Skip to main content
SpringerLink
Log in

Metabotropic Glutamate Receptors for New Treatments in Schizophrenia

  • Chapter
  • First Online:
Novel Antischizophrenia Treatments

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 213))

Abstract

Metabotropic glutamate receptors (mGluRs) represent exciting targets for the development of novel therapeutic agents for schizophrenia. Recent studies indicate that selective activation of specific mGluR subtypes may provide potential benefits for not only the positive symptoms, but also the negative symptoms and cognitive impairments observed in individuals with schizophrenia. Although optimization of traditional orthosteric agonists may still offer a feasible approach for the activation of mGluRs, important progress has been made in the discovery of novel subtype-selective allosteric ligands, including positive allosteric modulators (PAMs) of mGluR2 and mGluR5. These allosteric mGluR ligands have improved properties for clinical development and have served as key preclinical tools for a more in-depth understanding of the potential roles of these different mGluR subtypes for the treatment of schizophrenia.

Beth Herman and Micheal Bubser contributed equally to the authorship of this text.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 349.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 449.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 449.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

5-CSRTT:

5-Choice serial reaction time task

7TM:

7-Transmembrane domain

A-841720:

9-Dimethylamino-3-(N-hexamethyleneiminyl)-3H-5-thia-1,3,6-triazafluoren-4-one

AAPA:

Active allothetic place avoidance

AC:

Adenylyl cyclase

ACPT-I:

(1S,3R,4S)-1-Aminocyclopentane-1,3,4-tricarboxylic acid

ADX-47273:

S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone

AIDA:

(RS)-1-Aminoindan-1,5-dicarboxylic acid

AMPA:

α-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionate

AMPAR:

α-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor

BAY26-7620 BAY 36-7620:

(3aS,6aS)-Hexahydro-5-methylene-6a-(2-naphthalenylmethyl)-1H-cyclopenta[c]furan-1-one

BINA:

3′-[[(2-Cyclopentyl-2,3-dihydro-6,7-dimethyl-1-oxo-1H-inden-5-yl)oxy]methyl]-[1,1′-biphenyl]-4-carboxylic acid

cAMP:

Cyclic adenosine monophosphate

CBiPES:

N-(4′-Cyano-[1,1′-biphenyl]-3-yl-N-(3-pyridinylmethyl))-ethanesulfonamide hydrochloride

CDPPB:

3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide

CFMTI:

2-Cyclopropyl-5-(1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl)-2,3-dihydro-1H-isoindol-1-one

CGI-S:

Clinical global impression—severity score

CPCCOEt:

7-(Hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester

CPPZ:

1-(4-(2-Chloro-4-fluorophenyl)piperazin-1-yl)-2-(pyridin-4-ylmethoxy)ethanone

CPT:

Continuous Performance Test

DAG:

Diacyl-glycerol

DCG-IV:

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

DFB:

Desformylflustrabromine hydrochloride

DMTP:

Delayed matching-to-position task

DOB:

2,5-Dimethoxy-4-bromoamphetamine

DOI:

(±)1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane

EAAC1:

Excitatory amino acid carrier 1

EAAT:

Excitatory amino acid transporter

EPSP:

Excitatory postsynaptic potential

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinase

FTIDC:

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

GABA:

γ-Aminobutyric acid

GKAP:

Guanylate kinase-associated protein

GLAST:

Glutamate aspartate transporter

GLT-1:

Glial glutamate transporter 1

Glu:

Glutamate

GPCR:

G protein-coupled receptor

GTP:

Guanosine triphosphate

IP3 :

Inositol 1,4,5-triphosphate

JNJ16567083:

(3-Ethyl-2-(11 C)methyl-quinolin-6-yl)-(cis-4-methoxycyclohexyl)methanone

JNJ16259685:

(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxy cyclohexyl)-methanone

KO:

Knockout

LCCG:

L-2-(Carboxycyclopropyl)glycine

LCCG-I:

(2S,1′S,2′S)-2-(Carboxycyclopropyl)glycine

LSP1-2111:

(2 S)-2-Amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitro-phenyl)methyl]phosphoryl]butanoic acid

LTD:

Long-term depression

LTP:

Long-term potentiation

LY2140023:

(1R,4S,5S,6S)-2-Thiabicyclo[3.1.0]-hexane-4,6-dicarboxylic acid,4-[(2S)-2-amino-4-(methylthio)-1-oxobutyl]amino-, 2,2-dioxide monohydrate

LY314582:

(+)-(1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate

LY341495:

(1S,2S)-2-[(1R)-1-Amino-1-carboxy-2-(2,6-dioxo-3H-purin-9-yl)ethyl]cyclopropane-1-carboxylic acid

LY354740:

(1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

LY366563:

2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

LY367385:

2-Methyl-4-carboxyphenylglycine; alpha-methyl-4-carboxyphenylglycine

LY379268:

(1S,2R,5R,6R)-2-Amino-4-oxabicyclo[3.1.0]hexane-2,6-dicarboxylic acid

LY404039:

(−)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid

LY418426:

(1S,2S,5R,6R)-2-Amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

LY487379:

N-(4-(2-Methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine

LY544344:

(1S,2S,5R,6S)-2-[(2′S)-(2′-Amino)propionyl]aminobicyclo [3.1.0]hexane-2,6-dicarboxylic acid hydrochloride

MAPK:

Mitogen-activated protein kinase

mGluR:

Metabotropic glutamate receptor

mGluR1a:

Splice variant of mGluR1

mGluR5a:

Splice variant of mGluR5

mGluR5b:

Splice variant of mGluR5

MGS0008:

5-[2-[4-(6-Fluoro-1H-indole-3-yl) piperidin-1-yl]ethyl]-4-(4-fluorophenyl)thiazole-2-carboxylic acid amide

MGS0028:

(1R, 2S, 5S, 6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate

MGS0039:

(1R,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

MK-801:

(5S,10R)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate

MPEP:

6-Methyl-2-(phenylethynyl)-pyridin

MTEP:

3-((2-Methyl-4-thiazolyl)ethynyl)pyridine

NAM:

Negative allosteric modulator

NMDA:

N-methyl-d-aspartate

NMDAR:

N-methyl-d-aspartate receptor

NR1:

NMDA receptor subunit 1

PCP:

Phencyclidine

PAM:

Positive allosteric modulator

PANSS:

Positive and negative syndrome scale

PDZ:

Postsynaptic density 95, discs large, zona occludens 1 domain

PI3 kinase:

Phosphatidylinositol 3-kinase

PIKE-L:

PI3 kinase enhancer long form

PIP2 :

Phosphatidylinositol biphosphate

PKA:

Protein kinase A

PKC:

Protein kinase C

PP2A:

Protein phosphatase 2A

PPI:

Prepulse inhibition of the acoustic startle response

PP2C:

Protein phosphatase 2 C

PSD-95:

Postsynaptic density

(R)-CPP:

3-((R)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid

R214127:

1-(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1- ethanone

Ro 01-6128:

Diphenylacetyl-carbamic acid ethyl ester

Ro 67-4853:

9H-Xanthen-9-ylcarbonyl-carbamic acid

Ro 67-7476:

(2S)-2-(4-Fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-pyrrolidine

SKF-82958:

3-Allyl-6-chloro-1-phenyl-1,2,4,5-tetrahydro-3-benzazepine-7,8-diol

TBS:

Threshold theta burst stimulation

VFD:

Venus fly trap domain

VU29:

4-Nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide

VU0092273:

(4-Hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

VU0360172:

N-Cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide

VU0361747:

(6-((3-Fluorophenyl)ethynyl)pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone

VU0364289:

2-(4-(2-(Benzyloxy)acetyl)piperazin-1-yl)benzonitrile

YM298198:

6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide hydrochloride

References

  • Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A (1999) Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 156:1646–1649

    PubMed  CAS  Google Scholar 

  • Aghajanian GK, Marek GJ (1999) Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res 825:161–171

    PubMed  CAS  Google Scholar 

  • Aiba A, Chen C, Herrup K, Rosenmund C, Stevens CF, Tonegawa S (1994a) Reduced hippocampal long-term potentiation and context-specific deficit in associative learning in mGluR1 mutant mice. Cell 79:365–375

    PubMed  CAS  Google Scholar 

  • Aiba A, Kano M, Chen C, Stanton ME, Fox GD, Herrup K, Zwingman TA, Tonegawa S (1994b) Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. Cell 79:377–388

    PubMed  CAS  Google Scholar 

  • Alagarsamy S, Marino MJ, Rouse ST, Gereau RW, Heinemann SF, Conn PJ (1999) Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems. Nat Neurosci 2:234–240

    PubMed  CAS  Google Scholar 

  • Alagarsamy S, Saugstad J, Warren L, Mansuy IM, Gereau RW 4th, Conn PJ (2005) NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin. Neuropharmacology 49(Suppl 1):135–145

    PubMed  CAS  Google Scholar 

  • Altinbilek B, Manahan-Vaughan D (2009) A specific role for group II metabotropic glutamate receptors in hippocampal long-term depression and spatial memory. Neuroscience 158:149–158

    PubMed  CAS  Google Scholar 

  • American_Psychiatric_Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Publishing, Washington, DC

    Google Scholar 

  • Amitai N, Markou A (2010a) Disruption of performance in the five-choice serial reaction time task induced by administration of N-methyl-D-aspartate receptor antagonists: relevance to cognitive dysfunction in schizophrenia. Biol Psychiatry 68:5–16

    PubMed  CAS  Google Scholar 

  • Amitai N, Markou A (2010b) Effects of metabotropic glutamate receptor 2/3 agonism and antagonism on schizophrenia-like cognitive deficits induced by phencyclidine in rats. Eur J Pharmacol 639:67–80

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Aronica E, van Vliet EA, Mayboroda OA, Troost D, da Silva FH, Gorter JA (2000) Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy. Eur J Neurosci 12(7):2333–44

    PubMed  CAS  Google Scholar 

  • Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, Troost D (2003a) Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur J Neurosci 17:2106–2118

    PubMed  Google Scholar 

  • Aronica E, Gorter JA, Jansen GH, van Veelen CW, van Rijen PC, Ramkema M, Troost D (2003b) Expression and cell distribution of group I and group II metabotropic glutamate receptor subtypes in taylor-type focal cortical dysplasia. Epilepsia 44:785–795

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Aultman JM, Moghaddam B (2001) Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task. Psychopharmacology 153:353–364

    PubMed  CAS  Google Scholar 

  • Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ (2000) 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

    PubMed  CAS  Google Scholar 

  • Ayala JE, Chen Y, Banko JL, Sheffler DJ, Williams R, Telk AN, Watson NL, Xiang Z, Zhang Y, Jones PJ, Lindsley CW, Olive MF, Conn PJ (2009) mGluR5 Positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology 34:2057–2071

    PubMed  CAS  Google Scholar 

  • Balázs R, Miller S, Romano C, de Vries A, Chun Y, Cotman CW (1997) Metabotropic glutamate receptor mGluR5 in astrocytes: pharmacological properties and agonist regulation. J Neurochem 69:151–163

    PubMed  Google Scholar 

  • Bari A, Dalley JW, Robbins TW (2008) The application of the 5-choice serial reaction time task for the assessment of visual attentional processes and impulse control in rats. Nat Protoc 3:759–767

    PubMed  CAS  Google Scholar 

  • Barker GR, Bashir ZI, Brown MW, Warburton EC (2006) A temporally distinct role for group I and group II metabotropic glutamate receptors in object recognition memory. Learn Mem 13:178–186

    PubMed  CAS  Google Scholar 

  • Bellesi M, Conti F (2010) The mGluR2/3 agonist LY379268 blocks the effects of GLT-1 upregulation on prepulse inhibition of the startle reflex in adult rats. Neuropsychopharmacology 35:1253–1260

    PubMed  CAS  Google Scholar 

  • Bellone C, Lüscher C, Mameli M (2008) Mechanisms of synaptic depression triggered by metabotropic glutamate receptors. Cell Mol Life Sci 65:2913–2923

    PubMed  CAS  Google Scholar 

  • Beneken J, Tu JC, Xiao B, Nuriya M, Yuan JP, Worley PF, Leahy DJ (2000) Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition. Neuron 26:143–154

    PubMed  CAS  Google Scholar 

  • Benneyworth MA, Xiang Z, Smith RL, Garcia EE, Conn PJ, Sanders-Bush E (2007) A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Mol Pharmacol 72:477–484

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Berger MA, Defagot MC, Villar MJ, Antonelli MC (2001) D4 dopamine and metabotropic glutamate receptors in cerebral cortex and striatum in rat brain. Neurochem Res 26:345–352

    PubMed  CAS  Google Scholar 

  • Berger UV, DeSilva TM, Chen W, Rosenberg PA (2005) Cellular and subcellular mRNA localization of glutamate transporter isoforms GLT1a and GLT1b in rat brain by in situ hybridization. J Comp Neurol 492:78–89

    PubMed  CAS  Google Scholar 

  • Bespalov A, Jongen-Relo AL, van Gaalen M, Harich S, Schoemaker H, Gross G (2007) Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice: reversal by antipsychotic drugs. J Pharmacol Exp Ther 320:944–950

    PubMed  CAS  Google Scholar 

  • Biber K, Laurie DJ, Berthele A, Sommer B, Tölle TR, Gebicke-Härter PJ, van Calker D, Boddeke HW (1999) Expression and signaling of group I metabotropic glutamate receptors in astrocytes and microglia. J Neurochem 72:1671–1680

    PubMed  CAS  Google Scholar 

  • Bird MK, Reid CA, Chen F, Tan HO, Petrou S, Lawrence AJ (2010) Cocaine-mediated synaptic potentiation is absent in VTA neurons from mGlu5-deficient mice. Int J Neuropsychopharmacol 13:133–141

    PubMed  CAS  Google Scholar 

  • Blednov YA, Walker D, Osterndorf-Kahanek E, Harris RA (2004) Mice lacking metabotropic glutamate receptor 4 do not show the motor stimulatory effect of ethanol. Alcohol 34:251–259

    PubMed  CAS  Google Scholar 

  • Blümcke I, Behle K, Malitschek B, Kuhn R, Knöpfel T, Wolf HK, Wiestler OD (1996) Immunohistochemical distribution of metabotropic glutamate receptor subtypes mGluR1b, mGluR2/3, mGluR4a and mGluR5 in human hippocampus. Brain Res 736:217–226

    PubMed  Google Scholar 

  • Boer K, Encha-Razavi F, Sinico M, Aronica E (2010) Differential distribution of group I metabotropic glutamate receptors in developing human cortex. Brain Res 1324:24–33

    PubMed  CAS  Google Scholar 

  • Bonnefous C, Vernier JM, Hutchinson JH, Gardner MF, Cramer M, James JK, Rowe BA, Daggett LP, Schaffhauser H, Kamenecka TM (2005) Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor. Bioorg Med Chem Lett 15:4354–4358

    PubMed  CAS  Google Scholar 

  • Bradbury MJ, Campbell U, Giracello D, Chapman D, King C, Tehrani L, Cosford ND, Anderson J, Varney MA, Strack AM (2005) Metabotropic glutamate receptor mGlu5 is a mediator of appetite and energy balance in rats and mice. J Pharmacol Exp Ther 313:395–402

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Bradley SR, Rees HD, Yi H, Levey AI, Conn PJ (1998) Distribution and developmental regulation of metabotropic glutamate receptor 7a in rat brain. J Neurochem 71:636–645

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Braff DL, Geyer MA (1990) Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 47:181–188

    PubMed  CAS  Google Scholar 

  • Breier A, Adler CM, Weisenfeld N, Su T-P, Elman I, Picken L, Malhotra AK, Pickar D (1998) Effects of NMDA antagonism on striatal dopamine release in healthy subjects: Application of a novel PET approach. Synapse 29:142–147

    PubMed  CAS  Google Scholar 

  • Brnardic EJ, Fraley ME, Garbaccio RM, Layton ME, Sanders JM, Culberson C, Jacobson MA, Magliaro BC, Hutson PH, O’Brien JA, Huszar SL, Uslaner JM, Fillgrove KL, Tang C, Kuo Y, Sur SM, Hartman GD (2010) 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts. Bioorg Med Chem Lett 20:3129–3133

    PubMed  CAS  Google Scholar 

  • Brody SA, Geyer MA (2004) Interactions of the mGluR5 gene with breeding and maternal factors on startle and prepulse inhibition in mice. Neurotox Res 6:79–90

    PubMed  Google Scholar 

  • Brody SA, Conquet F, Geyer MA (2003) Disruption of prepulse inhibition in mice lacking mGluR1. Eur J Neurosci 18:3361–3366

    PubMed  CAS  Google Scholar 

  • Brody SA, Conquet F, Geyer MA (2004a) Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice. Psychopharmacology (Berl) 172:187–195

    CAS  Google Scholar 

  • Brody SA, Dulawa SC, Conquet F, Geyer MA (2004b) Assessment of a prepulse inhibition deficit in a mutant mouse lacking mGlu5 receptors. Mol Psychiatry 9:35–41

    PubMed  CAS  Google Scholar 

  • Bubser M, Schmidt WJ (1990) 6-Hydroxydopamine lesion of the rat prefrontal cortex increases locomotor activity, impairs acquisition of delayed alternation tasks, but does not affect uninterrupted tasks in the radial maze. Behav Brain Res 37:157–168

    PubMed  CAS  Google Scholar 

  • Bubser M, Keseberg U, Notz PK, Schmidt WJ (1992) Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats. Eur J Pharmacol 229:75–82

    PubMed  CAS  Google Scholar 

  • 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. Sci World J 2:730–737

    CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Campbell UC, Lalwani K, Hernandez L, Kinney GG, Conn PJ, Bristow LJ (2004) The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats. Psychopharmacology (Berl) 175:310–318

    CAS  Google Scholar 

  • Canales JJ, Elayadi A, Errami M, Llansola M, Cauli O, Felipo V (2003) Chronic hyperammonemia alters motor and neurochemical responses to activation of group I metabotropic glutamate receptors in the nucleus accumbens in rats in vivo. Neurobiol Dis 14:380–390

    PubMed  CAS  Google Scholar 

  • Carlsson M, Carlsson A (1989) The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J Neural Transm 75:221–226

    PubMed  CAS  Google Scholar 

  • Carroll FY, Stolle A, Beart PM, Voerste A, Brabet I, Mauler 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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Cartmell J, Monn JA, Schoepp DD (1999) The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J Pharmacol Exp Ther 291:161–170

    PubMed  CAS  Google Scholar 

  • Cartmell J, Monn JA, Schoepp DD (2000a) The mGlu(2/3) receptor agonist LY379268 selectively blocks amphetamine ambulations and rearing. Eur J Pharmacol 400:221–224

    PubMed  CAS  Google Scholar 

  • Cartmell J, Perry KW, Salhoff CR, Monn JA, Schoepp DD (2000b) The potent, selective mGlu2/3 receptor agonist LY379268 increases extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindole-3-acetic acid in the medial prefrontal cortex of the freely moving rat. J Neurochem 75:1147–1154

    PubMed  CAS  Google Scholar 

  • Cartmell J, Perry KW, Salhoff CR, Monn JA, Schoepp DD (2001) Acute increases in monoamine release in the rat prefrontal cortex by the mGlu2/3 agonist LY379268 are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade. Neuropharmacology 40:847–855

    PubMed  CAS  Google Scholar 

  • Cauli B, Porter JT, Tsuzuki K, Lambolez B, Rossier J, Quenet B, Audinat E (2000) Classification of fusiform neocortical interneurons based on unsupervised clustering. Proc Natl Acad Sci USA 97:6144–6149

    PubMed  CAS  Google Scholar 

  • Chaki S, Yoshikawa R, Okuyama S (2006) Group II metabotropic glutamate receptor-mediated regulation of dopamine release from slices of rat nucleus accumbens. Neurosci Lett 404:182–186

    PubMed  CAS  Google Scholar 

  • Chan MH, Chiu PH, Sou JH, Chen HH (2008) Attenuation of ketamine-evoked behavioral responses by mGluR5 positive modulators in mice. Psychopharmacology (Berl) 198:141–148

    CAS  Google Scholar 

  • Chen Y, Nong Y, Goudet C, Hemstapat K, de Paulis T, Pin JP, Conn PJ (2007) Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses. Mol Pharmacol 71:1389–1398

    PubMed  CAS  Google Scholar 

  • Chen Y, Goudet C, Pin JP, Conn PJ (2008) N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors. Mol Pharmacol 73:909–918

    PubMed  CAS  Google Scholar 

  • Chen HH, Stoker A, Markou A (2010) The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice. Psychopharmacology (Berl) 209:343–350

    CAS  Google Scholar 

  • Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F (2001) Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci 4:873–874

    PubMed  CAS  Google Scholar 

  • Chu Z, Hablitz JJ (1998) Activation of group I mGluRs increases spontaneous IPSC frequency in rat frontal cortex. J Neurophysiol 80:621–627

    PubMed  CAS  Google Scholar 

  • Ciccarelli R, Sureda FX, Casabona G, Di Iorio P, Caruso A, Spinella F, Condorelli DF, Nicoletti F, Caciagli F (1997) Opposite influence of the metabotropic glutamate receptor subtypes mGlu3 and -5 on astrocyte proliferation in culture. Glia 21:390–398

    PubMed  CAS  Google Scholar 

  • Clark M, Johnson BG, Wright RA, Monn JA, Schoepp DD (2002) Effects of the mGlu2/3 receptor agonist LY379268 on motor activity in phencyclidine-sensitized rats. Pharmacol Biochem Behav 73:339–346

    PubMed  CAS  Google Scholar 

  • Cole BJ, Robbins TW (1992) Forebrain norepinephrine: role in controlled information processing in the rat. Neuropsychopharmacology 7:129–142

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Conn PJ, Christopoulos A, Lindsley CW (2009a) Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov 8:41–54

    PubMed  CAS  Google Scholar 

  • Conn PJ, Lindsley CW, Jones CK (2009b) Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol Sci 30:25–31

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Corti C, Aldegheri L, Somogyi P, Ferraguti F (2002) Distribution and synaptic localisation of the metabotropic glutamate receptor 4 (mGluR4) in the rodent CNS. Neuroscience 111:403–420

    Google Scholar 

  • Costall B, Naylor RJ, Nohria V (1978) Climbing behaviour induced by apomorphine in mice: a potential model for the detection of neuroleptic activity. Eur J Pharmacol 50:39–81

    PubMed  CAS  Google Scholar 

  • Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384

    PubMed  CAS  Google Scholar 

  • Cube RV, Vernier JM, Hutchinson JH, Gardner MF, James JK, Rowe BA, Schaffhauser H, Daggett L, Pinkerton AB (2005) 3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy]butoxy}ph enyl)propanoic acid: a brain penetrant allosteric potentiator at the metabotropic glutamate receptor 2 (mGluR2). Bioorg Med Chem Lett 15:2389–2393

    PubMed  CAS  Google Scholar 

  • Davis S, Butcher SP, Morris RG (1992) The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. J Neurosci 12:21–34

    PubMed  CAS  Google Scholar 

  • de Paulis T, Hemstapat K, Chen Y, Zhang Y, Saleh S, Alagille D, Baldwin RM, Tamagnan GD, Conn PJ (2006) Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes. J Med Chem 49:3332–3344

    PubMed  Google Scholar 

  • De Vry J, Horvath E, Schreiber R (2001) Neuroprotective and behavioral effects of the selective metabotropic glutamate mGlu(1) receptor antagonist BAY 36-7620. Eur J Pharmacol 428:203–214

    PubMed  Google Scholar 

  • Dedeurwaerdere S, Wintmolders C, Straetemans R, Pemberton D, Langlois X (2011) Memantine-induced brain activation as a model for the rapid screening of potential novel antipsychotic compounds: exemplified by activity of an mGlu2/3 receptor agonist. Psychopharmacology (Berl) 214:505–514

    CAS  Google Scholar 

  • Didriksen M, Skarsfeldt T, Arnt J (2007) Reversal of PCP-induced learning and memory deficits in the Morris’ water maze by sertindole and other antipsychotics. Psychopharmacology (Berl) 193:225–233

    CAS  Google Scholar 

  • Dingledine R, Borges K, Bowie D, Traynelis SF (1999) The glutamate receptor ion channels. Pharmacol Rev 51:7–61

    PubMed  CAS  Google Scholar 

  • Duplantier AJ, Efremov I, Candler J, Doran AC, Ganong AH, Haas JA, Hanks AN, Kraus KG, Lazzaro JT Jr, Lu J, Maklad N, McCarthy SA, O’Sullivan TJ, Rogers BN, Siuciak JA, Spracklin DK, Zhang L (2009) 3-Benzyl-1,3-oxazolidin-2-ones as mGluR2 positive allosteric modulators: Hit-to lead and lead optimization. Bioorg Med Chem Lett 19:2524–2429

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • Ehlers MD (1999) Synapse structure: glutamate receptors connected by the shanks. Curr Biol 9:R848–R850

    PubMed  CAS  Google Scholar 

  • Ehrengruber MU, Kato A, Inokuchi K, Hennou S (2004) Homer/Vesl proteins and their roles in CNS neurons. Mol Neurobiol 29:213–227

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Ellenbroek BA, van den Kroonenberg PT, Cools AR (1998) The effects of an early stressful life event on sensorimotor gating in adult rats. Schizophr Res 30:251–260

    PubMed  CAS  Google Scholar 

  • Engers DW, Rodriguez AL, Williams R, Hammond AS, Venable D, Oluwatola O, Sulikowski GA, Conn PJ, Lindsley CW (2009) Synthesis, SAR and unanticipated pharmacological profiles of analogues of the mGluR5 ago-potentiator ADX-47273. ChemMedChem 4:505–511

    PubMed  CAS  Google Scholar 

  • Fell MJ, Svensson KA, Johnson BG, Schoepp DD (2008) Evidence for the role of metabotropic glutamate (mGlu)2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther 326:209–217

    PubMed  CAS  Google Scholar 

  • Fell MJ, Perry KW, Falcone JF, Johnson BG, Barth VN, Rash KS, Lucaites VL, Threlkeld PG, Monn JA, McKinzie DL, Marek GJ, Svensson KA, Nelson DL (2009) In vitro and in vivo evidence for a lack of interaction with dopamine D2 receptors by the metabotropic glutamate 2/3 receptor agonists 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate (LY354740) and (−)-2-oxa-4-aminobicyclo[3.1.0] hexane-4,6-dicarboxylic acid (LY379268). J Pharmacol Exp Ther 331:1126–1136

    PubMed  CAS  Google Scholar 

  • Fendt M, Bürki H, Imobersteg S, van der Putten H, McAllister K, Leslie JC, Shaw D, Hölscher C (2010) The effect of mGlu8 deficiency in animal models of psychiatric diseases. Genes Brain Behav 9:33–44

    PubMed  CAS  Google Scholar 

  • Ferraguti F, Klausberger T, Cobden P, Baude A, Roberts JD, Szucs P, Kinoshita A, Shigemoto R, Somogyi P, Dalezios Y (2005) Metabotropic glutamate receptor 8-expressing nerve terminals target subsets of GABAergic neurons in the hippocampus. J Neurosci 25:10520–10536

    PubMed  CAS  Google Scholar 

  • Flajolet M, Rakhilin S, Wang H, Starkova N, Nuangchamnong N, Nairn AC, Greengard P (2003) Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3. Proc Natl Acad Sci USA 100:16006–16011

    PubMed  CAS  Google Scholar 

  • Fotuhi M, Standaert DG, Testa CM, Penney JB Jr, Young AB (1994) Differential expression of metabotropic glutamate receptors in the hippocampus and entorhinal cortex of the rat. Mol Brain Res 21:283–292

    PubMed  CAS  Google Scholar 

  • Fowler SW, Ramsey AK, Walker JM, Serfozo P, Olive MF, Schachtman TR, Simonyi A (2011) Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats. Neurobiol Learn Mem 95:73–79

    PubMed  CAS  Google Scholar 

  • Fraley ME (2009) Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia. Exp Opin Therap Patent 19:1259–1275

    CAS  Google Scholar 

  • Francesconi W, Cammalleri M, Sanna PP (2004) The metabotropic glutamate receptor 5 is necessary for late-phase long-term potentiation in the hippocampal CA1 region. Brain Res 1022:12–18

    PubMed  CAS  Google Scholar 

  • Fukuda J, Suzuki G, Kimura T, Nagatomi Y, Ito S, Kawamoto H, Ozaki S, Ohta H (2009) Identification of a novel transmembrane domain involved in the negative modulation of mGluR1 using a newly discovered allosteric mGluR1 antagonist, 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one. Neuropharmacology 57:438–445

    PubMed  CAS  Google Scholar 

  • Galici R, Echemendia NG, Rodriguez AL, Conn PJ (2005) 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 315:1181–1187

    PubMed  CAS  Google Scholar 

  • 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 subtype 2, has antipsychotic- and anxiolytic-like effects in mice. J Pharmacol Exp Ther 318:173–185

    PubMed  CAS  Google Scholar 

  • Gasparini F, Lingenhöhl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, Varney MA, Johnson EC, Hess SD, Rao SP, Sacaan AI, Santori EM, Veliçelebi G, Kuhn R (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonis. Neuropharmacology 38:1493–1503

    PubMed  CAS  Google Scholar 

  • Gerlai R, Roder JC, Hampson DR (1998) Altered spatial learning and memory in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. Behav Neurosci 112:525–532

    PubMed  CAS  Google Scholar 

  • Gerlai R, Adams B, Fitch T, Chaney S, Baez M (2002) Performance deficits of mGluR8 knockout mice in learning tasks: the effects of null mutation and the background genotype. Neuropharmacology 43:235–249

    PubMed  CAS  Google Scholar 

  • Geurts JJ, Wolswijk G, Bö L, van der Valk P, Polman CH, Troost D, Aronica E (2003) Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis. Brain 126:1755–1766

    PubMed  CAS  Google Scholar 

  • Gewirtz JC, Marek GJ (2000) Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology 23:569–576

    PubMed  CAS  Google Scholar 

  • Geyer MA, Markou A (1995) Animal models of psychiatric disorders. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven, New York

    Google Scholar 

  • Geyer MA, Moghaddam B (2002) Animal models relevant to schizophrenia. In: Davis KL, Charney D, Coyle JT (eds) Neuropsychopharmacology: the fifth generation of progress. American College of Neuropsychopharmacology, Nashville, TN, pp 689–701

    Google Scholar 

  • Geyer MA, Wilkinson LS, Humby T, Robbins TW (1993) Isolation rearing of rats produces a deficit in prepulse inhibition of acoustic startle similar to that in schizophrenia. Biol Psychiatry 34:361–372

    PubMed  CAS  Google Scholar 

  • Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl) 156:117–154

    CAS  Google Scholar 

  • Geyer MA, McIlwain KL, Paylor R (2002) Mouse genetic models for prepulse inhibition: an early review. Mol Psychiatry 7:1039–1053

    PubMed  CAS  Google Scholar 

  • Gillard SE, Tzaferis J, Tsui HC, Kingston AE (2003) Expression of metabotropic glutamate receptors in rat meningeal and brain microvasculature and choroid plexus. J Comp Neurol 461:317–332

    PubMed  CAS  Google Scholar 

  • Gil-Sanz C, Delgado-García 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

    PubMed  Google Scholar 

  • Glaum SR, Miller RJ (1993) Metabotropic glutamate receptors depress afferent excitatory transmission in the rat nucleus tractus solitarii. J Neurophysiol 70:2669–2672

    PubMed  CAS  Google Scholar 

  • Goddyn H, Callaerts-Vegh Z, Stroobants S, Dirikx T, Vansteenwegen D, Hermans D, van der Putten H, D’Hooge R (2008) Deficits in acquisition and extinction of conditioned responses in mGluR7 knockout mice. Neurobiol Learn Mem 90:103–111

    PubMed  CAS  Google Scholar 

  • Goldman-Rakic PS, Castner SA, Svensson TH, Siever LJ, Williams GV (2004) Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl) 174:3–16

    CAS  Google Scholar 

  • Govek SP, Bonnefous C, Hutchinson JH, Kamenecka T, McQuiston J, Pracitto R, Zhao LX, Gardner MF, James JK, Daggett LP, Rowe BA, Schaffhauser H, Bristow LJ, Campbell UC, Rodriguez DE, Vernier JM (2005) Benzazoles as allosteric potentiators of metabotropic glutamate receptor 2 (mGluR2): Efficacy in an animal model for schizophrenia. Bioorg Med Chem Lett 15:4068–4072

    PubMed  CAS  Google Scholar 

  • Gozzi A, Large CH, Schwarz A, Bertani S, Crestan V, Bifone A (2008) Differential effects of antipsychotic and glutamatergic agents on the phMRI response to phencyclidine. Neuropsychopharmacology 33:1690–1703

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Gray L, van den Buuse M, Scarr E, Dean B, Hannan AJ (2009) Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-D-aspartic acid receptor up-regulation. Int J Neuropsychopharmacol 12:45–60

    PubMed  CAS  Google Scholar 

  • Grayson B, Idris NF, Neill JC (2007) Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat. Behav Brain Res 184:31–38

    PubMed  CAS  Google Scholar 

  • Greco B, Invernizzi RW, Carli M (2005) Phencyclidine-induced impairment in attention and response control depends on the background genotype of mice: reversal by the mGLU(2/3) receptor agonist LY379268. Psychopharmacology (Berl) 179:68–76

    CAS  Google Scholar 

  • Gresack JE, Risbrough VB, Scott CN, Coste S, Stenzel-Poore M, Geyer MA, Powell SB (2010) Isolation rearing-induced deficits in contextual fear learning do not require CRF(2) receptors. Behav Brain Res 209:80–84

    PubMed  CAS  Google Scholar 

  • Gruber AJ, Calhoon GG, Shusterman I, Schoenbaum G, Roesch MR, O’Donnell P (2010) More is less: a disinhibited prefrontal cortex impairs cognitive flexibility. J Neurosci 30:17102–17110

    PubMed  CAS  Google Scholar 

  • Grueter BA, Winder DG (2005) Group II and III metabotropic glutamate receptors suppress excitatory synaptic transmission in the dorsolateral bed nucleus of the stria terminalis. Neuropsychopharmacology 30:1302–1311

    PubMed  CAS  Google Scholar 

  • Gu G, Lorrain DS, Wei H, Cole RL, Zhang X, Daggett LP, Schaffhauser HJ, Bristow LJ, Lechner SM (2008) Distribution of metabotropic glutamate 2 and 3 receptors in the rat forebrain: Implication in emotional responses and central disinhibition. Brain Res 1197:47–62

    PubMed  CAS  Google Scholar 

  • Gubellini P, Saulle E, Centonze D, Bonsi P, Pisani A, Bernardi G, Conquet F, Calabresi P (2001) Selective involvement of mGlu1 receptors in corticostriatal LTD. Neuropharmacology 40:839–846

    PubMed  CAS  Google Scholar 

  • Gubellini P, Saulle E, Centonze D, Costa C, Tropepi D, Bernardi G, Conquet F, Calabresi P (2003) Corticostriatal LTP requires combined mGluR1 and mGluR5 activation. Neuropharmacology 44:8–16

    PubMed  CAS  Google Scholar 

  • Gupta DS, McCullumsmith RE, Beneyto M, Haroutunian V, Davis KL, Meador-Woodruff JH (2005) Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia. Synapse 57:123–131

    PubMed  CAS  Google Scholar 

  • Hackler EA, Byun NE, Jones CK, Williams JM, Baheza R, Sengupta S, Grier MD, Avison M, Conn PJ, Gore JC (2010) Selective potentiation of the metabotropic glutamate receptor subtype 2 blocks phencyclidine-induced hyperlocomotion and brain activation. Neuroscience 168:209–218

    PubMed  CAS  Google Scholar 

  • Halberstadt A, Lehmann-Masten V, Geyer M, Powell S (2011) Interactive effects of mGlu5 and 5-HT2A receptors on locomotor activity in mice. Psychopharmacology (Berl) 215:81–92

    CAS  Google Scholar 

  • Hanson JE, Smith Y (1999) Group I metabotropic glutamate receptors at GABAergic synapses in monkeys. J Neurosci 19:6488–6496

    PubMed  CAS  Google Scholar 

  • Harich S, Gross G, Bespalov A (2007) Stimulation of the metabotropic glutamate 2/3 receptor attenuates social novelty discrimination deficits induced by neonatal phencyclidine treatment. Psychopharmacology (Berl) 192:511–519

    CAS  Google Scholar 

  • Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10:40–68

    PubMed  CAS  Google Scholar 

  • Heffner TG, Downs DA, Meltzer LT, Wiley JN, Williams AE (1989) CI-943, a potential antipsychotic agent. I. Preclinical behavioral effects. J Pharmacol Exp Ther 251:105–112

    PubMed  CAS  Google Scholar 

  • Heidinger V, Manzerra P, Wang XQ, Strasser U, Yu SP, 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

    PubMed  CAS  Google Scholar 

  • Hemstapat K, de Paulis T, Chen Y, Brady AE, Grover VK, Alagille D, Tamagnan GD, Conn PJ (2006) A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators. Mol Pharmacol 70:616–626

    PubMed  CAS  Google Scholar 

  • Henry SA, Lehmann-Masten V, Gasparini F, Geyer MA, Markou A (2002) The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity. Neuropharmacology 43:1199–1209

    PubMed  CAS  Google Scholar 

  • Heresco-Levy U, Javitt DC (2004) Comparative effects of glycine and D-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis. Schizophr Res 66:89–96

    PubMed  Google Scholar 

  • Heresco-Levy U, Ermilov M, Lichtenberg P, Bar G, Javitt DC (2004) High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry 55:165–171

    PubMed  CAS  Google Scholar 

  • Hermans E, Challiss RA (2001) Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. Biochem J 359:465–484

    PubMed  CAS  Google Scholar 

  • Higgins GA, Ballard TM, Kew JNC, Grayson Richards J, Kemp JA, Adam G, Woltering T, Nakanishi S, Mutel V (2004) Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent. Neuropharmacology 46:907–917

    PubMed  CAS  Google Scholar 

  • Hikichi H, Nishino M, Fukushima M, Satow A, Maehara S, Kawamoto H, Ohta H (2010) Pharmacological effects of metabotropic glutamate receptor ligands on prepulse inhibition in DBA/2J mice. Eur J Pharmacol 639:99–105

    PubMed  CAS  Google Scholar 

  • Hoffman DC (1992) Typical and atypical neuroleptics antagonize MK-801-induced locomotion and stereotypy in rats. J Neural Transm Gen Sect 89:1–10

    PubMed  CAS  Google Scholar 

  • Hoffman DC, Donovan H, Cassella JV (1993) The effects of haloperidol and clozapine on the disruption of sensorimotor gating induced by the noncompetitive glutamate antagonist MK-801. Psychopharmacology (Berl) 111:339–344

    CAS  Google Scholar 

  • Hölscher 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

    PubMed  Google Scholar 

  • Hölscher 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

    PubMed  Google Scholar 

  • Homayoun H, Moghaddam B (2008) Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs. Proc Natl Acad Sci USA 105:18041–18046

    PubMed  CAS  Google Scholar 

  • Horiguchi M, Huang M, Meltzer HY (2011a) Interaction of mGlu2/3 agonism with clozapine and lurasidone to restore novel object recognition in subchronic phencyclidine-treated rats. Psychopharmacology (Berl) 217:13–24

    CAS  Google Scholar 

  • Horiguchi M, Huang M, Meltzer HY (2011b) The role of 5-hydroxytryptamine 7 receptors in the phencyclidine-induced novel object recognition deficit in rats. J Pharmacol Exp Ther 338:605–614

    PubMed  CAS  Google Scholar 

  • Hu G, Duffy P, Swanson C, Ghasemzadeh MB, Kalivas PW (1999) The regulation of dopamine transmission by metabotropic glutamate receptors. J Pharmacol Exp Ther 289:412–416

    PubMed  CAS  Google Scholar 

  • Huang H, van den Pol AN (2007) Rapid direct excitation and long-lasting enhancement of NMDA response by group I metabotropic glutamate receptor activation of hypothalamic melanin-concentrating hormone neurons. J Neurosci 27:11560–11572

    PubMed  CAS  Google Scholar 

  • Huang Y, Narendran R, Bischoff F, Guo N, Zhu Z, Bae SA, Lesage AS, Laruelle M (2005) A positron emission tomography radioligand for the in vivo labeling of metabotropic glutamate 1 receptor: (3-ethyl-2-[11C]methyl-6-quinolinyl)(cis- 4-methoxycyclohexyl)methanone. J Med Chem 48:5096–5099

    PubMed  CAS  Google Scholar 

  • Huber KM, Roder JC, Bear MF (2001) Chemical induction of mGluR5- and protein synthesis–dependent long-term depression in hippocampal area CA1. J Neurophysiol 86:321–325

    PubMed  CAS  Google Scholar 

  • Hubert GW, Paquet M, Smith Y (2001) Differential subcellular localization of mGluR1a and mGluR5 in the rat and monkey Substantia nigra. J Neurosci 21:1838–1847

    PubMed  CAS  Google Scholar 

  • Iacovelli L, Bruno V, Salvatore L, Melchiorri D, Gradini R, Caricasole A, Barletta E, De Blasi A, Nicoletti F (2002) Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways. J Neurochem 82:216–223

    PubMed  CAS  Google Scholar 

  • Imre G, Salomons A, Jongsma M, Fokkema DS, Den Boer JA, Ter Horst GJ (2006) Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat. Pharmacol Biochem Behav 84:392–399

    PubMed  CAS  Google Scholar 

  • Inglis WL, Olmstead MC, Robbins TW (2001) Selective deficits in attentional performance on the 5-choice serial reaction time task following pedunculopontine tegmental nucleus lesions. Behav Brain Res 123:117–131

    PubMed  CAS  Google Scholar 

  • Javitt DC (1987) Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia. Hillside J Clin Psychiatry 9:12–35

    PubMed  CAS  Google Scholar 

  • Jia Z, Lu Y, Henderson J, Taverna F, Romano C, Abramow-Newerly W, Wojtowicz JM, Roder J (1998) Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5. Learn Mem 5:331–343

    PubMed  CAS  Google Scholar 

  • 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-3-ylmethylamine. J Med Chem 46:3189–3192

    PubMed  CAS  Google Scholar 

  • Johnson MP, Barda D, Britton TC, Emkey R, Hornback WJ, Jagdmann GE, McKinzie DL, Nisenbaum ES, Tizzano JP, Schoepp DD (2005) Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s). Psychopharmacology (Berl) 179:271–283

    CAS  Google Scholar 

  • Johnson KA, Niswender CM, Conn PJ, Xiang Z (2011) Activation of group II metabotropic glutamate receptors induces long-term depression of excitatory synaptic transmission in the substantia nigra pars reticulata. Neurosci Lett 504:102–106

    PubMed  CAS  Google Scholar 

  • Joly C, Gomeza J, Brabet I, Curry K, Bockaert J, Pin JP (1995) Molecular, functional, and pharmacological characterization of the metabotropic glutamate receptor type 5 splice variants: comparison with mGluR1. J Neurosci 15:3970–3981

    PubMed  CAS  Google Scholar 

  • Jones CK, Eberle EL, Peters SC, Monn JA, Shannon HE (2005a) Analgesic effects of the selective group II (mGlu2/3) metabotropic glutamate receptor agonists LY379268 and LY389795 in persistent and inflammatory pain models after acute and repeated dosing. Neuropharmacology 49(1):206–18

    PubMed  CAS  Google Scholar 

  • Jones CK, Eberle EL, Shaw DB, McKinzie DL, Shannon HE (2005b) Pharmacologic interactions between the muscarinic cholinergic and dopaminergic systems in the modulation of prepulse inhibition in rats. J Pharmacol Exp Ther 312:1055–1063

    PubMed  CAS  Google Scholar 

  • Jones DNC, Garlton JE, Minassian A, Perry W, Geyer MA (2008) Developing new drugs for schizophrenia: From animals to the clinic. In: McArthur RA, Borsini F (eds) Animal and translational models for CNS drug discovery: psychiatric disorders. Academic, Burlington, MA, pp 199–262

    Google Scholar 

  • Jones CA, Brown AM, Auer DP, Fone KC (2011) The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat. Psychopharmacology (Berl) 214:269–283

    CAS  Google Scholar 

  • Julio-Pieper M, Flor PJ, Dinan TG, Cryan JF (2011) Exciting times beyond the brain: metabotropic glutamate receptors in peripheral and non-neural tissues. Pharmacol Rev 63:35–58

    PubMed  CAS  Google Scholar 

  • Kahn L, Alonso G, Robbe D, Bockaert J, Manzoni OJ (2001) Group 2 metabotropic glutamate receptors induced long term depression in mouse striatal slices. Neurosci Lett 316:178–182

    PubMed  CAS  Google Scholar 

  • Kalivas PW (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10:561–572

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Kelley AE, Delfs JM (1994) Excitatory amino acid receptors mediate the orofacial stereotypy elicited by dopaminergic stimulation of the ventrolateral striatum. Neuroscience 60:85–95

    PubMed  CAS  Google Scholar 

  • Kelly PH, Iversen SD (1976) Selective 6OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulant-induced locomotor activity in rats. Eur J Pharmacol 40:45–56

    PubMed  CAS  Google Scholar 

  • Kelly PH, Seviour PW, Iversen SD (1975) Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res 94:507–522

    PubMed  CAS  Google Scholar 

  • Kilbride J, Rush AM, Rowan MJ, Anwyl R (2001) Presynaptic group II mGluR inhibition of short-term depression in the medial perforant path of the dentate gyrus in vitro. J Neurophysiol 85:2509–2515

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Kinney GG, Burno M, Campbell UC, Hernandez LM, Rodriguez D, Bristow LJ, Conn PJ (2003) Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. J Pharmacol Exp Ther 306:116–123

    PubMed  CAS  Google Scholar 

  • Kinney GG, O’Brien JA, Lemaire W, Burno M, Bickel DJ, Clements MK, Chen TB, Wisnoski DD, Lindsley CW, Tiller PR, Smith S, Jacobson MA, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DLJ (2005) 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 313:199–206

    PubMed  CAS  Google Scholar 

  • Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S, Jackson K, Kryzhanovskaya L, Jarkova N (2011a) A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV Schizophrenia. J Clin Psychopharmacol 31:349–55

    PubMed  CAS  Google Scholar 

  • Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S, Jackson K, Kryzhanovskaya L, Jarkova N, Group at HS (2011b) A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol 31:349–355

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Kinzie JM, Saugstad JA, Westbrook GL, Segerson TP (1995) Distribution of metabotropic glutamate receptor 7 messenger RNA in the developing and adult rat brain. Neuroscience 69:167–176

    PubMed  CAS  Google Scholar 

  • Kiss J, Görcs TJ, Kuhn R, Knöpfel T, Csáky A, Halász B (1996) Distribution of metabotropic glutamate receptor 1a in the rat hypothalamus: an immunocytochemical study using monoclonal and polyclonal antibody. Acta Biol Hung 47:221–237

    PubMed  CAS  Google Scholar 

  • Kłodzinska A, Bijak M, Tokarski K, Pilc A (2002) Group II mGlu receptor agonists inhibit behavioural and electrophysiological effects of DOI in mice. Pharmacol Biochem Behav 73:327–332

    PubMed  Google Scholar 

  • Knoflach F, Mutel V, Jolidon S, Kew JN, Malherbe P, Vieira E, Wichmann J, Kemp JA (2001) Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. Proc Natl Acad Sci USA 98:13402–13407

    PubMed  CAS  Google Scholar 

  • Koch M, Bubser M (1994) Deficient sensorimotor gating after 6-hydroxydopamine lesion of the rat medial prefrontal cortex is reversed by haloperidol. Eur J Neurosci 6:1837–1845

    PubMed  CAS  Google Scholar 

  • Kohara A, Toya T, Tamura S, Watabiki T, Nagakura Y, Shitaka Y, Hayashibe S, Kawabata S, Okada M (2005) Radioligand binding properties and pharmacological characterization of 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198), a high-affinity, selective, and noncompetitive antagonist of metabotropic glutamate receptor type 1. J Pharmacol Exp Ther 315:163–169

    PubMed  CAS  Google Scholar 

  • Kosinski CM, Risso Bradley S, Conn PJ, Levey AI, Landwehrmeyer GB, Penney JB Jr, Young AB, Standaert DG (1999) Localization of metabotropic glutamate receptor 7 mRNA and mGluR7a protein in the rat basal ganglia. J Comp Neurol 415:266–284

    PubMed  CAS  Google Scholar 

  • Krivoy A, Fischel T, Weizman A (2008) The possible involvement of metabotropic glutamate receptors in schizophrenia. Eur Neuropsychopharmacol 18:395–405

    PubMed  CAS  Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MBJ, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214

    PubMed  CAS  Google Scholar 

  • Krystal JH, Abi-Saab W, Perry E, D’Souza DC, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L, Breier A (2005a) 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 agonist, LY354740, in healthy human subjects. Psychopharmacology (Berl) 179:303–309

    CAS  Google Scholar 

  • Krystal JH, Perry EB Jr, Gueorguieva R, Belger A, Madonick SH, Abi-Dargham A, Cooper TB, Macdougall L, Abi-Saab W, D’Souza DC (2005b) Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function. Arch Gen Psychiatry 62:985–994

    PubMed  CAS  Google Scholar 

  • Lahti AC, Koffel B, LaPorte D, Tamminga CA (1995) Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13:9–19

    PubMed  CAS  Google Scholar 

  • Lapointe V, Morin F, Ratte S, Croce A, Conquet F, Lacaille JC (2004) Synapse-specific mGluR1-dependent long-term potentiation in interneurones regulates mouse hippocampal inhibition. J Physiol 555:125–135

    PubMed  CAS  Google Scholar 

  • Lavreysen H, Janssen C, Bischoff F, Langlois X, Leysen JE, Lesage AS (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

    PubMed  CAS  Google Scholar 

  • Lavreysen H, Wouters R, Bischoff F, Nóbrega Pereira S, Langlois X, Blokland S, Somers M, Dillen L, Lesage AS (2004) JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist. Neuropharmacology 47:961–972

    PubMed  CAS  Google Scholar 

  • Le Pen G, Moreau JL (2002) Disruption of prepulse inhibition of startle reflex in a neurodevelopmental model of schizophrenia: reversal by clozapine, olanzapine and risperidone but not by haloperidol. Neuropsychopharmacology 27:1–11

    PubMed  Google Scholar 

  • Lecourtier L, Homayoun H, Tamagnan G, Moghaddam B (2007) 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 62:739–746

    PubMed  CAS  Google Scholar 

  • Lesage A, Steckler T (2010) Metabotropic glutamate mGlu1 receptor stimulation and blockade: Therapeutic opportunities in psychiatric illness. Eur J Pharmacol 639:2–16

    PubMed  CAS  Google Scholar 

  • Levenes C, Daniel H, Crepel F (2001) Retrograde modulation of transmitter release by postsynaptic subtype 1 metabotropic glutamate receptors in the rat cerebellum. J Physiol 537:125–140

    PubMed  CAS  Google Scholar 

  • Levin ED, Bushnell PJ, Rezvani AH (2011) Attention-modulating effects of cognitive enhancers. Pharmacol Biochem Behav 99:146–154

    PubMed  CAS  Google Scholar 

  • Lewis DA, Moghaddam B (2006) Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 63:1372–1376

    PubMed  Google Scholar 

  • Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324

    PubMed  CAS  Google Scholar 

  • Lieberman JA, Tollefson G, Tohen M, Green AI, Gur RE, Kahn R, McEvoy J, Perkins D, Sharma T, Zipursky R, Wei H, Hamer RM, HGDH_Study_Group (2003) Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine vs haloperidol. Am J Psychiatry 160:1396–1404

    PubMed  Google Scholar 

  • Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK, Clinical_Antipsychotic_Trials_of_Intervention_Effectiveness_(CATIE)_Investigators (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New Eng J Med 353:1209–1223.

    Google Scholar 

  • Linden AM, Johnson BG, Peters SC, Shannon HE, Tian M, Wang Y, Yu JL, Köster A, Baez M, Schoepp DD (2002) Increased anxiety-related behavior in mice deficient for metabotropic glutamate 8 (mGlu8) receptor. Neuropharmacology 43:251–259

    PubMed  CAS  Google Scholar 

  • Linden AM, Baez M, Bergeron M, Schoepp DD (2006) Effects of mGlu2 or mGlu3 receptor deletions on mGlu2/3 receptor agonist (LY354740)-induced brain c-Fos expression: specific roles for mGlu2 in the amygdala and subcortical nuclei, and mGlu3 in the hippocampus. Neuropharmacology 51:213–228

    PubMed  CAS  Google Scholar 

  • Lindsley CW, Wisnoski DD, Leister WH, O’brien JA, Lemaire W, Williams DL Jr, Burno M, Sur C, Kinney GG, Pettibone DJ, Tiller PR, Smith S, Duggan ME, Hartman GD, Conn PJ, Huff JR (2004) Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo. J Med Chem 47:5825–5828

    PubMed  CAS  Google Scholar 

  • Lipina T, Weiss K, Roder J (2007) The ampakine CX546 restores the prepulse inhibition and latent inhibition deficits in mGluR5-deficient mice. Neuropsychopharmacology 32:745–756

    PubMed  CAS  Google Scholar 

  • Liu J, Moghaddam B (1995) Regulation of glutamate efflux by excitatory amino acid receptors: evidence for tonic inhibitory and phasic excitatory regulation. J Pharmacol Exp Ther 274:1209–1215

    PubMed  CAS  Google Scholar 

  • Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G, Atkinson PJ, Popiolek M, Wantuch C, Khawaja X, Smith D, Olsen M, Kouranova E, Lai M, Pruthi F, Pulicicchio C, Day M, Gilbert A, Pausch MH, Brandon NJ, Beyer CE, Comery TA, Logue S, Rosenzweig-Lipson S, Marquis KL (2008) ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities. J Pharmacol Exp Ther 327:827–839

    PubMed  CAS  Google Scholar 

  • Ljungberg T, Ungerstedt U (1985) A rapid and simple behavioural screening method for simultaneous assessment of limbic and striatal blocking effects of neuroleptic drugs. Pharmacol Biochem Behav 23:479–485

    PubMed  CAS  Google Scholar 

  • Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA (2003) Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 117:697–706

    PubMed  CAS  Google Scholar 

  • Lu YM, Jia Z, Janus C, Henderson JT, Gerlai R, Wojtowicz JM, Roder JC (1997) Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J Neurosci 17:5196–5205

    PubMed  CAS  Google Scholar 

  • Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Keller R (1959) Study of a new schizophrenomimetic drug; sernyl. AMA Arch Neurol Psychiatry 81:363–369

    PubMed  CAS  Google Scholar 

  • Luján R, Roberts JD, Shigemoto R, Ohishi H, Somogyi P (1997) Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1 alpha, mGluR2 and mGluR5, relative to neurotransmitter release sites. J Chem Neuroanat 13:219–241

    PubMed  Google Scholar 

  • Lyon L, Kew JN, Corti C, Harrison PJ, Burnet PW (2008) Altered hippocampal expression of glutamate receptors and transporters in GRM2 and GRM3 knockout mice. Synapse 62:842–845

    PubMed  CAS  Google Scholar 

  • Lyon L, Borel M, Carrión M, Kew JN, Corti C, Harrison PJ, Burnet PW, Paulsen O, Rodríguez-Moreno A (2011a) Hippocampal mossy fiber long-term depression in Grm2/3 double knockout mice. Synapse 65:945–954

    PubMed  CAS  Google Scholar 

  • Lyon L, Burnet PW, Kew JN, Corti C, Rawlins JN, Lane T, De Filippis B, Harrison PJ, Bannerman DM (2011b) Fractionation of spatial memory in GRM2/3 (mGlu2/mGlu3) double knockout mice reveals a role for group II metabotropic glutamate receptors at the interface between arousal and cognition. Neuropsychopharmacology 36:2616–2628

    PubMed  CAS  Google Scholar 

  • Mabire D, Coupa S, Adelinet C, Poncelet A, Simonnet Y, Venet M, Wouters R, Lesage AS, Van Beijsterveldt L, Bischoff F (2005) Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists. J Med Chem 48:2134–2153

    PubMed  CAS  Google Scholar 

  • Maciejak P, Taracha E, Lehner M, Szyndler J, Bidziński A, Skórzewska A, Wisłowska A, Zienowicz M, Płaźnik A (2003) Hippocampal mGluR1 and consolidation of contextual fear conditioning. Brain Res Bull 62:39–45

    PubMed  CAS  Google Scholar 

  • Manahan-Vaughan D (1998) Priming of group 2 metabotropic glutamate receptors facilitates induction of long-term depression in the dentate gyrus of freely moving rats. Neuropharmacology 37:1459–1464

    PubMed  CAS  Google Scholar 

  • Manahan-Vaughan D, Braunewell KH (2005) The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity. Cereb Cortex 15(11):1703–13

    PubMed  Google Scholar 

  • Mannaioni G, Marino MJ, Valenti O, Traynelis SF, Conn PJ (2001) Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function. J Neurosci 21:5925–5934

    PubMed  CAS  Google Scholar 

  • Mansbach RM, Geyer MA (1989) Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology 2:299–308

    PubMed  CAS  Google Scholar 

  • Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology (Berl) 94:507–514

    CAS  Google Scholar 

  • Mao L, Wang JQ (2002a) Glutamate cascade to cAMP response element-binding protein phosphorylation in cultured striatal neurons through calcium-coupled group I metabotropic glutamate receptors. Mol Pharmacol 62:473–484

    PubMed  CAS  Google Scholar 

  • Mao L, Wang JQ (2002b) Interactions between ionotropic and metabotropic glutamate receptors regulate cAMP response element-binding protein phosphorylation in cultured striatal neurons. Neuroscience 115:395–402

    PubMed  CAS  Google Scholar 

  • Mao L, Conquet F, Wang JQ (2001) Augmented motor activity and reduced striatal preprodynorphin mRNA induction in response to acute amphetamine administration in metabotropic glutamate receptor 1 knockout mice. Neuroscience 106:303–312

    PubMed  CAS  Google Scholar 

  • Mao L, Conquet F, Wang JQ (2002) Impaired preprodynorphin, but not preproenkephalin, mRNA induction in the striatum of mGluR1 mutant mice in response to acute administration of the full dopamine D(1) agonist SKF-82958. Synapse 44:86–93

    PubMed  CAS  Google Scholar 

  • Mao L, Yang L, Tang Q, Samdani S, Zhang G, Wang JQ (2005) The scaffold protein Homer1b/c links metabotropic glutamate receptor 5 to extracellular signal-regulated protein kinase cascades in neurons. J Neurosci 25:2741–2752

    PubMed  CAS  Google Scholar 

  • Marino MJ, Conn PJ (2002a) Direct and indirect modulation of the N-methyl D-aspartate receptor. Curr Drug Targets CNS Neurol Disord 1:1–16

    PubMed  CAS  Google Scholar 

  • Marino MJ, Conn PJ (2002b) Modulation of the basal ganglia by metabotropic glutamate receptors: potential for novel therapeutics. Curr Drug Targets CNS Neurol Disord 1:239–250

    PubMed  CAS  Google Scholar 

  • Markham JA, Taylor AR, Taylor SB, Bell DB, Koenig JI (2010) Characterization of the cognitive impairments induced by prenatal exposure to stress in the rat. Front Behav Neurosci 4:173

    PubMed  Google Scholar 

  • Martin LJ, Blackstone CD, Huganir RL, Price DL (1992) Cellular localization of a metabotropic glutamate receptor in rat brain. Neuron 9:259–270

    PubMed  CAS  Google Scholar 

  • Masugi M, Yokoi M, Shigemoto R, Muguruma K, Watanabe Y, Sansig G, van der Putten H, Nakanishi S (1999) Metabotropic glutamate receptor subtype 7 ablation causes deficit in fear response and conditioned taste aversion. J Neurosci 19:955–963

    PubMed  CAS  Google Scholar 

  • Matrisciano F, Tueting P, Maccari S, Nicoletti F, Guidotti A (2011) Pharmacological activation of group-II metabotropic glutamate receptors corrects a schizophrenia-like phenotype induced by prenatal stress in mice. Neuropsychopharmacology 37(4):929–38

    PubMed  Google Scholar 

  • McGeehan AJ, Janak PH, Olive MF (2004) Effect of the mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant properties of cocaine, D-amphetamine, and the dopamine reuptake inhibitor GBR12909 in mice. Psychopharmacology (Berl) 174:266–273

    CAS  Google Scholar 

  • McNamara RK, Skelton RW (1993) The neuropharmacological and neurochemical basis of place learning in the Morris water maze. Brain Res Rev 18:33–49

    PubMed  CAS  Google Scholar 

  • Merlin LR, Wong RK (1997) Role of group I metabotropic glutamate receptors in the patterning of epileptiform activities in vitro. J Neurophysiol 78:539–544

    PubMed  CAS  Google Scholar 

  • Merlin LR, Bergold PJ, Wong RK (1999) Requirement of protein synthesis for group I mGluR-mediated induction of epileptiform discharges. J Neurophysiol 80:989–993

    Google Scholar 

  • Miller S, Sehati N, Romano C, Cotman CW (1996) Exposure of astrocytes to thrombin reduces levels of the metabotropic glutamate receptor mGluR5. J Neurochem 67:1435–1447

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Moghaddam B (2004) Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology (Berl) 174:39–44

    CAS  Google Scholar 

  • Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352

    PubMed  CAS  Google Scholar 

  • Moghaddam B, Jackson ME (2003) Glutamatergic animal models of schizophrenia. Ann N Y Acad Sci 1003:131–137

    PubMed  CAS  Google Scholar 

  • Moghaddam B, Adams B, Verma A, Daly D (1997) 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 17:2921–2927

    PubMed  CAS  Google Scholar 

  • Monn JA, Valli MJ, Massey SM, Wright RA, Salhoff CR, Johnson BG, Howe T, Alt CA, Rhodes GA, Robey RL, Griffey KR, Tizzano JP, Kallman MJ, Helton DR, Schoepp DD (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

    PubMed  CAS  Google Scholar 

  • Moore H, Jentsch JD, Ghajarnia M, Geyer MA, Grace AA (2006) A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia. Biol Psychiatry 60:253–264

    PubMed  CAS  Google Scholar 

  • Morè L, Gravius A, Pietraszek M, Belozertseva I, Malyshkin A, Shekunova E, Barberi C, Schaefer D, Schmidt WJ, Danysz W (2007) Comparison of the mGluR1 antagonist A-841720 in rat models of pain and cognition. Behav Pharmacol 18:273–281

    PubMed  Google Scholar 

  • Moreno JL, Sealfon SC, González-Maeso J (2009) Group II metabotropic glutamate receptors and schizophrenia. Cell Mol Life Sci 66:3777–3785

    PubMed  CAS  Google Scholar 

  • Morishima Y, Miyakawa T, Furuyashiki T, Tanaka Y, Mizuma H, Nakanishi S (2005) Enhanced cocaine responsiveness and impaired motor coordination in metabotropic glutamate receptor subtype 2 knockout mice. Proc Natl Acad Sci USA 102:4170–7175

    PubMed  CAS  Google Scholar 

  • Moroni F, Lombardi G, Thomsen C, Leonardi P, Attucci S, Peruginelli F, Torregrossa SA, Pellegrini-Giampietro DE, Luneia R, Pellicciari R (1997) Pharmacological characterization of 1-aminoindan-1,5-dicarboxylic acid, a potent mGluR1 antagonist. J Pharmacol Exp Ther 281:721–729

    PubMed  CAS  Google Scholar 

  • Moroni F, Cozzi A, Lombardi G, Sourtcheva S, Leonardi P, Carfì M, Pellicciari R (1998) Presynaptic mGlu1 type receptors potentiate transmitter output in the rat cortex. Eur J Pharmacol 347:189–195

    PubMed  CAS  Google Scholar 

  • Morris RG, Schenk F, Tweedie F, Jarrard LE (1990) Ibotenate lesions of hippocampus and/or subiculum: dissociating components of allocentric spatial learning. Eur J Neurosci 2:1016–1028

    PubMed  Google Scholar 

  • Muir JL, Bussey TJ, Everitt BJ, Robbins TW (1996) Dissociable effects of AMPA-induced lesions of the vertical limb diagonal band of Broca on performance of the 5-choice serial reaction time task and on acquisition of a conditional visual discrimination. Behav Brain Res 82:31–44

    PubMed  CAS  Google Scholar 

  • Muly EC, Maddox M, Smith Y (2003) Distribution of mGluR1alpha and mGluR5 immunolabeling in primate prefrontal cortex. J Comp Neurol 467:521–535

    PubMed  CAS  Google Scholar 

  • Muly EC, Mania I, Guo JD, Rainnie DG (2007) Group II metabotropic glutamate receptors in anxiety circuitry: correspondence of physiological response and subcellular distribution. J Comp Neurol 505:682–700

    PubMed  CAS  Google Scholar 

  • Murphy BL, Arnsten AF, Goldman-Rakic PS, Roth RH (1996) Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc Natl Acad Sci USA 93:1325–1329

    PubMed  CAS  Google Scholar 

  • Naie K, Manahan-Vaughan D (2005) Pharmacological antagonism of metabotropic glutamate receptor 1 regulates long-term potentiation and spatial reference memory in the dentate gyrus of freely moving rats via N-methyl-D-aspartate and metabotropic glutamate receptor-dependent mechanisms. Eur J Neurosci 21:411–421

    PubMed  Google Scholar 

  • Nakazato A, Kumagai T, Sakagami K, Yoshikawa R, Suzuki Y, Chaki S, Ito H, Taguchi T, Nakanishi S, Okuyama S (2000) Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. J Med Chem 43:4893–4909

    PubMed  CAS  Google Scholar 

  • Négyessy L, Vidnyánszky Z, Kuhn R, Knöpfel T, Görcs TJ, Hámori J (1997) Light and electron microscopic demonstration of mGluR5 metabotropic glutamate receptor immunoreactive neuronal elements in the rat cerebellar cortex. J Comp Neurol 385:641–650

    PubMed  Google Scholar 

  • Neki A, Ohishi H, Kaneko T, Shigemoto R, Nakanishi S, Mizuno N (1996a) Metabotropic glutamate receptors mGluR2 and mGluR5 are expressed in two non-overlapping populations of Golgi cells in the rat cerebellum. Neuroscience 75:815–826

    PubMed  CAS  Google Scholar 

  • Neki A, Ohishi H, Kaneko T, Shigemoto R, Nakanishi S, Mizuno N (1996b) Pre- and postsynaptic localization of a metabotropic glutamate receptor, mGluR2, in the rat brain: an immunohistochemical study with a monoclonal antibody. Neurosci Lett 202:197–200

    PubMed  CAS  Google Scholar 

  • Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20:106–118

    PubMed  CAS  Google Scholar 

  • Nicholls RE, Zhang XL, Bailey CP, Conklin BR, Kandel ER, Stanton PK (2006) mGluR2 acts through inhibitory Galpha subunits to regulate transmission and long-term plasticity at hippocampal mossy fiber-CA3 synapses. Proc Natl Acad Sci USA 103:6380–6385

    PubMed  CAS  Google Scholar 

  • Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP (2011) Metabotropic glutamate receptors: From the workbench to the bedside. Neuropharmacology 60:1017–1041

    PubMed  CAS  Google Scholar 

  • Nikiforuk A, Popik P, Drescher KU, van Gaalen M, Relo AL, Mezler M, Marek G, Schoemaker H, Gross G, Bespalov A (2011) Effects of a positive allosteric modulator of group II metabotropic glutamate receptors, LY487379, on cognitive flexibility and impulsive-like responding in rats. J Pharmacol Exp Ther 335:665–673

    Google Scholar 

  • Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295–322

    PubMed  CAS  Google Scholar 

  • Noetzel MJ, Rook JM, Vinson PN, Cho H, Days E, Zhou Y, Rodriguez AL, Lavreysen H, Stauffer SR, Niswender CM, Xiang Z, Daniels JS, Jones CK, Lindsley CW, Weaver CD, Conn PJ (2011) Functional impact of allosteric agonist activity of selective positive allosteric modulators of mGlu5 in regulating CNS function. Mol Pharmacol 81(2):120–33

    PubMed  Google Scholar 

  • Nomura A, Shigemoto R, Nakamura Y, Okamoto N, Mizuno N, Nakanishi S (1994) Developmentally regulated postsynaptic localization of a metabotropic glutamate receptor in rat rod bipolar cells. Cell 77:361–369

    PubMed  CAS  Google Scholar 

  • Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Heaton RK (2004) Identification of separable cognitive factors in schizophrenia. Schizophr Res 72:29–39

    PubMed  Google Scholar 

  • O’Brien JA, Lemaire W, Chen TB, Chang RS, Jacobson MA, Ha SN, Lindsley CW, Schaffhauser HJ, Sur C, Pettibone DJ, Conn PJ, Williams DL Jr (2003) A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Mol Pharmacol 64:731–740

    PubMed  Google Scholar 

  • O’Brien JA, Lemaire W, Wittmann M, Jacobson MA, Ha SN, Wisnoski DD, Lindsley CW, Schaffhauser HJ, Rowe B, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL Jr (2004) A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain. J Pharmacol Exp Ther 309:568–577

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Ohishi H, Neki A, Mizuno N (1998) Distribution of a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat and mouse: an immunohistochemical study with a monoclonal antibody. Neurosci Res 30:65–82

    PubMed  CAS  Google Scholar 

  • Ong WY, He Y, Tan KK, Garey LJ (1998) Differential localisation of the metabotropic glutamate receptor mGluR1a and the ionotropic glutamate receptor GluR2/3 in neurons of the human cerebral cortex. Exp Brain Res 119:367–374

    PubMed  CAS  Google Scholar 

  • Ossowska K, Pietraszek M, Wardas J, Nowak G, Zajaczkowski W, Wolfarth S, Pilc A (2000) The role of glutamate receptors in antipsychotic drug action. Amino Acids 19:87–94

    PubMed  CAS  Google Scholar 

  • Pałucha-Poniewiera A, Kłodzińska A, Stachowicz K, Tokarski K, Hess G, Schann S, Frauli M, Neuville P, Pilc A (2008) Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents. Neuropharmacology 55:517–524

    PubMed  Google Scholar 

  • Parmentier ML, Galvez T, Acher F, Peyre B, Pellicciari R, Grau Y, Bockaert J, Pin JP (2000) Conservation of the ligand recognition site of metabotropic glutamate receptors during evolution. Neuropharmacology 39:1119–1131

    PubMed  CAS  Google Scholar 

  • Parmentier-Batteur S, Obrien JA, Doran S, Nguyen SJ, Flick RB, Uslaner JM, Chen H, Finger EN, Williams TM, Jacobson MA, Hutson PH (2010) Differential effects of the mGluR5 positive allosteric modulator CDPPB in the cortex and striatum following repeated administration. Neuropharmacology 62:1453–1460

    Google Scholar 

  • Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (2007a) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 13:1102–1107

    PubMed  CAS  Google Scholar 

  • Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (2007b) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 13:1102–1107

    PubMed  CAS  Google Scholar 

  • Pehrson AL, Moghaddam B (2010) Impact of metabotropic glutamate 2/3 receptor stimulation on activated dopamine release and locomotion. Psychopharmacology (Berl) 211:443–455

    CAS  Google Scholar 

  • Pekhletski R, Gerlai R, Overstreet LS, Huang XP, Agopyan N, Slater NT, Abramow-Newerly W, Roder JC, Hampson DR (1996) Impaired cerebellar synaptic plasticity and motor performance in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. J Neurosci 16:6364–6373

    PubMed  CAS  Google Scholar 

  • Pellicciari R, Costantino G (1999) Metabotropic G-protein-coupled glutamate receptors as therapeutic targets. Curr Opin Chem Biol 3:433–440

    PubMed  CAS  Google Scholar 

  • Petralia RS, Wang YX, Niedzielski AS, Wenthold RJ (1996) The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 71:949–976

    PubMed  CAS  Google Scholar 

  • Phillips T, Rees S, Augood S, Waldvogel H, Faull R, Svendsen C, Emson P (2000) Localization of metabotropic glutamate receptor type 2 in the human brain. Neuroscience 95:1139–1156

    PubMed  CAS  Google Scholar 

  • Pietraszek M, Gravius A, Schafer D, Weil T, Trifanova D, Danysz W (2005) mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition. Neuropharmacology 49:73–85

    PubMed  CAS  Google Scholar 

  • Pilowsky LS, Bressan RA, Stone JM, Erlandsson K, Mulligan RS, Krystal JH, Ell PJ (2006) First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry 11:118–119

    PubMed  CAS  Google Scholar 

  • Pinheiro PS, Mulle C (2008) Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nat Rev Neurosci 9:423–436

    PubMed  CAS  Google Scholar 

  • Pinkerton AB, Vernier JM, Schaffhauser H, Rowe BA, Campbell UC, Rodriguez DE, Lorrain DS, Baccei CS, Daggett LP, Bristow LJ (2004) Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor. J Med Chem 47:4595–4599

    PubMed  CAS  Google Scholar 

  • Pinkerton AB, Cube RV, Hutchinson JH, James JK, Gardner MF, Rowe BA, Schaffhauser H, Rodriguez DE, Campbell UC, Daggett LP, Vernier JM (2005) Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 3: Identification and biological activity of indanone containing mGlu2 receptor potentiators. Bioorg Med Chem Lett 15:1565–1571

    PubMed  CAS  Google Scholar 

  • Pisani A, Gubellini P, Bonsi P, Conquet F, Picconi B, Centonze D, Bernardi G, Calabresi P (2001) Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons. Neuroscience 106:579–587

    PubMed  CAS  Google Scholar 

  • Poisik O, Raju DV, Verreault M, Rodriguez A, Abeniyi OA, Conn PJ, Smith Y (2005) Metabotropic glutamate receptor 2 modulates excitatory synaptic transmission in the rat globus pallidus. Neuropharmacology 2005:135–145

    Google Scholar 

  • Porsolt RD, Moser PC, Castagné V (2010) Behavioral indices in antipsychotic drug discovery. J Pharmacol Exp Ther 333:632–638

    PubMed  CAS  Google Scholar 

  • Pozzi L, Baviera M, Sacchetti G, Calcagno E, Balducci C, Invernizzi RW, Carli M (2011) Attention deficit induced by blockade of N-methyl d-aspartate receptors in the prefrontal cortex is associated with enhanced glutamate release and cAMP response element binding protein phosphorylation: role of metabotropic glutamate receptors 2/3. Neuroscience 176:336–348

    PubMed  CAS  Google Scholar 

  • Pramyothin P, Khaodhiar L (2010) Metabolic syndrome with the atypical antipsychotics. Curr Opin Endocrinol Diabetes Obes 17:460–466

    PubMed  CAS  Google Scholar 

  • Pratt SD, Mezler M, Geneste H, Bakker MH, Hajduk PJ, Gopalakrishnan SM (2011) Identification and characterization of mGlu3 ligands using a high throughput FLIPR assay for detection of agonists, antagonists, and allosteric modulators. Comb Chem High Throughput Screen 14:631–641

    PubMed  CAS  Google Scholar 

  • Prézeau L, Gomeza J, Ahern S, Mary S, Galvez T, Bockaert J, Pin JP (1996) Changes in the carboxyl-terminal domain of metabotropic glutamate receptor 1 by alternative splicing generate receptors with differing agonist-independent activity`. Mol Pharmacol 49:422–429

    PubMed  Google Scholar 

  • Profaci CP, Krolikowski KA, Olszewski RT, Neale JH (2011) Group II mGluR agonist LY354740 and NAAG peptidase inhibitor effects on prepulse inhibition in PCP D-amphetamine models of schizophrenia. Psychopharmacology (Berl) 216:235–243

    CAS  Google Scholar 

  • Ramsey AJ (2009) NR1 knockdown mice as a representative model of the glutamate hypothesis of schizophrenia. Prog Brain Res 179:51–58

    PubMed  CAS  Google Scholar 

  • Reichel CM, Schwendt M, McGinty JF, Olive MF, See RE (2011) Loss of object recognition memory produced by extended access to methamphetamine self-administration is reversed by positive allosteric modulation of metabotropic glutamate receptor 5. Neuropsychopharmacology 36:782–792

    PubMed  CAS  Google Scholar 

  • Renger JJ, Hartman KN, Tsuchimoto Y, Yokoi M, Nakanishi S, Hensch TK (2002) Experience-dependent plasticity without long-term depression by type 2 metabotropic glutamate receptors in developing visual cortex. Proc Natl Acad Sci USA 99:1041–1046

    PubMed  CAS  Google Scholar 

  • Richardson-Burns SM, Haroutunian V, Davis KL, Watson SJ, Meador-Woodruff JH (1999) Metabotropic glutamate receptors mRNA expression in the schizophrenic thalamus. Biol Psychiatry 47:22–28

    Google Scholar 

  • Robbe D, Alonso G, Chaumont S, Bockaert J, Manzoni OJ (2002) Role of p/q-Ca2+ channels in metabotropic glutamate receptor 2/3-dependent presynaptic long-term depression at nucleus accumbens synapses. J Neurosci 22:4346–4356

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Rodriguez AL, Nong Y, Sekaran NK, Alagille D, Tamagnan GD, Conn PJ (2005) A close structural analog of 2-methyl-6-(phenylethynyl)-pyridine acts as a neutral allosteric site ligand on metabotropic glutamate receptor subtype 5 and blocks the effects of multiple allosteric modulators. Mol Pharmacol 68:1793–1802

    PubMed  CAS  Google Scholar 

  • Rodriguez AL, Grier MD, Jones CK, Herman EJ, Kane AS, Smith RL, Williams R, Zhou Y, Marlo JE, Days EL, Blatt TN, Jadhav S, Menon UN, Vinson PN, Rook JM, Stauffer SR, Niswender CM, Lindsley CW, Weaver CD, Conn PJ (2010) Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. Mol Pharmacol 78:1105–1123

    PubMed  CAS  Google Scholar 

  • Rondard P, Goudet C, Kniazeff J, Pin JP, Prezeau L (2011) The complexity of their activation mechanism opens new possibilities for the modulation of mGlu and GABAB class C G protein-coupled receptors. Neuropharmacology 60:82–92

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Rorick-Kehn LM, Johnson BG, Burkey JL, Wright RA, Calligaro DO, Marek GJ, Nisenbaum ES, Catlow JT, Kingston AE, Giera DD, Herin MF, Monn JA, McKinzie DL, Schoepp DD (2007a) 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 321:308–317

    PubMed  CAS  Google Scholar 

  • Rorick-Kehn LM, Johnson BG, Knitowski KM, Salhoff CR, Witkin JM, Perry KW, Griffey KI, Tizzano JP, Monn JA, McKinzie DL, Schoepp DD (2007b) In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders. Psychopharmacology (Berl) 193:121–136

    CAS  Google Scholar 

  • Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT (2006) Neurobiology of schizophrenia. Neuron 52:139–153

    PubMed  CAS  Google Scholar 

  • Ross JR, Porter BE, Buckley PT, Eberwine JH, Robinson MB (2011) mRNA for the EAAC1 subtype of glutamate transporter is present in neuronal dendrites in vitro and dramatically increases in vivo after a seizure. Neurochem Int 58:366–375

    PubMed  CAS  Google Scholar 

  • Rowe BA, Schaffhauser H, Morales S, Lubbers LS, Bonnefous C, Kamenecka TM, McQuiston J, Daggett LP (2008) Transposition of three amino acids transforms the human metabotropic glutamate receptor (mGluR)-3 positive allosteric modulation site to mGluR2, and additional characterization of the mGluR2 positive allosteric modulation site. J Pharmacol Exp Ther 326:240–251

    PubMed  CAS  Google Scholar 

  • Sadler TR, Nguyen PT, Yang J, Givrad TK, Mayer EA, Maarek JM, Hinton DR, Holschneider DP (2011) Antenatal maternal stress alters functional brain responses in adult offspring during conditioned fear. Brain Res 1385:163–174

    PubMed  CAS  Google Scholar 

  • Salmi P, Samuelsson J, Ahlenius S (1994) A new computer-assisted two-way avoidance conditioning equipment for rats: behavioral and pharmacological validation. J Pharmacol Toxicol Methods 32:155–159

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Sato T, Tanaka K, Ohnishi Y, Irifune M, Nishikawa T (2003) Effect of donepezil on group II mGlu receptor agonist- or antagonist-induced amnesia on passive avoidance in mice. Neural Plast 10:319–325

    PubMed  CAS  Google Scholar 

  • Sato T, Tanaka K, Ohnishi Y, Teramoto T, Irifune M, Nishikawa T (2004) Inhibitory effects of group II mGluR-related drugs on memory performance in mice. Physiol Behav 80:747–758

    PubMed  CAS  Google Scholar 

  • Satow A, Maehara S, Ise S, Hikichi H, Fukushima M, Suzuki G, Kimura T, Tanak 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]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide]. J Pharmacol Exp Ther 326:577–586

    PubMed  CAS  Google Scholar 

  • Satow A, Suzuki G, Maehara S, Hikichi H, Murai T, Kawagoe-Takaki H, Hata M, Ito S, Ozaki S, Kawamoto H, Ohta H (2009) Unique Antipsychotic Activities of the Selective Metabotropic Glutamate Receptor 1 Allosteric Antagonist 2-Cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one. J Pharmacol Exp Ther 330:179–190

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Schaffhauser H, Rowe BA, Morales S, Chavez-Noriega LE, Yin R, Jachec C, Rao SP, Bain G, Pinkerton AB, Vernier JM, Bristow LJ, Varney MA, Daggett LP (2003) Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2. Mol Pharmacol 64:798–810

    PubMed  CAS  Google Scholar 

  • Schenk F, Morris RG (1985) Dissociation between components of spatial memory in rats after recovery from the effects of retrohippocampal lesions. Exp Brain Res 58:11–28

    PubMed  CAS  Google Scholar 

  • Schlumberger C, Pietraszek M, Gravius A, Klein K-U, Greco S, Morè L, Danysz W (2009a) Comparison of the mGlu5 receptor positive allosteric modulator ADX47273 and the mGlu2/3 receptor agonist LY354740 in tests for antipsychotic-like activity. Eur J Pharmacol 623:73–83

    PubMed  CAS  Google Scholar 

  • Schlumberger C, Schäfer D, Barberi C, Morè L, Nagel J, Pietraszek M, Schmidt WJ, Danysz W (2009b) Effects of a metabotropic glutamate receptor group II agonist LY354740 in animal models of positive schizophrenia symptoms and cognition. Behav Pharmacol 20:56–66

    PubMed  CAS  Google Scholar 

  • Schlumberger C, Pietraszek M, Gravius A, Danysz W (2010a) Effects of a positive allosteric modulator of mGluR5 ADX47273 on conditioned avoidance response and PCP-induced hyperlocomotion in the rat as models for schizophrenia. Pharmacol Biochem Behav 95:23–30

    PubMed  CAS  Google Scholar 

  • Schlumberger C, Pietraszek M, Gravius A, Danysz W (2010b) Effects of a positive allosteric modulator of mGluR5 ADX47273 on conditioned avoidance response and PCP-induced hyperlocomotion in the rat as models for schizophrenia. Pharmacol Biochem Behav 95:23–30

    PubMed  CAS  Google Scholar 

  • Schmidt WJ (1986) Intrastriatal injection of DL-2-amino-5-phosphonovaleric acid (AP-5) induces sniffing stereotypy that is antagonized by haloperidol and clozapine. Psychopharmacology (Berl) 90:123–130

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Schoepp DD, Johnson BG, Wright RA, Salhoff CR, Mayne NG, Wu S, Cockerman SL, Burnett JP, Belegaje R, Bleakman D, Monn JA (1997) LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. Neuropharmacology 36:1–11

    PubMed  CAS  Google Scholar 

  • Schoepp DD, Jane DE, Monn JA (1999) Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 38:1431–1476

    PubMed  CAS  Google Scholar 

  • Schoepp DD, Wright RA, Levine LR, Gaydos B, Potter WZ (2003) LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress 6:189–197

    PubMed  CAS  Google Scholar 

  • Schreiber R, Lowe D, Voerste A, De Vry J (2000) LY354740 affects startle responding but not sensorimotor gating or discriminative effects of phencyclidine. Eur J Pharmacol 388:R3–R4

    PubMed  CAS  Google Scholar 

  • Schröder UH, Muller T, Schreiber R, Stolle A, Zuschratter W, Balschun D, Jork R, Reymann KG (2008) The potent non-competitive mGlu1 receptor antagonist BAY 36-7620 differentially affects synaptic plasticity in area cornu ammonis 1 of rat hippocampal slices and impairs acquisition in the water maze task in mice. Neuroscience 157:385–395

    PubMed  Google Scholar 

  • Seeman P, Battaglia G, Corti C, Corsi M, Bruno V (2009) Glutamate receptor mGlu2 and mGlu3 knockout striata are dopamine supersensitive, with elevated D2High receptors and marked supersensitivity to the dopamine agonist (+)PHNO. Synapse 63:247–251

    PubMed  CAS  Google Scholar 

  • Semenova S, Markou A (2007) The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats’ performance in the 5-choice serial reaction time task. Neuropharmacology 52:863–872

    PubMed  CAS  Google Scholar 

  • Semyanov A, Kullmann DM (2000) Modulation of GABAergic signaling among interneurons by metabotropic glutamate receptors. Neuron 25:663–672

    PubMed  CAS  Google Scholar 

  • Shalin SC, Egli R, Birnbaum SG, Roth TL, Levenson JM, Sweatt JD (2006) Signal transduction mechanisms in memory disorders. Prog Brain Res 157:25–41

    PubMed  CAS  Google Scholar 

  • Shannon HE, Eberle EL (2006) Effects of biasing the location of stimulus presentation, and the muscarinic cholinergic receptor antagonist scopolamine, on performance of a 5-choice serial reaction time attention task in rats. Behav Pharmacol 17:71–85

    PubMed  CAS  Google Scholar 

  • Shannon HE, Hart JC, Bymaster FP, Calligaro DO, DeLapp NW, Mitch CH, Ward JS, Fink-Jensen A, Sauerberg P, Jeppesen L, Sheardown MJ, Swedberg MD (1999) Muscarinic receptor agonists, like dopamine receptor antagonist antipsychotics, inhibit conditioned avoidance response in rats. J Pharmacol Exp Ther 290:901–907

    PubMed  CAS  Google Scholar 

  • Sharma S, Kedrowski J, Rook JM, Smith RL, Jones CK, Rodriguez AL, Conn PJ, Lindsley CW (2009) Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines. J Med Chem 52:4103–4106

    PubMed  CAS  Google Scholar 

  • Sharp T, Zetterström T, Ljungberg T, Ungerstedt U (1987) A direct comparison of amphetamine-induced behaviours and regional brain dopamine release in the rat using intracerebral dialysis. Brain Res 401:322–330

    PubMed  CAS  Google Scholar 

  • Sheffler DJ, Conn PJ (2008) Allosteric potentiators of metabotropic glutamate receptor subtype 1a differentially modulate independent signaling pathways in Baby Hamster kidney cells. Neuropharmacology 55:419–427

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Shigemoto R, Kulik A, Roberts JD, Ohishi H, Nusser Z, Kaneko T, Somogyi P (1996) Target-cell-specific concentration of a metabotropic glutamate receptor in the presynaptic active zone. Nature 381:523–525

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Shimazaki T, Kaku A, Chaki S (2007) Blockade of the metabotropic glutamate 2/3 receptors enhances social memory via the AMPA receptor in rats. Eur J Pharmacol 575:94–97

    PubMed  CAS  Google Scholar 

  • Shimazoe T, Doi Y, Arai I, Yoshimatsu A, Fukumoto T, Watanabe S (2002) Both metabotropic glutamate I and II receptors mediate augmentation of dopamine release from the striatum in methamphetamine-sensitized rats. Jpn J Pharmacol 89:85–88

    PubMed  CAS  Google Scholar 

  • Shiraishi-Yamaguchi Y, Furuichi T (2007) The Homer family proteins. Genome Biol 8:206

    PubMed  Google Scholar 

  • Sidiropoulou K, Lu FM, Fowler MA, Xiao R, Phillips C, Ozkan ED, Zhu MX, White FJ, Cooper DC (2009) Dopamine modulates an mGluR5-mediated depolarization underlying prefrontal persistent activity. Nat Neurosci 12:190–199

    PubMed  CAS  Google Scholar 

  • Snead OC 3rd, Banerjee PK, Burnham M, Hampson D (2000) Modulation of absence seizures by the GABA(A) receptor: a critical rolefor metabotropic glutamate receptor 4 (mGluR4). J Neurosci 20:6218–6224

    PubMed  CAS  Google Scholar 

  • Sokolov BP (1998) Expression of NMDAR1, GluR1, GluR7, and KA1 glutamate receptor mRNAs is decreased in frontal cortex of “neuroleptic-free” schizophrenics: evidence on reversible up-regulation by typical neuroleptics. J Neurochem 71:2454–2464

    PubMed  CAS  Google Scholar 

  • Somogyi P, Dalezios Y, Luján R, Roberts JD, Watanabe M, Shigemoto R (2003) High level of mGluR7 in the presynaptic active zones of select populations of GABAergic terminals innervating interneurons in the rat hippocampus. Eur J Neurosci 17:2503–2520

    PubMed  Google Scholar 

  • Spear N, Gadient RA, Wilkins DE, Do M, Smith JS, Zeller KL, Schroeder P, Zhang M, Arora J, Chhajlani V (2011) Preclinical profile of a novel metabotropic glutamate receptor 5 positive allosteric modulator. Eur J Pharmacol 659:146–154

    PubMed  CAS  Google Scholar 

  • Spinelli S, Ballard T, Gatti-McArthur S, Richards GJ, Kapps M, Woltering T, Wichmann J, Stadler H, Feldon J, Pryce CR (2005) Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys. Psychopharmacology (Berl) 179:292–302

    CAS  Google Scholar 

  • 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:R1–R2

    PubMed  CAS  Google Scholar 

  • Stauffer SR (2011) Progress toward positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5). ACS Chem Neurosci 2:450–470

    PubMed  CAS  Google Scholar 

  • Steckler T, Oliveira AF, Van Dyck C, Van Craenendonck H, Mateus AM, Langlois X, Lesage AS, Prickaerts J (2005) Metabotropic glutamate receptor 1 blockade impairs acquisition and retention in a spatial Water maze task. Behav Brain Res 164:52–60

    PubMed  CAS  Google Scholar 

  • Stefani MR, Moghaddam B (2010) Activation of type 5 metabotropic glutamate receptors attenuates deficits in cognitive flexibility induced by NMDA receptor blockade. Eur J Pharmacol 639:26–32

    PubMed  CAS  Google Scholar 

  • Stoop R, Conquet F, Zuber B, Voronin LL, Pralong E (2003) Activation of metabotropic glutamate 5 and NMDA receptors underlies the induction of persistent bursting and associated long-lasting changes in CA3 recurrent connections. J Neurosci 23:5634–5644

    PubMed  CAS  Google Scholar 

  • Sukhotina IA, Dravolina OA, Novitskaya Y, Zvartau EE, Danysz W, Bespalov AY (2008) Effects of mGlu1 receptor blockade on working memory, time estimation, and impulsivity in rats. Psychopharmacology (Berl) 196:211–220

    CAS  Google Scholar 

  • 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 (2007) 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

    PubMed  CAS  Google Scholar 

  • Swanson CJ, Schoepp DD (2002) The group II metabotropic glutamate receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) and clozapine reverse phencyclidine-induced behaviors in monoamine-depleted rats. J Pharmacol Exp Ther 303:919–927

    PubMed  CAS  Google Scholar 

  • Swerdlow NR, Keith VA, Braff DL, Geyer MA (1988) Effects of spiperone, raclopride, SCH 23390 and clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat. J Pharmacol Exp Ther 256:530–536

    Google Scholar 

  • Swerdlow NR, Braff DL, Taaid N, Geyer MA (1994) Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry 51:139–154

    PubMed  CAS  Google Scholar 

  • Swerdlow NR, Bakshi V, Geyer MA (1996) Seroquel restores sensorimotor gating in phencyclidine-treated rats. J Pharmacol Exp Ther 279:1290–1299

    PubMed  CAS  Google Scholar 

  • Szapiro G, Barros DM, Ardenghi P, Vianna MR, Choi H, Silva T, Medina JH, Izquierdo I (2001) Facilitation and inhibition of retrieval in two aversive tasks in rats by intrahippocampal infusion of agonists of specific glutamate metabotropic receptor subtypes. Psychopharmacology (Berl) 156:397–401

    CAS  Google Scholar 

  • Taboada ME, Souto M, Hawkins H, Monti JM (1979) The actions of dopaminergic and noradrenergic antagonists on conditioned avoidance responses in intact and 6-hydroxydopamine-treated rats. Psychopharmacology (Berl) 62:83–88

    CAS  Google Scholar 

  • Takamori K, Hirota S, Chaki S, Tanaka M (2003) Antipsychotic action of selective group II metabotropic glutamate receptor agonist MGS0008 and MGS0028 on conditioned avoidance responses in the rat. Life Sci 73:1721–1728

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Tiedtke PI, Bischoff C, Schmidt WJ (1990) MK-801-induced stereotypy and its antagonism by neuroleptic drugs. J Neural Transm Gen Sect 81:173–182

    PubMed  CAS  Google Scholar 

  • Tomita N, Murata M, Watanabe H, Ichikawa T, Washiyama K, Kumanishi T, Takahashi Y (2000) The effects of DCG-IV and L-CCG-1 upon phencyclidine (PCP)-induced locomotion and behavioral changes in mice. Ann N Y Acad Sci 914:284–291

    PubMed  CAS  Google Scholar 

  • Tsai G, Coyle JT (2002) Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol 42:165–179

    PubMed  CAS  Google Scholar 

  • Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF (1999) Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23:583–592

    PubMed  CAS  Google Scholar 

  • Uslaner JM, Parmentier-Batteur S, Flick RB, Surles NO, Lam JSH, McNaughton CH, Jacobson MA, Hutson PH (2009a) Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus. Neuropharmacology 57:531–538

    PubMed  CAS  Google Scholar 

  • Uslaner JM, Smith SM, Huszar SL, Pachmerhiwala R, Hinchliffe RM, Vardigan JD, Hutson PH (2009b) Combined administration of an mGlu2/3 receptor agonist and a 5-HT 2A receptor antagonist markedly attenuate the psychomotor-activating and neurochemical effects of psychostimulants. Psychopharmacology 206:641–651

    PubMed  CAS  Google Scholar 

  • Vales K, Svoboda J, Benkovicova K, Bubenikova-Valesova V, Stuchlik A (2010) The difference in effect of mGlu2/3 and mGlu5 receptor agonists on cognitive impairment induced by MK-801. Eur J Pharmacol 639:91–98

    PubMed  CAS  Google Scholar 

  • Vardi N, Duvoisin R, Wu G, Sterling P (2000) Localization of mGluR6 to dendrites of ON bipolar cells in primate retina. J Comp Neurol 423:402–412

    PubMed  CAS  Google Scholar 

  • Vardigan JD, Huszar SL, McNaughton CH, Hutson PH, Uslaner JM (2010) MK-801 produces a deficit in sucrose preference that is reversed by clozapine, D-serine, and the metabotropic glutamate 5 receptor positive allosteric modulator CDPPB: relevance to negative symptoms associated with schizophrenia? Pharmacol Biochem Behav 95:223–229

    PubMed  CAS  Google Scholar 

  • Vidnyanszky Z, Gorcs TJ, Negyessy L, Borostyankio Z, Knopfel T, Hamori J (1996) Immunocytochemical visualization of the mGluR1a metabotropic glutamate receptor at synapses of corticothalamic terminals originating from area 17 of the rat. Eur J Neurosci 8:1061–1071

    PubMed  CAS  Google Scholar 

  • Vieira E, Huwyler J, Jolidon S, Knoflach F, Mutel V, Wichmann J (2005) 9H-Xanthene-9-carboxylic acid [1,2,4]oxadiazol-3-yl- and (2H-tetrazol-5-yl)-amides as potent, orally available mGlu1 receptor enhancers. Bioorg Med Chem Lett 15:4628–4631

    PubMed  CAS  Google Scholar 

  • Vieira E, Huwyler J, Jolidon S, Knoflach F, Mutel V, Wichmann J (2009) Fluorinated 9 H-xanthene-9-carboxylic acid oxazol-2-yl-amides as potent, orally available mGlu1 receptor enhancers. Bioorg Med Chem Lett 19:1666–1669

    PubMed  CAS  Google Scholar 

  • Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF (2007) Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 10:376–384

    PubMed  CAS  Google Scholar 

  • Volk LJ, Daly CA, Huber KM (2006) Differential roles for group 1 mGluR subtypes in induction and expression of chemically induced hippocampal long-term depression. J Neurophysiol 95:2427–2438

    PubMed  CAS  Google Scholar 

  • Wadenberg ML, Hicks PB (1999) The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics? Neurosci Biobehav Rev 23:851–862

    PubMed  CAS  Google Scholar 

  • Wang X, Ai J, Hampson DR, Snead OC 3rd (2005a) Altered glutamate and GABA release within thalamocortical circuitry in metabotropic glutamate receptor 4 knockout mice. Neuroscience 134:1195–1203

    PubMed  CAS  Google Scholar 

  • Wang X, Ai J, Hampson DR, Snead OCr (2005b) Altered glutamate and GABA release within thalamocortical circuitry in metabotropic glutamate receptor 4 knockout mice. Neuroscience 134:1195–1203

    PubMed  CAS  Google Scholar 

  • Wierońska JM, Stachowicz K, Acher F, Lech T, Pilc A (2011) Opposing efficacy of group III mGlu receptor activators, LSP1-2111 and AMN082, in animal models of positive symptoms of schizophrenia. Psychopharmacology 220(2):481–94

    PubMed  Google Scholar 

  • Williams R, Manka JT, Rodriguez AL, Vinson PN, Niswender CM, Weaver CD, Jones CK, Conn PJ, Lindsley CW, Stauffer SR (2011) Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold. Bioorg Med Chem Lett 21:1350–1353

    PubMed  CAS  Google Scholar 

  • Wishka DG, Walker DP, Yates KM, Reitz SC, Jia S, Myers JK, Olson KL, Jacobsen EJ, Wolfe ML, Groppi VE, Hanchar AJ, Thornburgh BA, Cortes-Burgos LA, Wong EH, Staton BA, Raub TJ, Higdon NR, Wall TM, Hurst RS, Walters RR, Hoffmann WE, Hajos M, Franklin S, Carey G, Gold LH, Cook KK, Sands SB, Zhao SX, Soglia JR, Kalgutkar AS, Arneric SP, Rogers BN (2006) Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship. J Med Chem 49:4425–4436

    PubMed  CAS  Google Scholar 

  • Woltering TJ, Wichmann J, Goetschi E, Knoflach F, Ballard TM, Huwyler J, Gatti S (2010) Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists. Bioorg Med Chem Lett 20:6969–6974

    PubMed  CAS  Google Scholar 

  • Wong RK, Bianchi R, Taylor GW, Merlin LR (1999) Role of metabotropic glutamate receptors in epilepsy. Adv Neurol 79:685–698

    PubMed  CAS  Google Scholar 

  • Woolley ML, Pemberton DJ, Bate S, Corti C, Jones DN (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 (Berl) 196:431–440

    CAS  Google Scholar 

  • Xiong H, Brugel TA, Balestra M, Brown DG, Brush KA, Hightower C, Hinkley L, Hoesch V, Kang J, Koether GM, McCauley JP Jr, McLaren FM, Panko LM, Simpson TR, Smith RW, Woods JM, Brockel B, Chhajlani V, Gadient RA, Spear N, Sygowski LA, Zhang M, Arora J, Breysse N, Wilson JM, Isaac M, Slassi A, King MM (2010) 4-Aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators. Bioorg Med Chem Lett 20:7381–7384

    PubMed  CAS  Google Scholar 

  • Xu J, Zhu Y, Contractor A, Heinemann SF (2009) mGluR5 has a critical role in inhibitory learning. J Neurosci 29:3676–3684

    PubMed  CAS  Google Scholar 

  • Yokoi M, Kobayashi K, Manabe T, Takahashi T, Sakaguchi I, Katsuura G, Shigemoto R, Ohishi H, Nomura S, Nakamura K, Nakao K, Katsuki M, Nakanishi S (1996) Impairment of hippocampal mossy fiber LTD in mice lacking mGluR2. Science 273:645–647

    PubMed  CAS  Google Scholar 

  • Zhang Y, Rodriguez AL, Conn PJ (2005) Allosteric potentiators of metabotropic glutamate receptor subtype 5 have differential effects on different signaling pathways in cortical astrocytes. J Pharmacol Exp Ther 315:1212–1219

    PubMed  CAS  Google Scholar 

  • Zhou Y, Manka JT, Rodriguez AL, Weaver CD, Days EL, Vinson PN, Jadhav S, Hermann EJ, Jones CK, Conn PJ, Lindsley CW, Stauffer SR (2010) Discovery of N-aryl piperazines as selective mGluR5 potentiators with improved in vivo utility. ACS Med Chem Lett 1:433–438

    CAS  Google Scholar 

Download references

Acknowledgments

Beth Herman and Michael Bubser contributed equally to the authorship of this text.

Author information

Authors and Affiliations

  1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, 2220 Pierce Ave, 418 PRB, Nashville, TN, 37232, USA

    E. J. Herman, M. Bubser, P. J. Conn & C. K. Jones

  2. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

    E. J. Herman, M. Bubser, P. J. Conn & C. K. Jones

Authors
  1. E. J. Herman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Bubser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. J. Conn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. K. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. K. Jones .

Editor information

Editors and Affiliations

  1. Dept. Psychiatry, University of California San Diego, Gilman Drive 9500, La Jolla, 92093-0804, California, USA

    Mark A. Geyer

  2. Institut für Pharmakologie, Universität, Neuroscience Research, Abbott GmbH & Co. KG, Knollstraße, Ludwigshafen, 67061, Germany

    Gerhard Gross

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Herman, E.J., Bubser, M., Conn, P.J., Jones, C.K. (2012). Metabotropic Glutamate Receptors for New Treatments in Schizophrenia. In: Geyer, M., Gross, G. (eds) Novel Antischizophrenia Treatments. Handbook of Experimental Pharmacology, vol 213. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-25758-2_11

Download citation

Publish with us

Policies and ethics

Search

Navigation