Effect of isoflurane and other potent inhaled anesthetics on minimum alveolar concentration, learning, and the righting reflex in mice engineered to express alpha1 gamma-aminobutyric acid type A receptors unresponsive to isoflurane.
BACKGROUND
Enhancement of the function of gamma-aminobutyric acid type A receptors containing the alpha1 subunit may underlie a portion of inhaled anesthetic action. To test this, the authors created gene knock-in mice harboring mutations that render the receptors insensitive to isoflurane while preserving sensitivity to halothane.


METHODS
The authors recorded miniature inhibitory synaptic currents in hippocampal neurons from hippocampal slices from knock-in and wild-type mice. They also determined the minimum alveolar concentration (MAC), and the concentration at which 50% of animals lost their righting reflexes and which suppressed pavlovian fear conditioning to tone and context in both genotypes.


RESULTS
Miniature inhibitory postsynaptic currents decayed more rapidly in interneurons and CA1 pyramidal cells from the knock-in mice compared with wild-type animals. Isoflurane (0.5-1 MAC) prolonged the decay phase of miniature inhibitory postsynaptic currents in neurons of the wild-type mice, but this effect was significantly reduced in neurons from knock-in mice. Halothane (1 MAC) slowed the decay of miniature inhibitory postsynaptic current in both genotypes. The homozygous knock-in mice were more resistant than wild-type controls to loss of righting reflexes induced by isoflurane and enflurane, but not to halothane. The MAC for isoflurane, desflurane, and halothane did not differ between knock-in and wild-type mice. The knock-in mice and wild-type mice did not differ in their sensitivity to isoflurane for fear conditioning.


CONCLUSIONS
gamma-Aminobutyric acid type A receptors containing the alpha1 subunit participate in the inhibition of the righting reflexes by isoflurane and enflurane. They are not, however, involved in the amnestic effect of isoflurane or immobilizing actions of inhaled agents.
Sonner
James M
JM
Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94143-0464, USA. sonnerj@anesthesia.ucsf.edu
Werner
David F
DF
Elsen
Frank P
FP
Xing
Yilei
Y
Liao
Mark
M
Harris
R Adron
RA
Harrison
Neil L
NL
Fanselow
Michael S
MS
Eger
Edmond I
EI
Homanics
Gregg E
GE
D018685:Anesthetics, Inhalation / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007530:Isoflurane / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D012018:Reflex / Q000187:drug effects*
D018685:Anesthetics, Inhalation; C546241:Gabra1 protein, mouse; D011963:Receptors, GABA-A; D007530:Isoflurane