Short-term memory impairment after isoflurane in mice is prevented by the α5 γ-aminobutyric acid type A receptor inverse agonist L-655,708.
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.
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.
Bechara J
BJ
Saab
Ashley J B
AJ
Maclean
Marijana
M
Kanisek
Agnieszka A
AA
Zurek
Loren J
LJ
Martin
John C
JC
Roder
Beverley A
BA
Orser
D000818:Animals; D015331:Cohort Studies; D054314:Drug Inverse Agonism; D005239:Fear / Q000187:drug effects / Q000502:physiology / Q000523:psychology; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology / Q000627:therapeutic use; D058785:GABA-A Receptor Agonists; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007530:Isoflurane / Q000009:adverse effects*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control*; D008570:Memory, Short-Term / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011183:Postoperative Complications / Q000139:chemically induced / Q000517:prevention & control; D011897:Random Allocation; D011963:Receptors, GABA-A / Q000502:physiology
D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; C496250:Gabra5 protein, mouse; D007093:Imidazoles; C105490:L 655,708; D011963:Receptors, GABA-A; D007530:Isoflurane