Differential effects of diazepam and MPEP on habituation and neuro-behavioural processes in inbred mice

doi:10.1186/1744-9081-8-30

Behav Brain Funct. 2012; 8: 30.

Published online 2012 June 11. doi: 10.1186/1744-9081-8-30

PMCID: PMC3464737

Differential effects of diazepam and MPEP on habituation and neuro-behavioural processes in inbred mice

Amber R Salomons,^1,² Nathaly Espitia Pinzon,¹ Hetty Boleij,^1,² Susanne Kirchhoff,^1,² Saskia S Arndt,^1,² Rebecca E Nordquist,^2,³ Lothar Lindemann,⁴ Georg Jaeschke,⁴ Will Spooren,⁴ and Frauke Ohl^1,²

¹Department of Animals in Science and Society, Division of Animal Welfare and Laboratory Animal Science, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 2, 3584, Utrecht, CM, The Netherlands

²Rudolf Magnus Institute of Neuroscience, Universiteitsweg 100, Utrecht, CG, 3584, The Netherlands

³Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 7, Utrecht, CL, 3584, The Netherlands

⁴F. Hoffmann-La Roche Ltd. Pharmaceuticals Division, Discovery Neuroscience, Basel, Switzerland

Corresponding author.

Amber R Salomons: ambersalomons/at/gmail.com; Nathaly Espitia Pinzon: nathapinzon/at/gmail.com; Hetty Boleij: h.boleij/at/uu.nl; Susanne Kirchhoff: s.kirchhoff/at/uu.nl; Saskia S Arndt: s.s.arndt/at/uu.nl; Rebecca E Nordquist: R.E.Nordquist1/at/uu.nl; Lothar Lindemann: lothar.lindemann/at/roche.com; Georg Jaeschke: georg.jaeschke/at/roche.com; Will Spooren: will.spooren/at/roche.com; Frauke Ohl: f.ohl/at/uu.nl

Received November 7, 2011; Accepted June 11, 2012.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Previous studies have demonstrated a profound lack of habituation in 129P3 mice compared to the habituating, but initially more anxious, BALB/c mice. The present study investigated whether this non-adaptive phenotype of 129P3 mice is primarily based on anxiety-related characteristics.

Methods

To test this hypothesis and extend our knowledge on the behavioural profile of 129P3 mice, the effects of the anxiolyticdiazepam (1, 3 and 5

mg/kg) and the putative anxiolytic metabotropic glutamate receptor 5 (mGlu5R) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP, 3, 10 and 30

mg/kg) treatment on within-trial (intrasession) habituation, object recognition (diazepam: 1

mg/kg; MPEP 10

mg/kg) and on the central-nervous expression of the immediate early gene c-Fos (diazepam: 1

mg/kg; MPEP 10

mg/kg) were investigated.

Results

Behavioural findings validated the initially high, but habituating phenotype of BALB/c mice, while 129P3 mice were characterized by impaired intrasession habituation. Diazepam had an anxiolytic effect in BALB/c mice, while in higher doses caused behavioural inactivity in 129P3 mice. MPEP revealed almost no anxiolytic effects on behaviour in both strains, but reduced stress-induced corticosterone responses only in 129P3 mice. These results were complemented by reduced expression of c-Fos after MPEP treatment in brain areas related to emotional processes, and increased c-Fos expression in higher integrating brain areas such as the prelimbic cortex compared to vehicle-treated 129P3 mice.

Conclusions

These results suggest that the strain differences observed in (non)adaptive anxiety behaviour are at least in part mediated by differences in gamma-aminobutyric acid- A and mGluR5 mediated transmission.

Keywords: Anxiety, Behavior, Benzodiazepines, C-Fos, Cortisosterone, mGluR5 antagonist

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