Document Detail

Short-term memory impairment after isoflurane in mice is prevented by the α5 γ-aminobutyric acid type A receptor inverse agonist L-655,708.
MedLine Citation:
PMID:  20966663     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Memory blockade is an essential component of the anesthetic state. However, postanesthesia memory deficits represent an undesirable and poorly understood adverse effect. Inhibitory α5 subunit-containing γ-aminobutyric acid subtype A receptors (α5GABAA) are known to play a critical role in memory processes and are highly sensitive to positive modulation by anesthetics. We postulated that inhibiting the activity of α5GABAA receptors during isoflurane anesthesia would prevent memory deficits in the early postanesthesia period. METHODS: Mice were pretreated with L-655,708, an α5GABAA receptor-selective inverse agonist, or vehicle. They were then exposed to isoflurane for 1 h (1.3%, or 1 minimum alveolar concentration, or air-oxygen control). Then, either 1 or 24 h later, mice were conditioned in fear-associated contextual and cued learning paradigms. In addition, the effect of L-655,708 on the immobilizing dose of isoflurane was studied. Motor coordination, sedation, anxiety, and the concentration of isoflurane in the brain at 5 min, 1 h, and 24 h after isoflurane were also examined. RESULTS: Motor and sensory function recovered within minutes after termination of isoflurane administration. In contrast, a robust deficit in contextual fear memory persisted for at least 24 h. The α5GABAA receptor inverse agonist, L-655,708, completely prevented memory deficits without changing the immobilizing dose of isoflurane. Trace concentrations of isoflurane were measured in the brain 24 h after treatment. CONCLUSIONS: Memory deficits occurred long after the sedative, analgesic, and anxiolytic effects of isoflurane subsided. L-655,708 prevented memory deficit, suggesting that an isoflurane interaction at α5GABAA receptors contributes to memory impairment during the early postanesthesia period.
Bechara J Saab; Ashley J B Maclean; Marijana Kanisek; Agnieszka A Zurek; Loren J Martin; John C Roder; Beverley A Orser
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anesthesiology     Volume:  113     ISSN:  1528-1175     ISO Abbreviation:  Anesthesiology     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-22     Completed Date:  2010-11-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1300217     Medline TA:  Anesthesiology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1061-71     Citation Subset:  AIM; IM    
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.
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MeSH Terms
Cohort Studies
Drug Inverse Agonism*
Fear / drug effects,  physiology,  psychology
GABA Agonists / pharmacology,  therapeutic use
Imidazoles / pharmacology,  therapeutic use*
Isoflurane / adverse effects*
Memory Disorders / chemically induced,  prevention & control*
Memory, Short-Term / drug effects*,  physiology
Mice, Inbred C57BL
Postoperative Complications / chemically induced,  prevention & control
Random Allocation
Receptors, GABA-A / agonists*,  physiology
Grant Support
MOP-13239//Canadian Institutes of Health Research; MOP-38028//Canadian Institutes of Health Research; MOP-79428//Canadian Institutes of Health Research
Reg. No./Substance:
0/GABA Agonists; 0/Gabra5 protein, mouse; 0/Imidazoles; 0/L 655,708; 0/Receptors, GABA-A; 26675-46-7/Isoflurane

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