The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats

Campbell, Una C.; Lalwani, Kush; Hernández, Lisa M.; Kinney, Gene G.; Conn, P. Jeffrey; Bristow, Linda J.

doi:10.1007/s00213-004-1827-5

Cited by 108 publications

(90 citation statements)

References 56 publications

(54 reference statements)

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“…Similar to the effects of NMDA receptor antagonists, blockade of mGluR5 with MPEP-induced impairments in spatial working memory and instrumental learning (e.g., Homayoun et al, 2004), and potentiated behavioral effects of different NMDA receptors antagonists (Campbell et al, 2004;Homayoun et al, 2004;Henry et al, 2002). The mGluR2/3 are localized predominantly presynaptically and serve as auto-receptors that regulate transmitter release (Shigemoto et al, 1997;Cartmell & Schoepp, 2000;Kew & Kemp, 2005).…”

Section: Effects Of Mpep and Ly341495 On 5csrtt Performancementioning

confidence: 93%

“…Glutamate mediates its actions via activation of both ionotropic and metabotropic (mGluR) receptors (Conn & Pin, 1997;Schoepp, 2001). There are synergistic interactions between postsynaptic NMDA receptors and mGluR5 indicated by electrophysiological and behavioral findings (Martin et al, 1997;Homayoun et al, 2004;Henry et al, 2002;Kinney et al, 2003;Campbell et al, 2004). Thus, it is predicted that mGluR5 antagonism would induce similar cognitive deficits to those induced by NMDA receptor blockade.…”

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The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats' performance in the 5-choice serial reaction time task

Semenova¹,

Markou²

2007

Neuropharmacology

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Schizophrenia is characterized by attentional deficits possibly associated with glutamate dysfunction. The role of postsynaptic metabotropic glutamate 5 (mGluR5) or presynaptic inhibitory mGluR2/3 on attention is currently unknown. We investigated the effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on attention in the 5-choice serial reaction time task (5CSRTT), as well as on food intake to evaluate their effects on food motivation. The effects of pre-feeding and the muscle relaxant curare were examined to characterize the effects of alterations in motivation or the ability to perform the task, respectively. MPEP had no effect on accuracy but overall decreased performance in the 5CSRTT, including decreased speed of responding and decreased premature responses. LY341495 had no significant effect on rats' performance in the 5CSRTT. LY341495 decreased food intake in the home cage to a greater extent than MPEP. Curare decreased the speed of correct responding, reflecting motor impairment. Free feeding decreased overall performance, number of trials completed and number of head entries into the feeder, reflecting decreased motivation to perform the task. Thus, blockade of mGluR5, but not mGluR2/3, decreased overall responding without affecting accuracy in the 5CSRTT. Keywordsattention; metabotropic glutamate receptors; MPEP; LY341495; schizophrenia; rat Cognitive deficits are now regarded as a core feature of schizophrenia (Elvevag & Goldberg, 2000;Lewis et al., 2004), and include disturbances in selective attention (Mirsky, 1969;Carter et al., 1992;Hagan & Jones, 2005;an der Heiden & Hafner, 2000;Hughes et al., 2003) and working memory (Carter et al., 1996;Gold et al., 1997). Presently available pharmacological treatments produce little improvement in the cognitive and attentional deficits in schizophrenia patients.Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors induced schizophrenia-like cognitive deficits in healthy subjects, and exacerbated positive and negative symptoms in schizophrenia patients (Krystal et al., 1994;Adler et al., 1999;Lahti et al., Correspondence to: Athina Markou.Athina Markou, Ph.D., Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive, M/C 0603, La Jolla, California 92093-0603, USA; tel: (858) 534-1572, fax: (858) 858-534-7653, e-mail: amarkou@ucsd.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Krystal et al., 2003;Moghaddam, 2003Moghaddam, , 2004Tamminga, 1998). Glutamate mediates its actions via activation of both ionotropic and metabotropic (...

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Section: Effects Of Mpep and Ly341495 On 5csrtt Performancementioning

confidence: 93%

mentioning

confidence: 99%

The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats' performance in the 5-choice serial reaction time task

Semenova¹,

Markou²

2007

Neuropharmacology

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“…For example, treatment with the mGlu5 antagonists, MPEP and MTEP, augments the hyperlocomotive effects of PCP and MK-801 (Henry et al, 2002;Campbell et al, 2004;Pietraszek et al, 2005) while mGlu5 knockout (KO) mice show baseline hyperactivity and a hypersensitivity to MK-801-induced hyperlocomotion (Lipina et al, 2007;Gray et al, 2009). mGlu5 KO mice also demonstrate impaired PPI (Kinney et al, 2003; and the amelioration of this deficit by chronic administration of clozapine is accompanied by an increase in NMDAR binding (Gray et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5

Burrows

McOmish

Buret

et al. 2015

Neuropsychopharmacol

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Schizophrenia arises from a complex interplay between genetic and environmental factors. Abnormalities in glutamatergic signaling have been proposed to underlie the emergence of symptoms, in light of various lines of evidence, including the psychotomimetic effects of NMDA receptor antagonists. Metabotropic glutamate receptor 5 (mGlu5) has also been implicated in the disorder, and has been shown to physically interact with NMDA receptors. To clarify the role of mGlu5-dependent behavioral expression by environmental factors, we assessed mGlu5 knockout (KO) mice after exposure to environmental enrichment (EE) or reared under standard conditions. The mGlu5 KO mice showed reduced prepulse inhibition (PPI), long-term memory deficits, and spontaneous locomotor hyperactivity, which were all attenuated by EE. Examining the cellular impact of genetic and environmental manipulation, we show that EE significantly increased pyramidal cell dendritic branching and BDNF protein levels in the hippocampus of wild-type mice; however, mGlu5 KO mice were resistant to these alterations, suggesting that mGlu5 is critical to these responses. A selective effect of EE on the behavioral response to the NMDA receptor antagonist MK-801 in mGlu5 KO mice was seen. MK-801-induced hyperlocomotion was further potentiated in enriched mGlu5 KO mice and treatment with MK-801 reinstated PPI disruption in EE mGlu5 KO mice only, a response that is absent under standard housing conditions. Together, these results demonstrate an important role for mGlu5 in environmental modulation of schizophreniarelated behavioral impairments. Furthermore, this role of the mGlu5 receptor is mediated by interaction with NMDA receptor function, which may inform development of novel therapeutics.

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“…Group I mGluRs are distributed widely in multiple brain regions. Positive allosteric modulators (PAMs) of group I mGluRs have emerged recently as useful tools to study their physiological roles and provide a promising approach for developing novel therapeutic agents for the treatment of psychiatric and cognitive disorders (Anwyl, 1999;Marino et al, 2001;Marino and Conn, 2002;O'Brien et al, 2003O'Brien et al, , 2004Campbell et al, 2004;Moghaddam, 2004;Kinney et al, 2005).…”

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confidence: 99%

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

Chen¹,

Goudet²,

Pin³

et al. 2007

Mol Pharmacol

Self Cite

108

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Recent studies suggest that a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor (mGluRs), mGluR5, termed 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), potentiates mGluR5 responses by actions at a site that is overlapping with the binding site of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a previously identified negative allosteric modulator of this receptor. It is interesting that a structurally distinct PAM, N-{4-Chloro-2- [(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), does not to bind to the MPEP site. We now report that CPPHA potentiates mGluR5 responses by a mechanism that is distinct from that of VU-29. VU-29-and CPPHA-induced potentiation of mGluR5 responses are blocked by a neutral ligand at the MPEP allosteric site termed 5-methyl-2-(phenylethynyl)pyridine (5MPEP). However, increasing concentrations of 5MPEP induce parallel rightward shifts in the VU-29 concentration-response curve, whereas 5MPEP inhibits CPPHA potentiation in a noncompetitive manner. Consistent with this, a mutation (A809V/mGluR5) that reduces binding of ligands to the MPEP site eliminates the effect of VU-29 but has no effect on the response to CPPHA. On the other hand, a mutation (F585I/mGluRs) that eliminates the effect of CPPHA does not alter the response to VU-29. CPPHA is also a PAM at mGluR1. It is interesting that the corresponding mutation of F585I/mGluR5 in mGluR1 (F599I/ mGluR1) eliminates CPPHA's effect without altering the potentiation of a known PAM of mGluR1, (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476). Likewise, another mutation (V757L/mGluR1) that abolishes potentiation of Ro 67-7476 has no effect on CPPHA. Finally, CPPHA does not displace binding of a radioligand for the mGluR1 allosteric antagonist characterized previously. Together, these data suggest that CPPHA acts at a novel allosteric site on both mGluR1 and -5 to potentiate responses to activation of these receptors.Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. In addition to eliciting fast excitatory synaptic responses, glutamate has neuromodulatory effects by activation of G protein-coupled receptors (GPCRs) termed metabotropic glutamate receptors (mGluRs). There are eight subtypes of mGluRs divided into three groups. Group I mGluRs (mGluR1 and mGluR5) couple to G␣ q/11 and activate phospholipase C. Group II (mGluR2 and mGluR3) and group III (mGluR4, mGluR6, mGluR7, and mGluR8) mGluRs couple to the inhibition of adenylyl cyclase and other effectors through G␣ i/o (Conn and Pin,

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The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats

Abstract: The mGluR5 antagonist, MPEP, potentiated the disruptions in learning and memory induced by PCP. These behavioral data extend previous behavioral findings and further suggest that mGluR5 can modulate NMDA receptor function in vivo.

Cited by 108 publications

References 56 publications

The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats' performance in the 5-choice serial reaction time task

The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats' performance in the 5-choice serial reaction time task

Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5

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

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