title: Role of α1- and α2-GABA(A)  receptors in mediating the respiratory changes associated with benzodiazepine sedation.
abstract: OBJECTIVE
  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 α1- and α2-GABA(A) receptors, which mediate the sedative and muscle relaxant action of diazepam, respectively, to these drug effects using point-mutated mice possessing either α1H101R- or α2H101R-GABA(A) receptors insensitive to benzodiazepine.
  
  
  METHODS
  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. α1H101R and α2H101R 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.
  
  
  RESULTS
  Diazepam (10 mg·kg(-1) ) decreased the time of expiration, thereby increasing the resting respiratory frequency, in WT and α2H101R mice, but not in α1H101R mice. The time of inspiration was shortened in WT and α1H101R mice, but not in α2H101R 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 α1H101R mice while absent in α2H101R mice.
  
  
  CONCLUSIONS
  These results identify a specific role for α1-GABA(A) receptors and α2-GABA(A) receptors in mediating the shortening by benzodiazepines of the expiratory and inspiratory phase of resting breathing respectively.
authors: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
authors: S
authors: S
authors: Masneuf
authors: J
authors: J
authors: Buetler
authors: C
authors: C
authors: Koester
authors: F
authors: F
authors: Crestani
mesh_terms: D000525:Alprazolam / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D051379:Mice; D008817:Mice, Mutant Strains; D010993:Plethysmography, Whole Body; D017354:Point Mutation; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D013997:Time Factors
chemical_list: C546241:Gabra1 protein, mouse; C493920:Gabra2 protein, mouse; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D003975:Diazepam; D000525:Alprazolam