ABSTRACT The γ-aminobutyric acid type A (GABAA) receptor is an ionotropic inhibitory ion channel. Inhibition mediated by GABAA receptors sets the level of activity in the brain, whereas in individual cells it determines the propensity of a cell to fire an action potential in response to excitatory input. The GABAA receptor is a major target for intravenous anesthetics and numerous endogenous compounds including neuroactive steroids. This project will investigate how combinations of endogenous and clinical compounds affect the functioning of the native GABAA receptor, and initiate the onset and offset of anesthesia. Specifically, we will: i) explore the kinetic and energetic aspects of activation and modulation of native synaptic and extrasynaptic GABAA receptors by clinically-relevant compounds; ii) determine the involvement of endogenous neurosteroids in the clinical actions of intravenous anesthetics to test the hypothesis that normal physiological changes in steroid levels modify responses to anesthetics; iii) probe ways for controllable recovery from anesthesia; and iv) test the feasibility of using partial allosteric agonists of the GABAA receptor as safe, mild sedatives.