In preliminary studies, the investigator has observed that two volatile anesthetics exert agent-specific actions on two physiologically distinct and anatomically segregated GABAA receptors in hippocampal CA1 pyramidal cells; he has provided evidence that these currents, the cell body GABAA/fast and the dendritic GABAA/slow, mediate suppression of bursting activity and paired-pulse depression, respectively, and thus may have different functional roles with respect to seizures and learning respectively. Preliminary results in which the ability of general anesthetics to enhance GABA function is lost under conditions in which the milieu of the intracellular side of the channel is changed have led to the suggestion that this unique effect of anesthetics on the GABA channel is due to an intracellular action. In the present study Dr. Pearce proposes to test the hypothesis that agent-specific effects on the two GABA currents may account for some clinical differences among agents, and to extend the results to the molecular level. In 3 specific aims, he will (1) test the hypothesis that the separate amnestic and convulsant properties of volatile anesthetics and related agents result from their agent-specific actions on these two currents by extending the series to additional agents including two experimental compounds; (2) examine the mechanisms by which anesthetics alter channel kinetic parameters; and (3) identify the intracellular factors necessary for anesthetic-induced alterations and define their roles. Methods include extracellular and whole cell ruptured patch recording in hippocampal slice, and single channel recordings from excised patches from the slice and from HEK293 cells in which GABAA receptors have been expressed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM055719-04
Application #
6181149
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
1997-05-01
Project End
2002-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
4
Fiscal Year
2000
Total Cost
$203,600
Indirect Cost
Name
University of Wisconsin Madison
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Bland, Brian H; Bland, Cheryl E; MacIver, M Bruce (2016) Median raphe stimulation-induced motor inhibition concurrent with suppression of type 1 and type 2 hippocampal theta. Hippocampus 26:289-300
Burkat, Paul M; Lor, Chong; Perouansky, Misha et al. (2014) Enhancement of ?5-containing ?-aminobutyric acid type A receptors by the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6) is abolished by the ?3(N265M) mutation. Anesth Analg 119:1277-84
Goldschen-Ohm, Marcel P; Haroldson, Alexander; Jones, Mathew V et al. (2014) A nonequilibrium binary elements-based kinetic model for benzodiazepine regulation of GABAA receptors. J Gen Physiol 144:27-39
Dai, Shuiping; Perouansky, Misha; Pearce, Robert A (2012) Isoflurane enhances both fast and slow synaptic inhibition in the hippocampus at amnestic concentrations. Anesthesiology 116:816-23
Pearce, R A; Duscher, P; Van Dyke, K et al. (2012) Isoflurane impairs odour discrimination learning in rats: differential effects on short- and long-term memory. Br J Anaesth 108:630-7
Perouansky, Misha; Pearce, Robert A (2011) How we recall (or don't): the hippocampal memory machine and anesthetic amnesia. Can J Anaesth 58:157-66
Perouansky, Misha; Hentschke, Harald; Perkins, Mark et al. (2007) Amnesic concentrations of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6, 2N) and isoflurane alter hippocampal theta oscillations in vivo. Anesthesiology 106:1168-76
Benkwitz, Claudia; Liao, Mark; Laster, Michael J et al. (2007) Determination of the EC50 amnesic concentration of etomidate and its diffusion profile in brain tissue: implications for in vitro studies. Anesthesiology 106:114-23
Borghese, C M; Werner, D F; Topf, N et al. (2006) An isoflurane- and alcohol-insensitive mutant GABA(A) receptor alpha(1) subunit with near-normal apparent affinity for GABA: characterization in heterologous systems and production of knockin mice. J Pharmacol Exp Ther 319:208-18
Boileau, Andrew J; Pearce, Robert A; Czajkowski, Cynthia (2005) Tandem subunits effectively constrain GABAA receptor stoichiometry and recapitulate receptor kinetics but are insensitive to GABAA receptor-associated protein. J Neurosci 25:11219-30

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