Document Detail


Bidirectional regulation of intravenous general anesthetic actions by α3-containing γ-aminobutyric acid A receptors.
MedLine Citation:
PMID:  23303487     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
CONCLUSION: 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:
Carolin J Straub; Hew Mun Lau; Rosanna Parlato; Guenther Schuetz; Jean-Marc Fritschy; Uwe Rudolph
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anesthesiology     Volume:  118     ISSN:  1528-1175     ISO Abbreviation:  Anesthesiology     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-22     Completed Date:  2013-04-19     Revised Date:  2014-03-17    
Medline Journal Info:
Nlm Unique ID:  1300217     Medline TA:  Anesthesiology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  562-76     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Anesthetics, General / administration & dosage*,  toxicity
Anesthetics, Intravenous / administration & dosage*,  toxicity
Animals
Hypnotics and Sedatives / metabolism
Hypothermia / chemically induced,  metabolism
Immobilization / methods
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, GABA-A / physiology*
Grant Support
ID/Acronym/Agency:
R01 GM086448/GM/NIGMS NIH HHS; R01-GM086448/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Anesthetics, General; 0/Anesthetics, Intravenous; 0/Gabra3 protein, mouse; 0/Hypnotics and Sedatives; 0/Receptors, GABA-A
Comments/Corrections

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