Exploratory Behavior Models of Anxiety in Mice

Parameters of exploratory behaviors responsive to anti-anxiety drugs are reviewed with respect to their sensitivity and specificity for anxiolytics in mice. Mouse models appear to rest on a disinhibition of natural exploratory tendencies by anxiolytic treatments. Analysis of agonists of the brain benzodiazepine binding site, such as chlordiazepoxide and diazepam, significantly increase exploration of a hole-board, of a two-chambered light in equilibrium dark apparatus, increase social interaction under high levels of illumination, increase consumption of a novel food in an unfamiliar environment, and increase punished crossings in a footshock conflict paradigm. These tests detect anxiolytic responses at doses of benzodiazepines well within the clinically effective range. Pharmacological specificity was established for the hole-board and light in equilibrium transition tests, showing that non-anxiolytic categories of psychoactive drugs did not produce false positives. Open field behaviors and isolation-induced aggression were reduced by anxiolytics, at doses which may be within the sedative-hypnotic range. Analysis of antagonists of the brain benzodiazepine binding site did not show active antagonist properties in the light in equilibrium transitions model, although the antagonist Ro-15-1788 appeared to have partial agonist properties in the open field test, suggesting that rat models may be more sensitive to anxiogenic compounds than are mouse models. The wide separation between anxiolytic and sedative doses in mouse models recommend these exploration paradigms as good predictive screens for the testing of novel anxiolytic compounds.