title: Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear.
abstract: 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.
authors.affiliation: Department of Anesthesiology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Sonner
authors.forename: Mike
authors.initials: M
authors.lastname: Cascio
authors.forename: Yilei
authors.initials: Y
authors.lastname: Xing
authors.forename: Michael S
authors.initials: MS
authors.lastname: Fanselow
authors.forename: Jason E
authors.initials: JE
authors.lastname: Kralic
authors.forename: A Leslie
authors.initials: AL
authors.lastname: Morrow
authors.forename: Esa R
authors.initials: ER
authors.lastname: Korpi
authors.forename: Steven
authors.initials: S
authors.lastname: Hardy
authors.forename: Brian
authors.initials: B
authors.lastname: Sloat
authors.forename: Edmond I
authors.initials: EI
authors.lastname: Eger
authors.forename: Gregg E
authors.initials: GE
authors.lastname: Homanics
mesh_terms: 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
chemical_list: D018685:Anesthetics, Inhalation; C546241:Gabra1 protein, mouse; D021122:Protein Subunits; D011963:Receptors, GABA-A