A comparative study with two types of elevated plus-maze (transparent vs. opaque walls) on the anxiolytic effects of midazolam, one-trial tolerance and fear-induced analgesia

Abstract

The phenomenon known as one-trial tolerance (OTT) to the anxiolytic effects of benzodiazepines observed in rats submitted to the elevated plus-maze test (EPM) is considered to be due to the emergence of phobic states across the test/retest sessions. Antinociception is a usual component of the defense reaction. Until now, no study has examined antinociception and OTT together in freely behaving rats in the EPM. This work is a new approach looking at the sensorimotor gatings underlying OTT through the examination of the changes in reactivity to noxious stimuli during OTT development. We used the tail-flick test to assess the reactivity of rats to noxious stimulus during the effects of midazolam in test/retest sessions using two types of EPM, one with opaque (standard EPM) and another one with transparent walls (modified EPM). The authors had previously shown that this modified test caused an overall stressful situation more related to anxiety while the standard test coursed with a mixture of anxiety and high fear levels. In both plus mazes, the study was conducted in two experiments: (i) midazolam before the first trial, and (ii) midazolam before the second trial. In each experimental condition the effects of midazolam were tested under two doses (0.5 and 1.0 mg/kg) against a control group that received injections of saline. The anxiolytic effects of midazolam were more pronounced in animals tested in the modified EPM than in the standard EPM. Stressful stimuli present in both types of maze were able to elicit one-trial tolerance to midazolam on re-exposure. However, anxiolytic-insensitive behaviors in the first and the reduction in exploratory activity in the second trial are more pronounced in the standard EPM indicating that this test is more prone to transfer fear-related states across trials than the modified maze test. Antinociception is not present upon the re-exposure of rats to the EPM. These findings show that animals tested in the modified EPM showed higher sensitivity to the anxiolytic effects of midazolam than the standard EPM. Antinociception was not a concomitant of the shift in the emotional state present in the retest sessions of the EPM. These results are in agreement with the premises that repeated stressful experience leads to anxiolytic-insensitive fear state different from anxiety.