Different effects of 5-HT1A receptor agonists and benzodiazepine anxiolytics on the emotional state of naive and stressed mice:: a study using the hole-board test

Objectives: The effects of 5-MT1A receptor agonists on the emotional behavior of naive or stressed mice were examined and compared with those of benzodiazepine anxiolytics. Methods: Changes in the emotional state of mice were evaluated in terms of changes in exploratory activity, i.e. total locomotor activity, numbers and duration of rearing and head-dipping and latency to the first head-dipping, using an automatic hole-board apparatus. Results: The 5-HT1A receptor full agonists flesinoxan (0.03-1 mg/kg, IF) and 8-OH-DPAT (0.03-1 mg/kg, IF), and the partial agonist buspirone (0.3-10 mg/kg, IF) dose-dependently decreased all of the exploratory behaviors. Significant decreases in both the number and duration of head-dips, and an increase in the latency to head-dipping were observed at 30 min after exposure to acute restraint stress (60 min). These emotional changes were scarcely improved by post-stress treatment with 5-HT1A receptor agonists, at doses that alone did not produce a significant behavioral effect. In contrast, pretreatment with flesinoxan (0.1-1 mg/kg, IF) or 8-OH-DPAT (0.1-1 mg/kg, IF) 24 h prior to exposure to stress dose-dependently suppressed the decrease in various exploratory behaviors that was observed immediately after the exposure to acute restraint stress. Moreover, pretreatment with buspirone (1-10 mg/kg, IF) 24 h prior to exposure to stress also significantly suppressed the decrease in rearing behavior and the increase in head-dip latency. However, changes in the emotional response to stress stimuli were not observed in mice that had been pretreated with the benzodiazepine anxiolytics diazepam (0.1-1 mg/kg, IF) and chlordiazepoxide (2-8 mg/kg, IF). Conclusions: The present study clearly demonstrates that the behavioral effects of 5-HT1A receptor agonists in both naive and stressed mice were quite different from those of benzodiazepine anxiolytics, as previously reported by us. Notably, 5-HT1A receptor agonists but not benzodiazepine anxiolytics protect against various emotional changes produced by stress stimuli, and the results suggest that activation of 5-HT1A receptors may facilitate some mechanism(s) involved in the recognition of and/or ability to cope with stressful situation.