Role of [alpha]1- and [alpha]2-GABAA receptors in mediating the respiratory changes associated with benzodiazepine sedation

• Published in: British journal of pharmacology 2012-05, Vol.166 (1), p.339
• Main Authors: Masneuf, S, Buetler, J, Koester, C, Crestani, F
• Format: Article
• Language: English
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01763.x

BACKGROUND AND PURPOSE The molecular substrates underlying the respiratory changes associated with benzodiazepine sedation are unknown. We examined the effects of different doses of diazepam and alprazolam on resting breathing in wild-type (WT) mice and clarified the contribution of [alpha]1- and [alpha]2-GABAA receptors, which mediate the sedative and muscle relaxant action of diazepam, respectively, to these drug effects using point-mutated mice possessing either [alpha]1H101R- or [alpha]2H101R-GABAA receptors insensitive to benzodiazepine. EXPERIMENTAL APPROACH Room air breathing was monitored using whole-body plethysmography. Different groups of WT mice were injected i.p. with diazepam (1-100 mg·kg-1), alprazolam (0.3, 1 or 3 mg·kg-1) or vehicle. [alpha]1H101R and [alpha]2H101R mice received 1 or 10 mg·kg-1 diazepam or 0.3 or 3 mg·kg-1 alprazolam. Respiratory frequency, tidal volume, time of expiration and time of inspiration before and 20 min after drug injection were analysed. KEY RESULTS Diazepam (10 mg·kg-1) decreased the time of expiration, thereby increasing the resting respiratory frequency, in WT and [alpha]2H101R mice, but not in [alpha]1H101R mice. The time of inspiration was shortened in WT and [alpha]1H101R mice, but not in [alpha]2H101R mice. Alprazolam (1-3 mg·kg-1) stimulated the respiratory frequency by shortening expiration and inspiration duration in WT mice. This tachypnoeic effect was partially conserved in [alpha]1H101R mice while absent in [alpha]2H101R mice. CONCLUSIONS AND IMPLICATIONS These results identify a specific role for [alpha]1-GABAA receptors and [alpha]2-GABAA receptors in mediating the shortening by benzodiazepines of the expiratory and inspiratory phase of resting breathing respectively. [PUBLICATION ABSTRACT]