title: Bidirectional regulation of intravenous general anesthetic actions by α3-containing γ-aminobutyric acid A receptors.
abstract: BACKGROUND
  γ-aminobutyric acid A (GABAA) receptors mediate the actions of several intravenous general anesthetics. However, the contribution of α3-containing GABAA receptors to the action of these drugs is unknown.
  
  
  METHODS
  The authors compared anesthetic endpoints (hypnosis, immobility, hypothermia) in response to various intravenous anesthetics in mice lacking the α3 subunit of the GABAA receptor (α3 knockout) and in wild-type mice. Furthermore, the authors generated and analyzed conditional mutant mice expressing the GABAA receptor α3 subunit exclusively in noradrenergic neurons.
  
  
  RESULTS
  α3 knockout mice displayed decreased hypnotic and hypothermic responses to etomidate and midazolam, but an increased response to pentobarbital. The hypnotic response to ketamine was unaltered, whereas the hypothermic response was increased. In contrast, the hypnotic but not the hypothermic response to medetomidine was increased. The combination of ketamine/xylazine displayed increased hypnotic, immobilizing, and hypothermic effects in α3 knockout mice. Mice expressing the α3 subunit exclusively in noradrenergic neurons were generated to assess whether the lack of α3 subunits on noradrenergic neurons may be responsible for this effect. In these mice, the increases of the hypnotic and immobilizing actions induced by ketamine/xylazine were largely absent, whereas the increase in the hypothermic action was still present.
  
  
  CONCLUSIONS
  α3-containing GABAA receptors bidirectionally regulate essential anesthetic actions: they mediate anesthetic actions of etomidate and midazolam, known to selectively act at GABAA receptors, and they negatively constrain anesthetic actions of compounds with targets partly or exclusively distinct from GABAA receptors such as medetomidine, ketamine, and pentobarbital. Furthermore, our results indicate that α3-containing GABAA receptors on noradrenergic neurons may contribute to this constraint.
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts, USA.
authors.forename: Carolin J
authors.initials: CJ
authors.lastname: Straub
authors.forename: Hew Mun
authors.initials: HM
authors.lastname: Lau
authors.forename: Rosanna
authors.initials: R
authors.lastname: Parlato
authors.forename: Guenther
authors.initials: G
authors.lastname: Schuetz
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
mesh_terms: D018681:Anesthetics, General / Q000008:administration & dosage* / Q000633:toxicity; D018686:Anesthetics, Intravenous / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D006993:Hypnotics and Sedatives / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced / Q000378:metabolism; D007103:Immobilization / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011963:Receptors, GABA-A / Q000502:physiology*
chemical_list: D018681:Anesthetics, General; D018686:Anesthetics, Intravenous; C546258:Gabra3 protein, mouse; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A