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The effect of the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison

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Abstract

Rationale

Antagonists at the metabotropic glutamate 5 (mGlu5) receptor produce robust anxiolytic effects in a number of rat tests. However, there is evidence that mGlu5 receptor antagonists may also impair working memory and spatial learning following intracerebroventricular administration.

Objectives

The aim of this study is to compare the effect of the potent and selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-piperidine (MPEP), administered systemically on rodent tests of cognition and anxiety.

Methods

MPEP was assessed in the following rodent tests, 60 min following oral administration: Geller–Seifter conflict, conditioned emotional response (CER), Vogel conflict, delayed match to position (DMTP) and Morris water maze. Diazepam was also tested as a comparator.

Results

MPEP had a significant anxiolytic effect, comparable in magnitude to diazepam, at 10–30 mg/kg in the two conflict and CER tasks. There was no effect of MPEP up to 30 mg/kg on working memory in the DMTP task, but at 100 mg/kg, there was a significant reduction in choice accuracy at the longest delay interval (24 s). MPEP (3–30 mg/kg) did not significantly impair spatial learning in the Morris water maze, although during the last probe trial, 30-mg/kg-treated rats were significantly less accurate than controls. In contrast, diazepam significantly impaired performance in both the DMTP and Morris water maze tests. Assessment of plasma and brain concentration of MPEP ∼75 min following oral administration showed a dose linearity from 3 to 30 mg/kg and good brain penetration, i.e. a brain/plasma ratio of 3.1.

Conclusions

Oral administration of the selective mGlu5 receptor antagonist MPEP induces a robust anxiolytic-like effect in rat conflict tests comparable to that seen with diazepam, but in contrast to diazepam, MPEP does not impair working memory or spatial learning at anxiolytic doses.

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Acknowledgements

We would like to acknowledge the expert technical assistance of Severine Bandinelli, Michel Enderlin, Yeter Kolb, Stefanie Sänger and Roger Wyler. We would like to thank Christophe Flament for analytical support.

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Author notes

  1. Marie L. Woolley

    Present address: Psychiatry CEDD, GlaxoSmithKline plc, Harlow, Essex, UK

Authors and Affiliations

  1. PRBD-N, Neuroscience Research, F. Hoffmann-La Roche Ltd., 4070, Basel, Switzerland

    Theresa M. Ballard, Marie L. Woolley, Eric Prinssen, Jörg Huwyler, Richard Porter & Will Spooren

  2. F. Hoffmann-La Roche, Psychiatry Disease Area, Building 72-148, 4070, Basel, Switzerland

    Will Spooren

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  1. Theresa M. Ballard
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Correspondence to Will Spooren.

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Ballard, T.M., Woolley, M.L., Prinssen, E. et al. The effect of the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison. Psychopharmacology 179, 218–229 (2005). https://doi.org/10.1007/s00213-005-2211-9

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  • DOI: https://doi.org/10.1007/s00213-005-2211-9

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