Are benzodiazepines really anxiolytic? Evidence from a 3D maze spatial navigation task.
The effects of diazepam and chlordiazepoxide were assessed in a 3D maze which is a modification of an 8-arm radial maze. Each arm of the maze is attached to a bridge radiating from a central platform. Animals exposed for the first time to the maze do not venture beyond the line that separate a bridge from an arm. The prime criteria set for an anxiolytic effect is whether mice would increase the frequency of entries onto arms and increase arm/bridge entries ratio. C57 mice readily cross the line on first exposure and make more than 8 arm visits onto arms on second exposure, while other strains (CD-1 and Balb/c) hold back and rarely cross the line on first exposure and require more sessions to make more than 8 arm entries. An anxiolytic drug is expected to encourage intermediate (CD-1) and high (Balb/c) anxiety mice to adventure onto the arms of the maze and make more visits to the arms to comparable levels seen with low anxiety c57 mice. In the present report, administration of different doses of diazepam (0.625, 1.25, 2.5 and 5 mg kg(-1) i.p.) and chlordiazepoxide (5, 10 and 15 mg kg(-1) i.p.) did not reduce anxiety in animals, with the lowest dose of diazepam increasing motor activity in Balb/c and increasing anxiety in c57 mice while the highest doses of both diazepam (2.5 and 5 mg kg(-1) i.p.) and chlordiazepoxide (15 mg kg(-1) i.p.) induced mild sedation. Our results raise some concerns about the methodological foundations in the current assessment of anxiety and anxiolytic compounds both in animal and human studies.
University of Sunderland, Sunderland Pharmacy School, Wharncliffe Street, Sunderland SR1 3SD, UK. abdel_ennaceur@yahoo.com <abdel_ennaceur@yahoo.com>
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Michalikova
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D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000517:prevention & control*; D002707:Chlordiazepoxide / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D013037:Spatial Behavior / Q000187:drug effects*; D013045:Species Specificity; D018709:Statistics, Nonparametric
D014151:Anti-Anxiety Agents; D002707:Chlordiazepoxide; D003975:Diazepam