TY - JOUR
T1 - Gamma-aminobutyric acid type A receptor alpha 4 subunit knockout mice are resistant to the amnestic effect of isoflurane
AU - Rau, Vinuta
AU - Iyer, Sangeetha V.
AU - Oh, Irene
AU - Chandra, Dev
AU - Harrison, Neil
AU - Eger, Edmond I.
AU - Fanselow, Michael S.
AU - Homanics, Gregg E.
AU - Sonner, James M.
PY - 2009/12
Y1 - 2009/12
N2 - BACKGROUND: General anesthesia produces multiple end points including immobility, hypnosis, sedation, and amnesia. Tonic inhibition via γ-aminobutyric acid type A receptors (GABAA-Rs) may play a role in mediating behavioral end points that are suppressed by low concentrations of anesthetics (e.g., hypnosis and amnesia). GABAA-Rs containing the α4 subunit are highly concentrated in the hippocampus and thalamus, and when combined with δ subunits they mediate tonic inhibition, which is sensitive to low concentrations of isoflurane. METHODS: In this study, we used a GABAA α4 receptor knockout mouse line to evaluate the contribution of α4-containing GABAA-Rs to the effects of immobility, hypnosis, and amnesia produced by isoflurane. Knockout mice and their wild-type counterparts were assessed on 3 behavioral tests: conditional fear (to assess amnesia), loss of righting reflex (to assess hypnosis), and the minimum alveolar concentration of inhaled anesthetic necessary to produce immobility in response to noxious stimulation in 50% of subjects (to assess immobility). RESULTS: Genetic inactivation of the α4 subunit reduced the amnestic effect of isoflurane, minimally affected loss of righting reflex, and had no effect on immobility. CONCLUSIONS: These results lend support to the hypothesis that different sites of action mediate different anesthetic end points and suggest that α4-containing GABAA-Rs are important mediators of the amnestic effect of isoflurane on hippocampal-dependent declarative memory.
AB - BACKGROUND: General anesthesia produces multiple end points including immobility, hypnosis, sedation, and amnesia. Tonic inhibition via γ-aminobutyric acid type A receptors (GABAA-Rs) may play a role in mediating behavioral end points that are suppressed by low concentrations of anesthetics (e.g., hypnosis and amnesia). GABAA-Rs containing the α4 subunit are highly concentrated in the hippocampus and thalamus, and when combined with δ subunits they mediate tonic inhibition, which is sensitive to low concentrations of isoflurane. METHODS: In this study, we used a GABAA α4 receptor knockout mouse line to evaluate the contribution of α4-containing GABAA-Rs to the effects of immobility, hypnosis, and amnesia produced by isoflurane. Knockout mice and their wild-type counterparts were assessed on 3 behavioral tests: conditional fear (to assess amnesia), loss of righting reflex (to assess hypnosis), and the minimum alveolar concentration of inhaled anesthetic necessary to produce immobility in response to noxious stimulation in 50% of subjects (to assess immobility). RESULTS: Genetic inactivation of the α4 subunit reduced the amnestic effect of isoflurane, minimally affected loss of righting reflex, and had no effect on immobility. CONCLUSIONS: These results lend support to the hypothesis that different sites of action mediate different anesthetic end points and suggest that α4-containing GABAA-Rs are important mediators of the amnestic effect of isoflurane on hippocampal-dependent declarative memory.
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U2 - 10.1213/ANE.0b013e3181bf6ae6
DO - 10.1213/ANE.0b013e3181bf6ae6
M3 - Article
C2 - 19923508
AN - SCOPUS:73949111037
SN - 0003-2999
VL - 109
SP - 1816
EP - 1822
JO - Anesthesia and analgesia
JF - Anesthesia and analgesia
IS - 6
ER -