Benzodiazepines and GABA_A receptor subtypes: Effects in open-field, elevated plus maze-discriminative avoidance task,...

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.

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).

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.

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.