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.
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.
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