SYNERGISTIC ACTIONS OF INTRAVENOUS ANESTHETICS

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DESCRIPTION (provided by applicant): The γ-aminobutyric acid type A (GABAA) receptor is a member of the Cys-loop family of transmitter-gated ion channels. The receptors respond to synaptically-released or ambient transmitter with a conformational change, resulting in the opening of the gate that allows ion movement through the channel. Potentiation of GABAA receptor activity underlies the anesthetic effects of many intravenous anesthetics, such as etomidate and propofol. Although not in active clinical use, neuroactive steroids are among the most potent and efficacious potentiators of the GABAA receptor. Propofol, etomidate and neuroactive steroids also directly activate the GABAA receptor, although the concentrations for direct activation are typically higher than those that cause potentiation. Our preliminary data demonstrate that some neuroactive steroids strongly potentiate gating by propofol or etomidate. Combination of a low concentration of GABA with a low concentration of steroid results in a remarkable, supra-additive, increase in the extent of potentiation. In tadpole and mouse behavioral assays, the presence of a low, subthreshold concentration of a potentiating steroid results in a leftward shift in the dose-response relationship for loss of righting whereas in a cel line the presence of a steroid does not affect etomidate-elicited suppression of cortisol release. The overall goal of the present work is to determine the mechanism of interactions of steroid analogues and intravenous anesthetics on GABAA receptors, and to explore the clinical significance of the findings. We will: i) examine the synergistic effects of steroids with allosterc activators on recombinant synaptic and extrasynaptic GABA expressed in heterologous expression systems; ii) examine the behavioral consequences of synergistic effects of steroids and intravenous anesthetics in tadpole and mouse behavioral assays; and iii) probe whether reduced doses of anesthetics required to produce sedation in the presence of steroids lead to reduced off-target effects. The completion of these aims will increase our understanding of how the GABAA receptor functions in health and disease, and lay a foundation for future development of novel therapeutic approaches.