Many clinically-used sedative and anesthetic agents act by modulating the function of the ?-aminobutyric acid type A (GABAA) receptor. The GABAA receptor is the major inhibitory transmittergated ion channel in the brain. Inhibition mediated by GABAA receptors sets the overall activity of the brain, while in individual cells it determines the propensity of a cell to fire an action potential in response to a given excitatory input. The GABAA receptor is also a target for numerous endogenous compounds including neuroactive steroids, that can reduce the dosage requirement for intravenous anesthetics. The overall goal of this project is to investigate how various endogenous compounds and clinically used drugs modify the functioning of the GABAA receptor and initiate the onset and offset of anesthesia. Specifically, we will: i) examine the interactions between binding sites for various classes of GABAergic anesthetics; ii) test the hypothesis that modulation of tonic activity from synaptic-type GABAA receptors contributes to the actions of anesthetics; iii) determine the effects of anesthetic drug combinations on the function of native GABAA receptors; iv) test the hypothesis that endogenous steroids act as co-agonists enhancing the behavioral effects of clinically used GABAergic anesthetic drugs; and v) test the usefulness of competitive steroid-antagonists in promoting emergence from anesthesia.

Public Health Relevance

The GABAA receptor is a major target for intravenous anesthetics. The project will investigate how various endogenous and clinically-used sedative compounds affect the functioning of the GABAA receptor and control the onset and offset of anesthesia.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM108580-06S1
Application #
10145994
Study Section
Program Officer
Justinova, Zuzana
Project Start
2014-08-01
Project End
2022-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Cao, Lily Q; Montana, Michael C; Germann, Allison L et al. (2018) Enhanced GABAergic actions resulting from the coapplication of the steroid 3?-hydroxy-5?-pregnane-11,20-dione (alfaxalone) with propofol or diazepam. Sci Rep 8:10341
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Chakrabarti, Sampurna; Qian, Mingxing; Krishnan, Kathiresan et al. (2016) Comparison of Steroid Modulation of Spontaneous Inhibitory Postsynaptic Currents in Cultured Hippocampal Neurons and Steady-State Single-Channel Currents from Heterologously Expressed ?1?2?2L GABA(A) Receptors. Mol Pharmacol 89:399-406
Bracamontes, John R; Akk, Gustav; Steinbach, Joe Henry (2016) Introduced Amino Terminal Epitopes Can Reduce Surface Expression of Neuronal Nicotinic Receptors. PLoS One 11:e0151071
Eaton, Megan M; Germann, Allison L; Arora, Ruby et al. (2016) Multiple Non-Equivalent Interfaces Mediate Direct Activation of GABAA Receptors by Propofol. Curr Neuropharmacol 14:772-80

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