Anxiolytic-like activity of MGS0039, a potent group II metabotropic glutamate receptor antagonist, in a marble-burying behavior test

Shimazaki, Toshiharu; Iijima, Michihiko; Chaki, Shigeyuki

doi:10.1016/j.ejphar.2004.08.016

Cited by 68 publications

(45 citation statements)

References 18 publications

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“…Therefore, the hypofuction of Y1 in comparison to Y2 (or maybe also other Y receptors) produces the anxiolysis. Anxiolytic effects of group II and III mGluR agonists were reported previously by some authors (Yoshimizu et al, 2006;Linden et al, 2005;Shimazaki et al, 2004;Tizzano et al, 2002) and by our group (Palucha et al, 2004;Tatarczynska et al, 2002). More detailed studies were performed with group III agonists, using Vogel drinking test for studying anxiolysis.…”

Section: Anxiolytic Effect Of Intrahippocampal Mglur Ligands and Npy supporting

confidence: 75%

The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y

Śmiałowska

Wierońska

Domin

et al. 2006

Neuropsychopharmacol

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Earlier studies conducted by our group and by other authors indicated that metabotropic glutamatergic receptor (mGluR) ligands might have anxiolytic activity and that amygdalar neuropeptide Y (NPY) neurons were engaged in that effect. Apart from the amygdala, the hippocampus, another limbic structure, also seems to be engaged in regulation of anxiety. It is rich in mGluRs and contains numerous NPY interneurons. In the present study, we investigated the anxiolytic activity of group II and III mGluR agonists after injection into the hippocampus, and attempted to establish whether hippocampal NPY neurons and receptors were engaged in the observed effects. Male Wistar rats were bilaterally microinjected with the group II mGluR agonist (2S,, NPY, the Y1 receptor antagonist BIBO 3304, and the Y2 receptor antagonist BIIE 0246 into the CA1 or dentate area (DG). The effect of those compounds on anxiety was tested in the elevated plus-maze. Moreover, the effects of L-CCG-I and L-SOP on the expression of NPYmRNA in the hippocampus were studied using in situ hybridization method. It was found that a significant anxiolytic effect was induced by L-SOP injection into the CA1 region or by L-CCG-I injection into the DG. The former effect was inhibited by BIBO 3304, the latter by BIIE 0246. NPY itself showed antianxiety action after injection into both structures. In the CA1 area, the effect of NPY was prevented by BIBO 3304, whereas in the DG by BIIE 0246. Both the mGluR agonists L-CCG-I and L-SOP induced a potent increase in NPYmRNA expression in the DG region of the hippocampal formation. The obtained results indicate that group II and III mGluR agonists, L-CCG-I and L-SOP, as well as NPY display anxiolytic activity in the hippocampus, but act differently in the CA1 and DG. It was observed that group III mGluRs and Y1 receptors were engaged in the response in the CA1 area, whereas group II mGluRs and Y2 receptors played a pivotal role in the DG region.

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Section: Anxiolytic Effect Of Intrahippocampal Mglur Ligands and Npy supporting

confidence: 75%

The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y

Śmiałowska

Wierońska

Domin

et al. 2006

Neuropsychopharmacol

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“…Although few reports have described the therapeutic significance of group II mGluR antagonists, recent studies have demonstrated that they may exhibit antidepressant-like activity and antiobsessive-compulsive disorder-like effects Shimazaki et al, 2004). Our current finding of negative allosteric modulators of group II mGluRs suggests that targeting of allosteric sites provides a viable approach for developing highly selective antagonists of these receptors.…”

Section: Discussionmentioning

confidence: 80%

“…Activation of group II mGluRs by group-selective agonists, including (Ϫ)-2-oxa-4-aminobicyclo [3.1.0]hexane-4,6-dicarboxylate (LY379268) and methyl substitution of 2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylate (LY354740), leads to robust anxiolytic-like effects and antipsychotic-like activity in rodents (Carter et al, 2004;Linden et al, 2005) and has also shown anxiolytic activity in humans (Grillon et al, 2003). Whereas the therapeutic significance of group II mGluR antagonists has not been widely investigated, recent studies of selective competitive group II mGluR antagonists, including 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propionic acid (LY341495) and (1R,2R,3R,5R,6R)-2-amino-3-(3, 4-dichlorobenzyloxy)-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (MGS0039), have suggested that these compounds exhibit antidepressant-like activity and antiobsessive-compulsive disorder-like effects in animal models Shimazaki et al, 2004;Palucha and Pilc, 2005). …”

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confidence: 99%

A Novel Family of Potent Negative Allosteric Modulators of Group II Metabotropic Glutamate Receptors

Hemstapat¹,

Costa²,

Nong³

et al. 2007

J Pharmacol Exp Ther

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Group II metabotropic glutamate receptors (mGluRs), mGluR2 and mGluR3, play a number of important roles in mammalian brain and represent exciting new targets for certain central nervous system disorders. We now report synthesis and characterization of a novel family of derivatives of dihydrobenzo[1,4]diazepin-2-one that are selective negative allosteric modulators for group II mGluRs. These compounds inhibit both mGluR2 and mGluR3 but have no activity at group I and III mGluRs. The novel mGluR2/3 antagonists also potently block mGluR2/3-mediated inhibition of the field excitatory postsynaptic potentials at the perforant path synapse in hippocampal slices. These compounds induce a rightward shift and decrease the maximal response in the glutamate concentrationresponse relationship, consistent with a noncompetitive antagonist mechanism of action. Furthermore, radioligand binding studies revealed no effect on binding of the orthosteric antag-Site-directed mutagenesis revealed that a single point mutation in transmembrane V (N735D), previously shown to be an important residue for potentiation activity of the mGluR2 allosteric potentiator LY487379 [N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine], is not critical for the inhibitory activity of negative allosteric modulators of group II mGluRs. However, this single mutation in human GluR2 almost completely blocked the enhancing activity of biphenyl-indanone A, a novel allosteric potentiator of mGluR2. Our data suggest that these two positive allosteric modulators of mGluR2 may share a common binding site and that this site may be distinct from the binding site for the new negative allosteric modulators of group II mGluRs.The eight known subtypes of metabotropic glutamate receptors (mGluRs) have been classified based on sequence homology, pharmacology, and signal transduction. These include group I (mGluR1 and 5), group II (mGluR2 and 3), and group III receptors (mGluR4, 6, 7, and 8). The group I receptors couple to G ␣q and phospholipase C, whereas group II and group III mGluRs couple to G ␣i (Conn and Pin, 1997;Schoepp et al., 1999). A large body of in vitro and in vivo preclinical studies suggest that specific mGluR subtypes play a broad range of neuromodulatory roles in different central nervous system circuits and that specific subtypes may provide viable targets for novel treatment strategies for a range of neurological and psychiatric disorders, including anxiety (Linden

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“…Kolb and Whishaw (1981) have shown that neonatal lesions that destroy frontal corticothalamic pathways abolish defensive burying in rats. Interestingly, marble burying has also been suggested as a murine model for obsessive-compulsive disorder (OCD) (Njung'e and Handley, 1991;Ichimaru et al, 1995), and a group II metabotropic glutamate receptor antagonist that reduced marble-burying in mice was suggested for clinical use in OCD (Shimazaki et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Vesicular Glutamate Transporter VGLUT2 Expression Levels Control Quantal Size and Neuropathic Pain

Moechars¹,

Weston²,

Leo³

et al. 2006

J. Neurosci.

183

178

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Uptake of L-glutamate into synaptic vesicles is mediated by vesicular glutamate transporters (VGLUTs). Three transporters (VGLUT1-VGLUT3) are expressed in the mammalian CNS, with partial overlapping expression patterns, and VGLUT2 is the most abundantly expressed paralog in the thalamus, midbrain, and brainstem. Previous studies have shown that VGLUT1 is necessary for glutamatergic transmission in the hippocampus, but the role of VGLUT2 in excitatory transmission is unexplored in glutamatergic neurons and in vivo. We examined the electrophysiological and behavioral consequences of loss of either one or both alleles of VGLUT2. We show that targeted deletion of VGLUT2 in mice causes perinatal lethality and a 95% reduction in evoked glutamatergic responses in thalamic neurons, although hippocampal synapses function normally. Behavioral analysis of heterozygous VGLUT2 mice showed unchanged motor function, learning and memory, acute nociception, and inflammatory pain, but acquisition of neuropathic pain, maintenance of conditioned taste aversion, and defensive marble burying were all impaired. Reduction or loss of VGLUT2 in heterozygous and homozygous VGLUT2 knock-outs led to a graded reduction in the amplitude of the postsynaptic response to single-vesicle fusion in thalamic neurons, indicating that the vesicular VGLUT content is critically important for quantal size and demonstrating that VGLUT2-mediated reduction of excitatory drive affects specific forms of sensory processing.

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Anxiolytic-like activity of MGS0039, a potent group II metabotropic glutamate receptor antagonist, in a marble-burying behavior test

Cited by 68 publications

References 18 publications

The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y

The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y

A Novel Family of Potent Negative Allosteric Modulators of Group II Metabotropic Glutamate Receptors

Vesicular Glutamate Transporter VGLUT2 Expression Levels Control Quantal Size and Neuropathic Pain

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