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mGlu5 Receptors (mglu5 + receptor)

Distribution by Scientific Domains

Life Sciences	85%

Selected Abstracts

Metabotropic glutamate receptor 5 localized in the limbic forebrain is critical for the development of morphine-induced rewarding effect in mice

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2004
Takeshi Aoki
Abstract The aim of the present study was to clarify the role of the metabotropic glutamate 5 (mGlu5) receptor subtype in the development of rewarding effect induced by a prototypical µ-opioid receptor agonist morphine in the mouse. In the conditioned place preference paradigm, intracerebroventricular (i.c.v.) administration of a selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), attenuated the morphine-induced rewarding effects. Using immunoblot analysis, we confirmed that the increased level of protein kinase C, (PKC,) isoform was observed in the limbic forebrain of ICR mice conditioned with morphine. Here we found for the first time that the treatment with MPEP significantly inhibited the up-regulation of PKC, isoform in the limbic forebrain of mice showing the significant place preference. Furthermore, it should be mentioned that the protein level of mGlu5 was significantly increased in membrane preparations of the limbic forebrain obtained from morphine-conditioned mice compared to those from saline-conditioned mice. As well as the result from the immunoblot analysis, we demonstrated using the receptor binding assay that the number of mGlu5 receptors in the mouse limbic forebrain was significantly increased by morphine conditioning. The present data provide direct evidence that the activation of mGlu5 receptor linked to the increased PKC, isoform in the mouse limbic forebrain is implicated in the development of rewarding effect of morphine. [source]

Comparison of the binding pockets of two chemically unrelated allosteric antagonists of the mGlu5 receptor and identification of crucial residues involved in the inverse agonism of MPEP

JOURNAL OF NEUROCHEMISTRY, Issue 2 2006
Pari Malherbe
Abstract Fenobam [N- (3-chlorophenyl)- N, -(4,5-dihydro-1-methyl-4-oxo-1H -imidazole-2-yl)urea], a clinically validated non-benzodiazepine anxiolytic, has been shown to be a potent and non-competitive metabotropic glutamate (mGlu)-5 receptor antagonist. In the present study, we have used the site-directed mutagenesis coupled with three-dimensional receptor-based pharmacophore modelling to elucidate the interacting mode of fenobam within the seven-transmembrane domain (7TMD) of mGlu5 receptor and its comparison with that of 2-methyl-6-(phenylethynyl)pyridine (MPEP), the prototype antagonist. The common residues involved in the recognition of MPEP and fenobam include Pro6543.36, Tyr6583.40, Thr7806.44, Trp7846.48, Phe7876.51, Tyr7916.55 and Ala8097.47. The differentiating residues between both modulators' interacting modes are Arg6473.29, Ser6573.39 and Leu7435.47. Our data suggest that these chemically unrelated mGlu5 antagonists act similarly, probing a functionally unique region of the 7TMD. Using [3H]inositol phosphates accumulation assay, we have also identified the critical residues involved in the inverse agonist effect of MPEP. The mutation W7846.48A completely blocked the inverse agonist activity of MPEP; two mutations F7876.51A and Y7916.55A, caused a drastic decrease in the MPEP inverse agonism. Furthermore, these three mutations led to an increased efficacy of quisqualate without having any effect on its potency. The fact that the residues Trp7846.48 and Phe7876.51 are essential equally in antagonism and inverse agonism effects emphasizes again the key role of these residues and the involvement of a common transmembrane network in receptor inactivation by MPEP. [source]

Metabotropic glutamate receptor 5 localized in the limbic forebrain is critical for the development of morphine-induced rewarding effect in mice

Metabotropic glutamate type 5, dopamine D2 and adenosine A2a receptors form higher-order oligomers in living cells

JOURNAL OF NEUROCHEMISTRY, Issue 5 2009
Nuria Cabello
Abstract G protein-coupled receptors are known to form homo- and heteromers at the plasma membrane, but the stoichiometry of these receptor oligomers are relatively unknown. Here, by using bimolecular fluorescence complementation, we visualized for the first time the occurrence of heterodimers of metabotropic glutamate mGlu5 receptors (mGlu5R) and dopamine D2 receptors (D2R) in living cells. Furthermore, the combination of bimolecular fluorescence complementation and bioluminescence resonance energy transfer techniques, as well as the sequential resonance energy transfer technique, allowed us to detect the occurrence receptor oligomers containing more than two protomers, mGlu5R, D2R and adenosine A2A receptor (A2AR). Interestingly, by using high-resolution immunoelectron microscopy we could confirm that the three receptors co-distribute within the extrasynaptic plasma membrane of the same dendritic spines of asymmetrical, putative glutamatergic, striatal synapses. Also, co-immunoprecipitation experiments in native tissue demonstrated the existence of an association of mGlu5R, D2R and A2AR in rat striatum homogenates. Overall, these results provide new insights into the molecular composition of G protein-coupled receptor oligomers in general and the mGlu5R/D2R/A2AR oligomer in particular, a receptor oligomer that might constitute an important target for the treatment of some neuropsychiatric disorders. [source]

Ethanol Attenuates Spatial Memory Deficits and Increases mGlu1a Receptor Expression in the Hippocampus of Rats Exposed to Prenatal Stress

ALCOHOLISM, Issue 8 2009
Vincent Van Waes
Background:, Although it is generally believed that chronic ethanol consumption impairs learning and memory, results obtained in experimental animals are not univocal, and there are conditions in which ethanol paradoxically improves cognitive functions. In the present work, we investigated the effects of prenatal stress and of chronic ethanol exposure during adulthood on spatial memory in rats. Methods:, Rats were subjected to a prenatal stress delivered as 3 daily 45-minute sections of restraint stress to the mothers during the last 10 days of pregnancy (PRS rats). After 7 months of ethanol exposure (ethanol 10%, oral intake), memory performances were evaluated in a spatial discrimination test in control and PRS male rats. Then, the oxidative damages and the expression of metabotropic glutamate (mGlu) receptors were assessed in their hippocampus. Results:, Chronic ethanol exposure resulted in a reduced performance in a spatial recognition task in control animals. Unexpectedly, however, the same treatment attenuated spatial memory deficits in rats that had been subjected to prenatal stress. This paradigm of ethanol administration did not produce detectable signs of oxidative damage in the hippocampus in either unstressed or PRS rats. Interestingly, ethanol intake resulted in differential effects in the expression of mGlu receptor subtypes implicated in mechanisms of learning and memory. In control rats, ethanol intake reduced mGlu2/3 and mGlu5 receptor levels in the hippocampus; in PRS rats, which exhibited a constitutive reduction in the levels of these mGlu receptor subtypes, ethanol increased the expression of mGlu1a receptors but did not change the expression of mGlu2/3 or mGlu5 receptors. Conclusion:, Our findings support the idea that stress-related events occurring before birth have long-lasting effects on brain function and behavior, and suggest that the impact of ethanol on cognition is not only dose- and duration-dependent, but also critically influenced by early life experiences. [source]

Potentiation of mouse vagal afferent mechanosensitivity by ionotropic and metabotropic glutamate receptors

THE JOURNAL OF PHYSIOLOGY, Issue 1 2006
James A. Slattery
Glutamate acts at central synapses via ionotropic (iGluR , NMDA, AMPA and kainate) and metabotropic glutamate receptors (mGluRs). Group I mGluRs are excitatory whilst group II and III are inhibitory. Inhibitory mGluRs also modulate peripherally the mechanosensitivity of gastro-oesophageal vagal afferents. Here we determined the potential of excitatory GluRs to play an opposing role in modulating vagal afferent mechanosensitivity, and investigated expression of receptor subunit mRNA within the nodose ganglion. The responses of mouse gastro-oesophageal vagal afferents to graded mechanical stimuli were investigated before and during application of selective GluR ligands to their peripheral endings. Two types of vagal afferents were tested: tension receptors, which respond to circumferential tension, and mucosal receptors, which respond only to mucosal stroking. The selective iGluR agonists NMDA and AMPA concentration-dependently potentiated afferent responses. Their corresponding antagonists AP-5 and NBQX alone attenuated mechanosensory responses as did the non-selective antagonist kynurenate. The kainate selective agonist SYM-2081 had minor effects on mechanosensitivity, and the antagonist UBP 302 was ineffective. The mGluR5 antagonist MTEP concentration-dependently inhibited mechanosensitivity. Efficacy of agonists and antagonists differed on mucosal and tension receptors. We conclude that excitatory modulation of afferent mechanosensitivity occurs mainly via NMDA, AMPA and mGlu5 receptors, and the role of each differs according to afferent subtypes. PCR data indicated that all NMDA, kainate and AMPA receptor subunits plus mGluR5 are expressed, and are therefore candidates for the neuromodulation we observed. [source]