Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear.
Inhaled anesthetics are believed to produce anesthesia by their actions on ion channels. Because inhaled anesthetics robustly enhance GABA A receptor (GABA(A)-R) responses to GABA, these receptors are considered prime targets of anesthetic action. However, the importance of GABA(A)-Rs and individual GABA(A)-R subunits to specific anesthetic-induced behavioral effects in the intact animal is unknown. We hypothesized that inhaled anesthetics produce amnesia, as assessed by loss of fear conditioning, by acting on the forebrain GABA(A)-Rs that harbor the alpha1 subunit. To test this, we used global knockout mice that completely lack the alpha1 subunit and forebrain-specific, conditional knockout mice that lack the alpha1 subunit only in the hippocampus, cortex, and amygdala. Both knockout mice were 75 to 145% less sensitive to the amnestic effects of the inhaled anesthetic isoflurane. These results indicate that alpha1-containing GABA(A)-Rs in the hippocampus, amygdala, and/or cortex influence the amnestic effects of inhaled anesthetics and may be an important molecular target of the drug isoflurane.
Sonner
James M
JM
Department of Anesthesiology, University of California, San Francisco, San Francisco, California, USA.
Cascio
Mike
M
Xing
Yilei
Y
Fanselow
Michael S
MS
Kralic
Jason E
JE
Morrow
A Leslie
AL
Korpi
Esa R
ER
Hardy
Steven
S
Sloat
Brian
B
Eger
Edmond I
EI
Homanics
Gregg E
GE
D000280:Administration, Inhalation; D018685:Anesthetics, Inhalation / Q000008:administration & dosage*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D021122:Protein Subunits / Q000172:deficiency* / Q000235:genetics; D011963:Receptors, GABA-A / Q000172:deficiency* / Q000235:genetics
D018685:Anesthetics, Inhalation; C546241:Gabra1 protein, mouse; D021122:Protein Subunits; D011963:Receptors, GABA-A