Lack of anxiolytic effect of chlordiazepoxide in novel 3-D maze model of anxiety

P.L. Chazot1, R. van Rensburg1, S. Michalikova2,3 and A. Ennaceur2 1Centre for Integrative Neuroscience, Durham Univ., UK, 2Sunderland Sch. Pharmacy, Univ. Sunderland, UK, 3Inst. Animal Biochem. & Genet., Slovak Acad. Sci., Slovakia

Anxiety is an emotional response induced “by concurrent and equivalent activation of fear (or frustration) and reward system”. It is induced by fear from potential threat, but unlike fear that induces escape or avoidance, in anxiety “fear is compounded with a tendency to approach the source of potential threat --producing an approach-avoidance conflict” (Ennaceur et al., 2006a, b). This approach/avoidance conflict has been exploited by neuroscientists to develop behavioural tests for anxiety. Unfortunately in these tests animals can avoid or escape the anxiogenic stimuli due to the presence of a safe alternative, thus these tests measure escape or avoidance responses rather than anxiety per se. Therefore, we have to keep an open mind about other possible underlying neural mechanisms of anxiety and therapeutic targets as the current available data are inconsistent and contradictory; they have been produced from behavioural models that have proved unreliable and lack construct validity. Benzodiazepines are always held up as the ‘gold standard’ for an anxiolytic drug. Here, we question whether benzodiazepines do in fact have anxiolytic properties (Ennaceur et al., 2006b).

Animals are tested in a 3D maze spatial navigation apparatus which is a modification of a radial maze with flexible arms that can be raised above or lowered below the horizontal level of a central platform. To access the arms animals need to cross the bridges that are linked to the central platform. This 3D maze can be used for assessing fear inducing anxiety (open arms and open central platform, OA_OCP) and fear inducing avoidance (open arms and enclosed central platform, OA_ECP).

In a recent experiment we investigated the effect of administration of Chlordiazepoxide (CDZ) on the emotional responses of CD1 mice to the 3D maze. Separate groups of mice were tested either in the OA_OCP (5, 10, 15 mg/kg i.p.) or the OA_ECP (10 mg/kg i.p.). CDZ was administered 30 min before introduction of animals to the test. The behaviour of CD1 is compared to that of C57 which are used as a group of reference. The results shows that CD1 treated with CDZ were very active on the central platform and made as many visits to the bridges as C57 mice, but their number of visits to arms is comparable to that of CD1 saline and dramatically lower to that of C57. CDZ does not appear to have anxiolytic properties in the 3D maze. CD1 were unable to overcome their emotional responses to novelty and open spaces in the 3D maze and adventure far from the central platform and move beyond the bridges to the arms of the maze after administration of CDZ.

LE= Lowered arm configuration and Enclosed central platform, RO= Raised arm configuration and Open central platform, 0= saline, 10= 10mg/kg CDZ i.p. (n = 7-10 individual animals)

Ennaceur A, Michalikova S, Chazot PL (2006a) Behav Brain Res 171: 26-49
Ennaceur A et al. (2006b) Behav Brain Res 174: 9-38

This work was funded in part by an RDF (AE) and South Tees Anaesthetics Department.