435 (2-3): 161–70
159.
Spooren WP, Gasparini F, van der Putten H, et al. 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 2000; 397(1): R1–2PubMedCrossRef
160.
Tatarczynska E, Klodzinska A, Kroczka B, et al. The antianxiety-like effects of antagonists of group I and agonists of group II and III metabotropic glutamate receptors after intrahippocampal administration. Psychopharmacologia 2001; 158(1): 94–9CrossRef
161.
Wieronska JM, Smialowska M, Branski P, et al. In the amygdala anxiolytic action of mGlu5 receptors antagonist MPEP involves neuropeptide Y but not GABAA signaling. Neuropsychopharmacology 2004; 29(3): 514–21PubMedCrossRef
162.
Perez de la Mora M, Lara-Garcia D, Jacobsen KX, et al. Anxiolytic-like effects of the selective metabotropic glutamate receptor 5 antagonist MPEP after its intra-amygdaloid microinjection in three different non-conditioned rat models of anxiety. Eur J Neurosci 2006; 23(10): 2749–59PubMedCrossRef
163.
Schulz B, Fendt M, Gasparini F, et al. The metabotropic glutamate receptor antagonist 2-methyl-6-(phenyl-ethynyl)-pyridine (MPEP) blocks fear conditioning in rats. Neuropharmacology 2001; 41(1): 1–7PubMedCrossRef
164.
Iijima M, Chaki S. Separation-induced ultrasonic vocalization in rat pups: further pharmacological characterization. Pharmacol Biochem Behav 2005; 82(4): 652–7PubMedCrossRef
165.
Rorick-Kehn LM, Perkins EJ, Knitowski KM, et al. Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY 544344. J Pharmacol Exp Ther 2006; 316(2): 905–13PubMedCrossRef
166.
Helton DR, Tizzano JP, Monn JA, et al. Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. J Pharmacol Exp Ther 1998; 284(2): 651–60PubMed
167.
Walker DL, Rattiner LM, Davis M. Group II metabotropic glutamate receptors within the amygdala regulate fear as assessed with potentiated startle in rats. Behav Neurosci 2002; 116(6): 1075–83PubMedCrossRef
168.
Tizzano JP, Griffey KI, Schoepp DD. 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 2002; 73(2): 367–74PubMedCrossRef
169.
Linden AM, Shannon H, Baez M, et al. Anxiolytic-like activity of the mGLU2/3 receptor agonist LY354740 in the elevated plus maze test is disrupted in metabotropic glutamate receptor 2 and 3 knock-out mice. Psycho-pharmacology (Berl) 2005; 179(1): 284–91CrossRef
170.
Monn JA, Valli MJ, Massey SM, 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 1997; 40(4): 528–37PubMedCrossRef
171.
Klodzinska A, Chojnacka-Wojcik E, Palucha A, et al. Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models. Neuropharmacology 1999; 38(12): 1831–9PubMedCrossRef
172.
Benvenga MJ, Overshiner CD, Monn JA, et al. Dis-inhibitory effects of LY354740, a new mGluR2 agonist, on behaviors suppressed by electric shock in rats and pigeons. Drug Devel Res 1999; 47(1): 37–44CrossRef
173.
Shekhar A, Keim SR. LY354740, a potent group II metabotropic glutamate receptor agonist prevents lactate-induced panic-like response in panic-prone rats. Neuropharmacology 2000; 39(7): 1139–46PubMedCrossRef
174.
Johnson MP, Baez M, Jagdmann Jr GE, 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 2003; 46(15): 3189–92PubMedCrossRef
175.
Johnson MP, Barda D, Britton TC, et al. Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s). Psycho-pharmacology (Berl) 2005; 179(1): 271–83CrossRef
176.
Bueno AB, Collado I, de Dios A, et al. Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-amino-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist. J Med Chem 2005; 48(16): 5305–20PubMedCrossRef
177.
Lin CH, Lee CC, Huang YC, et al. Activation of group II metabotropic glutamate receptors induces depotentiation in amygdala slices and reduces fear-potentiated startle in rats. Learn Mem 2005; 12(2): 130–7PubMedCrossRef
178.
Iijima M, Shimazaki T, Ito A, et al. Effects of metabotropic glutamate 2/3 receptor antagonists in the stress-induced hyperthermia test in singly housed mice. Psychopharmacology (Berl) 2007; 190(2): 233–9CrossRef
179.
Bespalov AY, van Gaalen MM, Sukhotina IA, et al. Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression. Eur J Pharmacol 2008; 592(1-3): 96–102PubMedCrossRef
180.
Shimazaki T, Iijima M, Chaki S. Anxiolytic-like activity of MGS0039, a potent group II metabotropic glutamate receptor antagonist, in a marble-burying behavior test. Eur J Pharmacol 2004; 501(1-3): 121–5PubMedCrossRef
181.
Yoshimizu T, Shimazaki T, Ito A, et al. An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats. Psychopharmacology (Berl) 2006; 186(4): 587–93CrossRef
182.
Chaki S, Yoshikawa R, Hirota S, et al. MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuro-pharmacology 2004; 46(4): 457–67
183.
Stachowicz K, Klak K, Klodzinska A, et al. Anxiolytic-like effects of PHCCC, an allosteric modulator of mGlu4 receptors, in rats. Eur J Pharmacol 2004; 498(1-3): 153–6PubMedCrossRef
184.
Stachowicz K, Chojnacka-Wojcik E, Klak K, et al. Anxiolytic-like effects of group III mGlu receptor ligands in the hippocampus involve GABAA signaling. Pharmacol Rep 2006; 58(6): 820–6PubMed
185.
Palucha A, Tatarczynska E, Branski P, et al. Group III mGlu receptor agonists produce anxiolytic- and antidepressant-like effects after central administration in rats. Neuropharmacology 2004; 46(2): 151–9PubMedCrossRef
186.
Stachowicz K, Chojnacka-Wojcik E, Klak K, et al. Anxiolytic-like effect of group III mGlu receptor antagonist is serotonin-dependent. Neuropharmacology 2007; 52(2): 306–12PubMedCrossRef
187.
Stachowicz K, Klak K, Pilc A, et al. Lack of the anti-anxiety-like effect of (S)-3,4-DCPG, an mGlu8 receptor agonist, after central administration in rats. Pharmacol Rep 2005; 57(6): 856–60PubMed
188.
Belozertseva IV, Kos T, Popik P, et al. Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests. Eur Neuropsychopharmacol 2007; 17(3): 172–9PubMedCrossRef
189.
Molina-Hernandez M, Tellez-Alcantara NP, Perez-Garcia J, et al. Antidepressant-like actions of minocycline combined with several glutamate antagonists. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32(2): 380–6PubMedCrossRef
190.
Smolders I, Clinckers R, Meurs A, et al. Direct enhancement of hippocampal dopamine or serotonin levels as a pharmacodynamic measure of combined antidepressant-anticonvulsant action. Neuropharmacology 2008; 54(6): 1017–28PubMedCrossRef
191.
Molina-Hernandez M, Tellez-Alcantara NP, Perez-Garcia J, et al. Antidepressant-like and anxiolytic-like actions of the mGlu5 receptor antagonist MTEP, microinjected into lateral septal nuclei of male Wistar rats. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30(6): 1129–35PubMedCrossRef
192.
Li X, Need AB, Baez M, et al. Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice. J Pharmacol Exp Ther 2006; 319(1): 254–9PubMedCrossRef
193.
Palucha A, Branski P, Szewczyk B, et al. Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist. Pharmacol Biochem Behav 2005; 81(4): 901–6PubMedCrossRef
194.
Klak K, Palucha A, Branski P, et al. Combined adminis-tration of PHCCC, a positive allosteric modulator of mGlu4 receptors and ACPT-I, mGlu III receptor agonist evokes antidepressant-like effects in rats. Amino Acids 2007; 32(2): 169–72PubMedCrossRef
195.
Coplan JD, Mathew SJ, Smith EL, et al. Effects of LY354740, a novel glutamatergic metabotropic agonist, on nonhuman primate hypothalamic-pituitary-adrenal axis and noradrenergic function. CNS Spectr 2001; 6(7): 607–12, 617PubMed
196.
Grillon C, Cordova J, Levine LR, et al. Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans. Psychopharmacology (Berl) 2003; 168(4): 446–54CrossRef
197.
Bergink V, Westenberg HG. Metabotropic glutamate II receptor agonists in panic disorder: a double blind clinical trial with LY 354740. Int Clin Psychopharmacol 2005; 20(6): 291–3PubMedCrossRef
198.
Michelson D, Levine LR, Dellva MA, et al. Clinical studies with mGlu2/3 receptor agonists: LY354740 compared with placebo in patients with generalized anxiety disorder. Neuropharmacology 2005; 49(S1): 84–257
199.
Dunayevich E, Erickson J, Levine L, et al. Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology 2008; 33(7): 1603–10PubMedCrossRef
200.
Rorick-Kehn LM, Johnson BG, Burkey JL, et al. Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (−)-(1R,4S,5S,6S) -4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4, 6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther 2007; 321(1): 308–17PubMedCrossRef
201.
Kellner M, Muhtz C, Stark K, et al. Effects of a metabotropic glutamate(2/3) receptor agonist (LY544344/ LY354740) on panic anxiety induced by cholecystokinin tetrapeptide in healthy humans: preliminary results. Psychopharmacology (Berl) 2005; 179(1): 310–5CrossRef
202.
Conn PJ, Roth BL. Opportunities and challenges of psychiatric drug discovery: roles for scientists in academic, industry, and government settings. Neuropsychopharmacology 2008; 33(9): 2048–60PubMedCrossRef
203.
Berman RM, Krystal JH, Charney DS. Mechanism of action of antidepressants: monoamine hypotheses and beyond. In: Watson SJ, editor. Biology of schizophrenia and affective disorders. Washington, DC: American Psychiatric Press, 1996: 295–368
204.
Pilc A, Chaki S, Nowak G, et al. Mood disorders: regulation by metabotropic glutamate receptors. Biochem Pharmacol 2008; 75(5): 997–1006PubMedCrossRef
205.
Hamidi M, Drevets WC, Price JL. Glial reduction in amygdala in major depressive disorder is due to oligo-dendrocytes. Biol Psychiatry 2004; 55(6): 563–9PubMedCrossRef
206.
Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A 1998; 95(22): 13290–5PubMedCrossRef
207.
Sanacora G, Gueorguieva R, Epperson CN, et al. Subtype specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 2004; 61: 705–13PubMedCrossRef
208.
Hasler G, Neumeister A, van der Veen JW, et al. Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy. Biol Psychiatry 2005; 58(12): 969–73PubMedCrossRef
209.
Hasler G, van der Veen JW, Tumonis T, et al. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2007; 64(2): 193–200PubMedCrossRef
210.
Mason G, Haga K, Appel M, et al. Measuring cortical GABA levels and neurotransmitter turnover with 1H-MRS and 13C-MRS. Biol Psychiatry 2001; 49: 148S
211.
Krystal JH, Sanacora G, Goddard A, et al. GABA levels and the function of glutamic acid decarboxylase in depression and panic disorder: insights from MRS. Int J Neuropsychopharmacology 2008; 11 Suppl. 1: 73
212.
Pittenger C, Sanacora G, Krystal JH. The NMDA receptor as a therapeutic target for major depressive disorder. CNS Neurol Disord Drug Targets 2007; 6(2): 101–15PubMedCrossRef
213.
Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47(4): 351–4PubMedCrossRef
214.
Zarate Jr CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63(8): 856–64PubMedCrossRef
215.
Krystal JH. Ketamine and the potential role for rapid-acting antidepressant medications. Swiss Med Wkly 2007; 137(15-16): 215–6PubMed
216.
Maeng S, Zarate Jr CA, Du J, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 2008; 63(4): 349–52PubMedCrossRef
217.
Paterson NE, Markou A. Animal models and treatments for addiction and depression co-morbidity. Neurotox Res 2007; 11(1): 1–32PubMedCrossRef
218.
Witkin JM, Marek GJ, Johnson BG, et al. Metabotropic glutamate receptors in the control of mood disorders. CNS Neurol Disord Drug Targets 2007; 6(2): 87–100PubMedCrossRef
219.
Palucha A, Pilc A. On the role of metabotropic glutamate receptors in the mechanisms of action of antidepressants. Pol J Pharmacol 2002; 54(6): 581–6PubMed
220.
D’Ascenzo M, Fellin T, Terunuma M, et al. mGluR5 stimulates gliotransmission in the nucleus accumbens. Proc Natl Acad Sci U S A 2007; 104(6): 1995–2000PubMedCrossRef
221.
Legutko B, Szewczyk B, Pomierny-Chamiolo L, et al. Effect of MPEP treatment on brain-derived neurotrophic factor gene expression. Pharmacol Rep 2006 May–Jun; 58(3): 427–30PubMed
222.
Krystal JH. Capitalizing on extrasynaptic glutamate neurotransmission to treat antipsychotic-resistant symptoms in schizophrenia. Biol Psychiatry 2008; 64(5): 358–60PubMedCrossRef
223.
Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder: a double-blind randomized placebo-controlled trial. Biol Psychiatry 2008; 64(6): 468–75PubMedCrossRef
224.
Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 2002; 5(5): 405–14PubMed
225.
Karasawa J, Shimazaki T, Kawashima N, et al. AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist. Brain Res 2005; 1042(1): 92–8PubMedCrossRef
Metadata
Title
Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists
Authors
Dr John H. Krystal
Sanjay J. Mathew
D. Cyril D’Souza
Amir Garakani
Handan Gunduz-Bruce
Dennis S. Charney
Publication date
01-08-2010
Publisher
Springer International Publishing
Published in
CNS Drugs / Issue 8/2010
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI
https://doi.org/10.2165/11533230-000000000-00000

Other articles of this Issue 8/2010

CNS Drugs 8/2010 Go to the issue

Review Article

Nervous System Effects of Antituberculosis Therapy

Leading Article

Awakenings and Awareness Recovery in Disorders of Consciousness

Original Research Article

Cost Effectiveness of Pharmacotherapy for the Prevention of Migraine

Adis Drug Profile

Low-Dose Doxepin

Review Article

The Relationship between Benzodiazepine Use and Traffic Accidents