Role of α1‐ and α2‐GABA_A receptors in mediating the respiratory changes associated with benzodiazepine sedation

Abstract

BACKGROUND AND PURPOSEThe 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 a1-and a2-GABAA receptors, which mediate the sedative and muscle relaxant action of diazepam, respectively, to these drug effects using point-mutated mice possessing either a1H101R-or a2H101R-GABAA receptors insensitive to benzodiazepine. EXPERIMENTAL APPROACHRoom 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. a1H101R and a2H101R 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 RESULTSDiazepam (10 mg·kg -1 ) decreased the time of expiration, thereby increasing the resting respiratory frequency, in WT and a2H101R mice, but not in a1H101R mice. The time of inspiration was shortened in WT and a1H101R mice, but not in a2H101R 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 a1H101R mice while absent in a2H101R mice. CONCLUSIONS AND IMPLICATIONSThese results identify a specific role for a1-GABAA receptors and a2-GABAA receptors in mediating the shortening by benzodiazepines of the expiratory and inspiratory phase of resting breathing respectively. AbbreviationWT, wild-type

The association of serotonin reuptake inhibitors and benzodiazepines with ictal central apnea

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