The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles

Varty, Geoffrey B.; Grilli, Mariagrazia; Forlani, Angelo; Fredduzzi, Silva; Grzelak, Michael E.; Guthrie, Donald H.; Hodgson, Robert A.; Lu, Shao Chun; Nicolussi, Elisa; Pond, Annamarie J.; Parker, Eric M.; Hunter, John C.; Higgins, Guy A.; Reggiani, Angelo; Bertorelli, Rosalia

doi:10.1007/s00213-005-2143-4

Cited by 151 publications

(110 citation statements)

References 50 publications

(66 reference statements)

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“…On the other hand, it could be suspected that the decreased levels of social interaction might have been indirectly caused by anxiogenic effects of the compounds, as all of them decreased exploration of the central zone of the arena. It seems, however, to be unlikely, as NMDA receptor antagonists have been found to possess rather anxiolytic than anxiogenic properties (Xie and Commissaris, 1992), and MTEP has been shown to display anxiolytic-like activity in a number of animal models of anxiety (Busse et al, 2004;Varty et al, 2005). There is rather a direct consequence of concomitantly present stereotyped behaviors manifested in walking in the periphery of an open field arena.…”

Section: Discussionmentioning

confidence: 99%

The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats

Koroś

Rosenbrock

Birk

et al. 2006

Neuropsychopharmacol

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It has repeatedly been shown that uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can mimic certain aspects of positive and negative symptoms of schizophrenia in human volunteers and laboratory animals. The purpose of the present study was to expand these findings and to determine whether the selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine), could induce similar effects in Wistar rats. First, MTEP (1.0-10.0 mg/kg; intraperitoneally) after acute and subchronic (daily for 5 days) administration as well as the uncompetitive antagonists of the NMDA receptor of either high affinity, phencyclidine (0.5-4.0 mg/kg; subcutaneously (s.c.)) and ( + )-MK-801 (0.03-0.25 mg/kg; s.c.), or low-moderate affinity, ketamine (2.0-16.0 mg/kg; s.c.) and memantine (0.15-20.0 mg/kg; s.c.), following daily administration for 3 days were tested in the social interaction test to determine their ability to reproduce the negative and positive symptoms measured by social isolation and stereotyped behavior, respectively. Second, the compounds were tested in the motility test following acute administration to determine their ability to induce locomotor hyperactivity reflecting the positive symptoms. In line with previous findings, all examined NMDA receptor antagonists produced social interaction deficits, locomotor hyperactivity, and stereotypy except memantine. Notably, this study found that MTEP following both acute and subchronic administration dose-dependently induced social isolation, but did not cause either locomotor hyperactivity or stereotypy. These data demonstrate that social behavior deficits in rats can be caused by both the blockade of the NMDA receptor and the inhibition of mGluR5, whereas mGluR5 antagonists may not independently be able to mimic the positive symptoms.

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Section: Discussionmentioning

confidence: 99%

The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats

Koroś

Rosenbrock

Birk

et al. 2006

Neuropsychopharmacol

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“…Systemic administration of MPEP and MTEP reduced hyperalgesia induced by formalin and mechanical allodynia following SNL and showed anxiolytic effects (203).…”

Section: Nociceptionmentioning

confidence: 98%

“…Both MPEP and MTEP were also tested in the mouse formalin and rat spinal nerve ligation (SNL) pain models, as well as in anxiety models including the Vogel conflict and conditioned lick suppression (CLS) tests for anxiety (203). Systemic administration of MPEP and MTEP reduced hyperalgesia induced by formalin and mechanical allodynia following SNL and showed anxiolytic effects (203).…”

Section: Nociceptionmentioning

confidence: 99%

Metabotropic Glutamate Receptor Subtype 5 Antagonists MPEP and MTEP

2006

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Glutamate regulates the function of central nervous system (CNS), in part, through the cAMP and/or IP3/DAG second messenger-associated metabotropic glutamate receptors (mGluRs). The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) has been extensively used to elucidate potential physiological and pathophysiological functions of mGluR5. Unfortunately, recent evidence indicates significant non-specific actions of MPEP, including inhibition of NMDA receptors. In contrast, in vivo and in vitro characterization of the newer mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) indicates that it is more highly selective for mGluR5 over mGluR1, has no effect on other mGluR subtypes, and has fewer off-target effects than MPEP. This article reviews literature on both of these mGluR5 antagonists, which suggests their possible utility in neurodegeneration, addiction, anxiety and pain management.

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“…Various studies examining the behavioral effects of MPEP and MTEP in animal models of CNS disorders have demonstrated positive effects after acute systemic administration (c.f., Brodkin et al, 2002b;Chiamulera et al, 2001;Pietraszek et al, 2005;Spooren et al, 2000;Tatarczynska et al, 2001;Tessari et al, 2004;Varty et al, 2005). However, some investigators have reported that multiple dosing procedures with these compounds produces increases efficacy in the anxiolytic, antidepressant or anti-addictive effects as compared with acute administration (Backstrom et al, 2004;Cowen et al, 2005;Klodzinska et al, 2004;Li et al, 2006;Nordquist et al, 2007;Pilc et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP

Gass

2008

European Journal of Pharmacology

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The development of selective type 5 metabotropic glutamate receptor (mGlu5) antagonists, such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), has revealed an important role for these receptors in various disorders of the nervous system including depression, anxiety, epilepsy, Parkinson's disease, drug addiction, and alcoholism. In this study, we used microarray technology to examine changes in gene expression induced by repeated administration of the mGlu5 antagonists MPEP and MTEP. Male Wistar rats (n=5 per treatment group) were administered MPEP (10 mg/kg), MTEP (10 mg/kg) or vehicle intraperitoneally twice daily for 5 days. Approximately 30 min following the final drug administration, rats were sacrificed and frontal cortices were then dissected and examined for changes in gene expression by cDNA microarray analysis. Changes in gene expression with P-values less than 0.01 were considered to be statistically significant. The expression of 63 genes was changed by both MPEP and MTEP, with 58 genes down-regulated and 5 genes up-regulated. Quantitative PCR verified the magnitude and direction of change in expression of 9 of these genes (r 2 =0.556, p=0.017). Pathway analysis revealed that many of the biological processes altered by repeated MPEP and MTEP treatment were related to ATP synthesis, hydrolase activity, and signaling pathways associated with mitogen-activated protein kinase (MAPK). Our results demonstrate diverse effects of MPEP and MTEP gene expression in the frontal cortex, and these results may help elucidate the mechanisms by which these compounds produce beneficial effects in animal models of various disorders of the central nervous system.

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The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles

Cited by 151 publications

References 50 publications

The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats

The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats

Metabotropic Glutamate Receptor Subtype 5 Antagonists MPEP and MTEP

Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP

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