An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats

Yoshimizu, Takao; Shimazaki, Toshiharu; Ito, Akie; Chaki, Shigeyuki

doi:10.1007/s00213-006-0390-7

Cited by 128 publications

(84 citation statements)

References 43 publications

(38 reference statements)

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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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“…The use of pharmacological agents that do not discriminate between mGlu2 and mGlu3 receptors has raised the question of whether agonists or antagonists should be used in the treatment of depressive disorders. Thus, the mGlu2/3 receptor antagonist MGS0039 exerts a clear-cut antidepressant effect (43,44), whereas, conversely, the mGlu2/3 receptor agonist LY379268 reinforces the antidepressant activity of CLO or fluoxetine. The lack of subtype-selectivity of MGS0039 and LY379268 may confound the interpretation of these findings.…”

Section: Discussionmentioning

confidence: 98%

L -acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors

Nasca

Xenos

Barone

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

233

217

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Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a welltolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.BDNF | histone acetylation | MDD | glutamatergic neurotransmission | chromatin

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“…The threshold elevation following withdrawal from chronic treatment with drugs of abuse has been proposed to reflect anhedonia (loss of interest or pleasure), which is a core symptom of depression [78], and provides additional evidence that mGlu2/3 receptor antagonists may have antidepressant effects. Moreover, subchronic administration of MGS0039 reduced escape failures in a learned helplessness paradigm, indicating antidepressant activity [79].…”

Section: Mglu2/3 Receptor Antagonistsmentioning

confidence: 98%

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

Yasuhara¹

2010

TOMCJ

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Metabotropic glutamate receptors (mGlu receptors) have emerged as new therapeutic targets for psychiatric disorders, such as schizophrenia, depression and anxiety with their regulatory roles in glutamatergic transmissions. To date, several ligands selective for each mGlu receptor have been synthesized, and pharmacological significances of these ligands have been demonstrated in animal models. Among them, mGlu2/3 receptor agonists have been proven to be effective for treating schizophrenia and anxiety disorders in clinical studies, which may prove utilities of mGlu receptor ligands for the treatment of psychiatric disorders. This article reviews recent advances in development of each mGlu receptor ligands and their therapeutic potential.

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An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats

Abstract: These results suggest that the blockade of mGluR2/3 with MGS0039 may be effective in the treatment of depressive and anxiety disorders.

Cited by 128 publications

References 43 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

L -acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

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