title: Closing the gap between the molecular and systemic actions of anesthetic agents.
abstract: Genetic approaches have been successfully used to relate the diverse molecular actions of anesthetic agents to their amnestic, sedative, hypnotic, and immobilizing properties. The hypnotic effect of etomidate, quantified as the duration of the loss of righting reflex in mice, is equally mediated by GABAA receptors containing β2- and β3-protein subunits. However, only β3-containing receptors are involved in producing electroencephalogram (EEG)-patterns typical of general anesthesia. The sedative action of diazepam is produced by α1-subunit-containing receptors, but these receptors do not contribute to the drug's characteristic EEG-"fingerprint." Thus, GABAA receptors with α1- and β2-subunits take a central role in causing benzodiazepine-induced sedation and etomidate-induced hypnosis, but the corresponding EEG-signature is difficult to resolve. Contrastingly, actions of etomidate and benzodiazepines mediated via α2- and β3-subunits modify rhythmic brain activity in vitro and in vivo at least in part by enhancing neuronal synchrony. The immobilizing action of GABAergic anesthetics predominantly involves β3-subunit-containing GABAA receptors in the spinal cord. Interestingly, this action is self-limiting as GABA-release is attenuated via the same receptors. Anesthetic-induced amnesia is in part mediated by GABAA receptors harboring α5-subunits that are highly enriched in the hippocampus and, in addition, by α1-containing receptors in the forebrain. Because there is accumulating evidence that in patients the expression pattern of GABAA receptor subtypes varies with age, is altered by the long-term use of drugs, and is affected by pathological conditions like inflammation and sepsis, further research is recommended to adapt the use of anesthetic agents to the specific requirements of individual patients.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology Section, Eberhard-Karls-University, Tübingen, Germany; Werner Reichardt Centre for Integrative Neuroscience, Eberhard-Karls-University, Tübingen, Germany. Electronic address: bernd.antkowiak@uni-tuebingen.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Antkowiak
mesh_terms: D000367:Age Factors; D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004569:Electroencephalography; D005045:Etomidate / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018681:Anesthetics, General; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005045:Etomidate
keywords: Amnesia; Etomidate; GABA(A)-receptor; General anesthesia; Unconsciousness; β3-Subunit