The mechanisms by which general anesthetics have their clinically desired effects are not understood. The work proposed in the Program seeks to define the molecular target(s) for these drugs, and to clarify the way in which action at these targets results in anesthesia. The underlying idea is that anesthetics act at defined sites on proteins and , in particular, the proteins involved in formation transfer between neurons. A major emphasis of the Program is to understand the properties of steroid anesthetics, as a result of progress in the preceding Program is to understand the properties of steroid anesthetics, as a result of progress in the preceding Program period. One objective of the Program is to define the actions of steroid anesthetics on several classes of membrane channel, including GABA- A receptors, glutamatergic receptors, neuronal nicotinic receptors and voltage-gate calcium channels. The second objective of the Program is to define the structural basis for steroid interaction with on specific target, the GABA-A receptor. These studies will involve complementary studies of steroid analogue structure and molecular manipulation of recombinant receptor subunits. Photo-activated site specific probes for steroid binding sites will also be developed. The third objective of the Program is to delineate the mechanisms by which steroid anesthetics have their effects on their targets. The final objective is to correlate pharmacological results with production of anesthesia or other states defined only at the whole animal level. Although the overall focus is on anesthetic steroids, the program will include examination of additional anesthetics for comparison to the steroids. Each project, then, addresses on or another aspect of the action of anesthetic drugs at the cellular and molecular level. The Program as a whole will integrate these complementary studies, and relate them to behavioral states.
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