Effect of H4R antagonism on motor and anxiety behaviours in a novel elevated platform open space test

Paul L Chazot1, Rushdie Abuhamdah1, Mwape Katebe1, Abdel Ennaceur2. 1University of Durham, Durham, UK, 2University of Sunderland, Sunderland, UK

The role of the histamine H4 receptor (H4R) in the brain is poorly understood, despite its known distribution in critical areas of the murine and human brain (1). Therefore, it is important to examine its potential role in motor activity, anxiety and memory. This report describes the behaviour of mice in a new anxiety test based upon exposure to an elevated platform with steep panels attached on two opposite sides (1). The elevated platform is divided into the central area covered with a thin white tile, an inner area surrounding the central area and an outer area. The outer area is further divided into areas that are adjacent to the downward slopes and areas adjacent to the void space. The surface of the inner area is equal in size to that of the outer area, validating the comparisons between these two areas. During the test, anxious animals were expected to make no entries onto the downward slopes, and to spend most of their time in the areas adjacent to the slopes. All data are expressed as mean ± s.e.m. Differences among group means values for each measurement were tested for significance with one-way ANOVA followed up with Newman–Keuls post-hoc comparisons. Results were considered significant with p≤0.05.

Balb/c mice (8 mice per group; three group design) treated with JNJ7777120 (JNJ) at 10 mg/kg and 20 mg/kg (i.p.) (30 min prior to test) made fewer crossings onto the inner and central areas, and spent less time in the innerand central areas compared to the saline counterparts (p< 0.05). In the elevated platform, JNJ at 10 and 20 mg/kg appears to affect motor exploration in Balb/c mice but there is no indication of reducing anxiety. These results show that JNJ administration did not facilitate crossing onto the slopes in Balb/c mice (high anxiety strain). Similarly, it did not affect the crossings of CD-1 mice (low anxiety strain), ie. not anxiogenic. Our results show that the JNJ-treated animals made fewer entries and spent less time in the inner and central areas of the platform.The present lack of effect of JNJ on anxiety cannot be attributed to the lack of sensitivity of the elevated platform with slopes. In our previous published studies (2,3), we demonstrated a dose-dependent increase in motor activity with both diazepam and amphetamine, though more than two-fold higher with the latter. All diazepam treated Balb/c mice crossed onto the slopes while none of the amphetamine treated mice crossed.Overall, JNJ 7777120-treated mice dose-dependently affected behaviour on the platform indicating a H4R central effect, but did not modify anxiety behaviour either positively or negatively. Further studies are in progress to assess the role of the H4R in spatial and non-spatial memory performance.

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2. Ennaceur A, van Rensburg R, Michalikova S et al. (2010) Behav Brain Res 207: 84-98

3. Ennaceur A,, van Rensburg R, Michalikova S et al. (2010) Behav Brain Res, 209: 154-64

4. Michalikova S, van Rensburg, R, Chazot, PL et al. Behav Brain Res(2010) 207:402-17.

5. Ennaceur A, Michalikova S, van Rensburg, R et al. Behav Brain Res (2010a) 207:84-98.

6. Ennaceur A, Michalikova S, van Rensburg, R et al. Behav Brain Res (2010b) 209:154-64.

ACKNOWLEDGEMENTS: This work was funded by grant from the BJA/RCoA (UK).