Benzodiazepines and GABA A receptor subtypes: Effects in open-field, elevated plus maze-discriminative avoidance task, and conditioned place preference in male mice

Introduction: Benzodiazepines (GABA A receptor positive allosteric modulators) have been used for decades as effective and safe anxiolytic medications. However, they also have addiction/dependence liability and side effects that include sedative-motor and memory impairment. Several of these side effects have been associated with activity at GABA A receptors containing α1 subunits (α1GABA A receptors), suggesting that compounds with reduced efficacy at this receptor subtype might have an improved therapeutic profile. In the present study, we investigated the behavioral effects of the novel benzodiazepine-like compounds, HZ-166 and KRM-II-81, which show preferential efficacy for α2/3GABA A receptors, in comparison with the α1GABA A -selective compound, zolpidem. Methods: Adult male mice were treated with vehicle or one of the compounds (3, 10, or 30 mg/kg, i.p.) and tested in the open-field, the elevated plus maze-discriminative avoidance task, and conditioned place preference (CPP). Results: In the open-field test, HZ-166 and KRM-II-81 showed anxiolytic-like, but not sedative-like effects. In the discriminative avoidance task, only KRM-II-81 showed anxiolytic-like effects, but, unlike HZ-166, also induced memory deficits in mice. HZ-166 and KRM-II-81 did not have rewarding effects in CPP, with KRM-II-81 inducing conditioned place aversion instead. In contrast, zolpidem induced sedation, memory impairment, and rewarding effects, without displaying anxiolytic-like activity. Conclusions: These findings reinforce the role of α1GABA A receptors in benzodiazepine-induced sedation, cognitive impairment, and addiction potential, and its lack of a role in anxiety-like behaviors. Drugs with selectivity for α2/3GABA A receptors might have an improved therapeutic profile compared to conventional benzodiazepines.