Mapping the Contribution of β3-containing GABAA Receptors to Volatile and Intravenous General Anesthetic Actions

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Mapping the Contribution of β3-containing GABAA Receptors to Volatile and Intravenous General Anesthetic Actions

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dc.contributor.author Zeller, Anja
dc.contributor.author Arras, Margarete
dc.contributor.author Jurd, Rachel
dc.contributor.author Rudolph, Uwe
dc.date.accessioned 2011-02-25T19:44:25Z
dc.date.issued 2007
dc.identifier.citation Zeller, Anja, Margarete Arras, Rachel Jurd, and Uwe Rudolph. 2007. Mapping the contribution of β3-containing GABAA receptors to volatile and intravenous general anesthetic actions. BMC Pharmacology 7: 2. en_US
dc.identifier.issn 1471-2210 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4732015
dc.description.abstract Background: Agents belonging to diverse chemical classes are used clinically as general anesthetics. The molecular targets mediating their actions are however still only poorly defined. Both chemical diversity and substantial differences in the clinical actions of general anesthetics suggest that general anesthetic agents may have distinct pharmacological targets. It was demonstrated previously that the immobilizing action of etomidate and propofol is completely, and the immobilizing action of isoflurane partly mediated, by β3-containing GABAA receptors. This was determined by using the β3(N265M) mice, which carry a point mutation known to decrease the actions of general anesthetics at recombinant GABAA receptors. In this communication, we analyzed the contribution of β3-containing GABAA receptors to the pharmacological actions of isoflurane, etomidate and propofol by means of β3(N265M) mice. Results: Isoflurane decreased core body temperature and heart rate to a smaller degree in β3(N265M) mice than in wild type mice, indicating a minor but significant role of β3-containing GABAA receptors in these actions. Prolonged time intervals in the ECG and increased heart rate variability were indistinguishable between genotypes, suggesting no involvement of β3-containing GABAA receptors. The anterograde amnesic action of propofol was indistinguishable in β3(N265M) and wild type mice, suggesting that it is independent of β3-containing GABAA receptors. The increase of heart rate variability and prolongation of ECG intervals by etomidate and propofol were also less pronounced in β3(N265M) mice than in wild type mice, pointing to a limited involvement of β3-containing GABAA receptors in these actions. The lack of etomidate- and propofol-induced immobilization in β3(N265M) mice was also observed in congenic 129X1/SvJ and C57BL/6J backgrounds, indicating that this phenotype is stable across different backgrounds. Conclusion: Our results provide evidence for a defined role of β3-containing GABAA receptors in mediating some, but not all, of the actions of general anesthetics, and confirm the multisite model of general anesthetic action. This pharmacological separation of anesthetic endpoints also suggests that subtype-selective substances with an improved side-effect profile may be developed. en_US
dc.language.iso en_US en_US
dc.publisher BioMed Central en_US
dc.relation.isversionof doi:10.1186/1471-2210-7-2 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810244/pdf/ en_US
dash.license LAA
dc.title Mapping the Contribution of β3-containing GABAA Receptors to Volatile and Intravenous General Anesthetic Actions en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal BMC Pharmacology en_US
dash.depositing.author Rudolph, Uwe
dc.date.available 2011-02-25T19:44:25Z
dash.affiliation.other HMS^Psychiatry-McLean Hospital en_US

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