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1 Subunit-Containing GABA Type A Receptors in Forebrain Contribute to the Effect of Inhaled Anesthetics on Conditioned Fear

Department of Anesthesiology, University of California, San Francisco, San Francisco, California (J.M.S., M.C., Y.X., E.I.E.); Department of Psychology, University of California, Los Angeles, Los Angeles, California (M.S.F.); Departments of Pharmacology, Psychiatry, and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.E.K., A.L.M.); Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland (E.R.K.); and Departments of Anesthesiology (S.H., B.S., G.E.H.) and Pharmacology (G.E.H.), University of Pittsburgh, Pittsburgh, Pennsylvania

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 1 subunit. To test this, we used global knockout mice that completely lack the 1 subunit and forebrain-specific, conditional knockout mice that lack the 1 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 1-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.

Address correspondence to: Dr. Gregg E. Homanics, University of Pittsburgh, Department of Anesthesiology, W1356 Biomedical Science Tower, Pittsburgh, PA 15261. E-mail: homanicsge{at}anes.upmc.edu

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