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

Salomons, Pinzon Nathaly, Boleij Hetty, Kirchhoff Susanne, Arndt, Nordquist, Lindemann Lothar, Jaeschke Georg, Spooren Will, Ohl, Ohl Frauke

Description

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.

Sujets

• Anxiety
• Behavior
• Benzodiazépine
• C-Fos

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 33
• Langue: English

Extrait

Salomonset al. Behavioral and Brain Functions2012,8:30 http://www.behavioralandbrainfunctions.com/content/8/1/30

R E S E A R C HOpen Access Differential effects of diazepam and MPEP on habituation and neurobehavioural processes in inbred mice 1,2* 11,2 1,21,2 Amber R Salomons, Nathaly Espitia Pinzon , Hetty Boleij, Susanne Kirchhoff, Saskia S Arndt, 2,3 44 41,2 Rebecca E Nordquist, Lothar Lindemann , Georg Jaeschke , Will Spoorenand Frauke Ohl

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

Background Adaptive anxiety in mice may be characterised by changes in behavioural responses over time, for example habituation to a novel environment. In contrast, non adaptive anxiety might be mirrored by a lack of such a habituation, a phenomenon which may severely interfere with the normal interaction of the animal with its phys ical and social environment [13].

* Correspondence: [e-mail] 1 Department 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 2 Rudolf Magnus Institute of Neuroscience, Universiteitsweg 100, Utrecht, CG 3584, The Netherlands Full list of author information is available at the end of the article

Recently, we found that 129P3/J mice are character ized by a profound lack of habituation to the modified hole board test as shown by highly increased avoidance behaviour over time while BALB/c mice, which have been reported to be highly anxious [4,5], show rapid ha bituation to the same test environment [2]. In addition, in 129P3/J mice cFos expression was found to be lower after the habituation procedure in distinct brain areas (e.g. prelimbic cortex and lateral septum) in comparison to BALB/c mice [2]. In a subsequent study we further demonstrated that exposure to chronic mild stress prior to repeated behavioural testing intensified the lack of ha bituation also in other behavioural parameters such as locomotion [6]. Other studies have found specific

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