Abstract
Highly selective positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have emerged as a potential approach to treat positive symptoms associated with schizophrenia. mGluR5 plays an important role in both long-term potentiation (LTP) and long-term depression (LTD), suggesting that mGluR5 PAMs may also have utility in improving impaired cognitive function. However, if mGluR5 PAMs shift the balance of LTP and LTD or induce a state in which afferent activity induces lasting changes in synaptic function that are not appropriate for a given pattern of activity, this could disrupt rather than enhance cognitive function. We determined the effect of selective mGluR5 PAMs on the induction of LTP and LTD at the Schaffer collateral-CA1 synapse in the hippocampus. mGluR5-selective PAMs significantly enhanced threshold θ-burst stimulation (TBS)-induced LTP. In addition, mGluR5 PAMs enhanced both DHPG-induced LTD and LTD induced by the delivery of paired-pulse low-frequency stimulation. Selective potentiation of mGluR5 had no effect on LTP induced by suprathreshold TBS or saturated LTP. The finding that potentiation of mGluR5-mediated responses to stimulation of glutamatergic afferents enhances both LTP and LTD and supports the hypothesis that the activation of mGluR5 by endogenous glutamate contributes to both forms of plasticity. Furthermore, two systemically active mGluR5 PAMs enhanced performance in the Morris water maze, a measure of hippocampus-dependent spatial learning. Discovery of small molecules that enhance both LTP and LTD in an activity-appropriate manner shows a unique action on synaptic plasticity that may provide a novel approach for the treatment of impaired cognitive function.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Andreasen NC (2000). Schizophrenia: the fundamental questions. Brain Res Brain Res Rev 31: 106–112.
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.
Balschun D, Zuschratter W, Wetzel W (2006). Allosteric enhancement of metabotropic glutamate receptor 5 function promotes spatial memory. Neuroscience 142: 691–702.
Banko JL, Hou L, Poulin F, Sonenberg N, Klann E (2006). Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor-dependent long-term depression. J Neurosci 26: 2167–2173.
Bear MF, Huber KM, Warren ST (2004). The mGluR theory of fragile X mental retardation. Trends Neurosci 27: 370–377.
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.
Berkeley JL, Levey AI (2003). Cell-specific extracellular signal-regulated kinase activation by multiple G protein-coupled receptor families in hippocampus. Mol Pharmacol 63: 128–135.
Berridge MJ, Downes CP, Hanley MR (1982). Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem J 206: 587–595.
Bikbaev A, Neyman S, Ngomba RT, Conn J, Nicoletti F, Manahan-Vaughan D (2008). MGluR5 mediates the interaction between late-LTP, network activity, and learning. PLoS ONE 3: e2155.
Bortolotto ZA, Fitzjohn SM, Collingridge GL (1999). Roles of metabotropic glutamate receptors in LTP and LTD in the hippocampus. Curr Opin Neurobiol 9: 299–304.
Brody SA, Conquet F, Geyer MA (2004a). Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice. Psychopharmacology (Berlin) 172: 187–195.
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.
Camodeca N, Breakwell NA, Rowan MJ, Anwyl R (1999). Induction of LTD by activation of group I mGluR in the dentate gyrus in vitro. Neuropharmacology 38: 1597–1606.
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 (Berlin) 175: 310–318.
Chan MH, Chiu PH, Sou JH, Chen HH (2008). Attenuation of ketamine-evoked behavioral responses by mGluR5 positive modulators in mice. Psychopharmacology (Berlin) 198: 141–148.
Chaouloff F, Hemar A, Manzoni O (2007). Acute stress facilitates hippocampal CA1 metabotropic glutamate receptor-dependent long-term depression. J Neurosci 27: 7130–7135.
Chaouloff F, Hemar A, Manzoni O (2008). Local facilitation of hippocampal metabotropic glutamate receptor-dependent long-term depression by corticosterone and dexamethasone. Psychoneuroendocrinology 33: 686–691.
Chen Y, Conn PJ (2008). mGluR5 positive allosteric modulators. Drugs of the Future 33: 355–360.
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-hy droxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors. Mol Pharmacol 73: 909–918.
Chen Y, Nong Y, Goudet C, Hemstapat K, de Paulis T, Pin JP et al (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.
Cohen AS, Raymond CR, Abraham WC (1998). Priming of long-term potentiation induced by activation of metabotropic glutamate receptors coupled to phospholipase C. Hippocampus 8: 160–170.
Collingridge GL, Bliss TV (1995). Memories of NMDA receptors and LTP. Trends Neurosci 18: 54–56.
Conn PJ, Christopoulos A, Lindsley CW (2009). Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov 8: 41–54.
Conn PJ, Lindsley CW, Jones CK (2009). Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol Sci 30 (1): 25–31.
Conn PJ, Pin JP (1997). Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37: 205–237.
Conn PJ, Sanders-Bush E (1986). Regulation of serotonin-stimulated phosphoinositide hydrolysis: relation to the serotonin 5-HT-2 binding site. J Neurosci 6: 3669–3675.
Darrah JM, Stefani MR, Moghaddam B (2008). Interaction of N-methyl-D-aspartate and group 5 metabotropic glutamate receptors on behavioral flexibility using a novel operant set-shift paradigm. Behav Pharmacol 19: 225–234.
de Paulis T, Hemstapat K, Chen Y, Zhang Y, Saleh S, Alagille D et al (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.
Doherty AJ, Palmer MJ, Bortolotto ZA, Hargreaves A, Kingston AE, Ornstein PL et al (2000). A novel, competitive mGlu(5) receptor antagonist (LY344545) blocks DHPG-induced potentiation of NMDA responses but not the induction of LTP in rat hippocampal slices. Br J Pharmacol 131: 239–244.
Doherty AJ, Palmer MJ, Henley JM, Collingridge GL, Jane DE (1997). (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) activates mGlu5, but no mGlu1, receptors expressed in CHO cells and potentiates NMDA responses in the hippocampus. Neuropharmacology 36: 265–267.
Faas GC, Adwanikar H, Gereau RWt, Saggau P (2002). Modulation of presynaptic calcium transients by metabotropic glutamate receptor activation: a differential role in acute depression of synaptic transmission and long-term depression. J Neurosci 22: 6885–6890.
Fitzjohn SM, Kingston AE, Lodge D, Collingridge GL (1999). DHPG-induced LTD in area CA1 of juvenile rat hippocampus; characterisation and sensitivity to novel mGlu receptor antagonists. Neuropharmacology 38: 1577–1583.
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.
Galici R, Jones CK, Hemstapat K, Nong Y, Echemendia NG, Williams LC et al (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.
Gallagher SM, Daly CA, Bear MF, Huber KM (2004). Extracellular signal-regulated protein kinase activation is required for metabotropic glutamate receptor-dependent long-term depression in hippocampal area CA1. J Neurosci 24: 4859–4864.
Gasparini F, Lingenhohl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I et al (1999). 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38: 1493–1503.
Gerber U, Gee CE, Benquet P (2007). Metabotropic glutamate receptors: intracellular signaling pathways. Curr Opin Pharmacol 7: 56–61.
Godfraind JM, Reyniers E, De Boulle K, D’Hooge R, De Deyn PP, Bakker CE et al (1996). Long-term potentiation in the hippocampus of fragile X knockout mice. Am J Med Genet 64: 246–251.
Hemstapat K, de Paulis T, Chen Y, Brady AE, Grover VK, Alagille D et al (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.
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.
Homayoun H, Stefani MR, Adams BW, Tamagan GD, Moghaddam B (2004). Functional interaction between NMDA and mGlu5 receptors: effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology 29: 1259–1269.
Hou L, Klann E (2004). Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci 24: 6352–6361.
Huang CC, Hsu KS (2006). Sustained activation of metabotropic glutamate receptor 5 and protein tyrosine phosphatases mediate the expression of (S)-3,5-dihydroxyphenylglycine-induced long-term depression in the hippocampal CA1 region. J Neurochem 96: 179–194.
Huang CC, You JL, Wu MY, Hsu KS (2004). Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. J Biol Chem 279: 12286–12292.
Huber KM, Gallagher SM, Warren ST, Bear MF (2002). Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci USA 99: 7746–7750.
Huber KM, Kayser MS, Bear MF (2000). Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288: 1254–1257.
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.
Jia Z, Lu Y, Henderson J, Taverna F, Romano C, Abramow-Newerly W et al (1998). Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5. Learn Mem 5: 331–343.
Johnson MP, Chamberlain M, Kelly GM (1999). Phosphoinositide hydrolysis in vivo with group I metabotropic glutamate receptor agonists. Brain Res 821: 539–545.
Kemp N, Bashir ZI (1997). NMDA receptor-dependent and -independent long-term depression in the CA1 region of the adult rat hippocampus in vitro. Neuropharmacology 36: 397–399.
Kemp N, Bashir ZI (1999). Induction of LTD in the adult hippocampus by the synaptic activation of AMPA/kainate and metabotropic glutamate receptors. Neuropharmacology 38: 495–504.
Kemp N, Bashir ZI (2001). Long-term depression: a cascade of induction and expression mechanisms. Prog Neurobiol 65: 339–365.
Kemp N, McQueen J, Faulkes S, Bashir ZI (2000). Different forms of LTD in the CA1 region of the hippocampus: role of age and stimulus protocol. Eur J Neurosci 12: 360–366.
Kingston AE, Griffey K, Johnson MP, Chamberlain MJ, Kelly G, Tomlinson R et al (2002). Inhibition of group I metabotropic glutamate receptor responses in vivo in rats by a new generation of carboxyphenylglycine-like amino acid antagonists. Neurosci Lett 330: 127–130.
Kinney GG, Burno M, Campbell UC, Hernandez LM, Rodriguez D, Bristow LJ et al (2003). Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. J Pharmacol Exp Ther 306: 116–123.
Kinney GG, O’Brien JA, Lemaire W, Burno M, Bickel DJ, Clements MK et al (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.
Kirschstein T, Bauer M, Muller L, Ruschenschmidt C, Reitze M, Becker AJ et al (2007). Loss of metabotropic glutamate receptor-dependent long-term depression via downregulation of mGluR5 after status epilepticus. J Neurosci 27: 7696–7704.
Kumar A, Foster TC (2007). Shift in induction mechanisms underlies an age-dependent increase in DHPG-induced synaptic depression at CA3 CA1 synapses. J Neurophysiol 98: 2729–2736.
Larson J, Lynch G (1989). Theta pattern stimulation and the induction of LTP: the sequence in which synapses are stimulated determines the degree to which they potentiate. Brain Res 489: 49–58.
Lauterborn JC, Rex CS, Kramar E, Chen LY, Pandyarajan V, Lynch G et al (2007). Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome. J Neurosci 27: 10685–10694.
Le Poul E, Bessis AS, Lutgens R, Bonnet B, Rocher JP, Epping-Jordan M et al (2005). In vitro pharmacological characterisation of selective MgluR5 positive allosteric modulators. 5th International Metabotropic Glutamate Receptors Meeting, Tormina, Italy.
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.
Li J, Pelletier MR, Perez Velazquez JL, Carlen PL (2002). Reduced cortical synaptic plasticity and GluR1 expression associated with fragile X mental retardation protein deficiency. Mol Cell Neurosci 19: 138–151.
Lindsley CW, Shipe WD, Wolkenberg SE, Theberge CR, Williams Jr DL, Sur C et al (2006). Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia. Curr Top Med Chem 6: 771–785.
Lindsley CW, Wisnoski DD, Leister WH, O’Brien JA, Lemaire W, Williams Jr DL et al (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.
Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G et al (2008). ADX47273: a novel metabotropic glutamate receptor 5 selective positive allosteric modulator with preclinical antipsychotic-like and pro-cognitive activities. J Pharmacol Exp Ther 327: 827–839.
Lu YM, Jia Z, Janus C, Henderson JT, Gerlai R, Wojtowicz JM et al (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.
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: 1703–1713.
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.
Marino MJ, Conn PJ (2002). Direct and indirect modulation of the N-methyl D-aspartate receptor. Curr Drug Targets CNS Neurol Disord 1: 1–16.
Merlin LR, Bergold PJ, Wong RK (1998). Requirement of protein synthesis for group I mGluR-mediated induction of epileptiform discharges. J Neurophysiol 80: 989–993.
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.
Mulkey RM, Malenka RC (1992). Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus. Neuron 9: 967–975.
Neyman S, Manahan-Vaughan D (2008). Metabotropic glutamate receptor 1 (mGluR1) and 5 (mGluR5) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro. Eur J Neurosci 27: 1345–1352.
Nosyreva ED, Huber KM (2005). Developmental switch in synaptic mechanisms of hippocampal metabotropic glutamate receptor-dependent long-term depression. J Neurosci 25: 2992–3001.
Nosyreva ED, Huber KM (2006). Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. J Neurophysiol 95: 3291–3295.
O’Brien JA, Lemaire W, Chen TB, Chang RS, Jacobson MA, Ha SN et al (2003). A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Mol Pharmacol 64: 731–740.
O’Brien JA, Lemaire W, Wittmann M, Jacobson MA, Ha SN, Wisnoski DD et al (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.
Palmer MJ, Irving AJ, Seabrook GR, Jane DE, Collingridge GL (1997). The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus. Neuropharmacology 36: 1517–1532.
Paradee W, Melikian HE, Rasmussen DL, Kenneson A, Conn PJ, Warren ST (1999). Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function. Neuroscience 94: 185–192.
Peavy RD, Chang MS, Sanders-Bush E, Conn PJ (2001). Metabotropic glutamate receptor 5-induced phosphorylation of extracellular signal-regulated kinase in astrocytes depends on transactivation of the epidermal growth factor receptor. J Neurosci 21: 9619–9628.
Peavy RD, Sorensen SD, Conn PJ (2002). Differential regulation of metabotropic glutamate receptor 5-mediated phosphoinositide hydrolysis and extracellular signal-regulated kinase responses by protein kinase C in cultured astrocytes. J Neurochem 83: 110–118.
Pisani A, Gubellini P, Bonsi P, Conquet F, Picconi B, Centonze D et al (2001). Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons. Neuroscience 106: 579–587.
Raymond CR, Thompson VL, Tate WP, Abraham WC (2000). Metabotropic glutamate receptors trigger homosynaptic protein synthesis to prolong long-term potentiation. J Neurosci 20: 969–976.
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.
Sacaan AI, Santori EM, Rao TS (1998). (S)-4-carboxy-3-hydroxyphenylglycine activates phosphatidyl inositol linked metabotropic glutamate receptors in different brain regions of the neonatal rat. Neurochem Int 32: 77–85.
Shalin SC, Hernandez CM, Dougherty MK, Morrison DK, Sweatt JD (2006). Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation. Neuron 50: 765–779.
Tan Y, Hori N, Carpenter DO (2003). The mechanism of presynaptic long-term depression mediated by group I metabotropic glutamate receptors. Cell Mol Neurobiol 23: 187–203.
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.
Wong RK, Bianchi R, Chuang SC, Merlin LR (2005). Group I mGluR-induced epileptogenesis: distinct and overlapping roles of mGluR1 and mGluR5 and implications for antiepileptic drug design. Epilepsy Curr 5: 63–68.
Wong RK, Bianchi R, Taylor GW, Merlin LR (1999). Role of metabotropic glutamate receptors in epilepsy. Adv Neurol 79: 685–698.
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.
Acknowledgements
MFO and NLW were supported by PHS grant DA024355.
Author information
Authors and Affiliations
Corresponding author
Additional information
Disclosure/Conflict of Interest
Dr Conn has received compensation over the past 2 years as a consultant from: Merck and Co., Johnson and Johnson, Hoffman La Roche, GlaxoSmithKline, Lundbeck Research USA, Epix Pharmaceuticals, Invitrogen Life Technologies, Evotec Inc., Addex Pharmaceuticals, Michael J Fox Foundation, Seaside Therapeutics, Cephalon Inc., AstraZeneca USA, NeurOp Inc., Forest Research Institute, LEK Consulting, The Frankel Group, Prestwick Chemical Co., Millipore Corp., Genentech, IMS Health, Primary Insight, and Otsuka. He has received honoraria as a speaker from: University of Toronto, American Society for Bone and Mineral Research, University of Alabama Birmingham, University of Michigan, Southern Research Inst., Harvard Medical School, and the University of North Carolina. He receives research support that includes salary support from NIH, Michael J Fox Foundation, Seaside Therapeutics, and Vanderbilt University. Dr Lindsley consults for Amgen and Eisai and receives research support that includes salary support from NIH, Michael J Fox, and Seaside Therapeutics. All other authors have nothing to disclose.
Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)
Supplementary information
Rights and permissions
About this article
Cite this article
Ayala, J., Chen, Y., Banko, J. et al. mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning. Neuropsychopharmacol 34, 2057–2071 (2009). https://doi.org/10.1038/npp.2009.30
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2009.30
Keywords
This article is cited by
-
Examining sex differences in responses to footshock stress and the role of the metabotropic glutamate receptor 5: an [18F]FPEB and positron emission tomography study in rats
Neuropsychopharmacology (2023)
-
Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia
CNS Drugs (2022)
-
Increased mGlu5 mRNA expression in BLA glutamate neurons facilitates resilience to the long-term effects of a single predator scent stress exposure
Brain Structure and Function (2021)
-
Metabotropic glutamate receptor 5 in bulimia nervosa
Scientific Reports (2020)
-
mGluR5 hypofunction is integral to glutamatergic dysregulation in schizophrenia
Molecular Psychiatry (2020)
