GENERAL ANESTHETICS& BRAIN N-METHYL-ASPARTATE RECEPTORS

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The specific sites at which general anesthetics act are unknown. However, we recently showed that 1) low concentrations of several clinically useful general anesthetics inhibit responses produced by excitatory brain N-methyl-D-aspartate (NMDA) receptors, and 2) NMDA receptor antagonists increase acute behavioral sensitivity to general anesthetics. Our results are consistent with the idea that brain NMDA receptors are a specific site acted upon by general anesthetics and that their inhibitory effects on NMDA receptors play a major role in the production of general anesthesia. Therefore, the hypothesis of this proposal is that anesthesia is produced, in part, by inhibition of the function of brain NMDA receptors. In the proposed studies, the effects of general anesthetics on NMDA-stimulated increases in intracellular calcium concentrations (Cai) will be determined in brain vesicles. Structure-activity relationships and correlations between inhibition of NMDA receptor responses in brain vesicles in vitro and the ability of NMDA receptor antagonists to increase general anesthetic potency in vivo will be examined. Possible mechanisms of general anesthetic inhibition of NMDA responses including action at an allosteric or channel blocking site of the NMDA receptor and/or alteration of the kinetics of receptor activation and inactivation will be distinguished. This study will increase our understanding of the role of NMDA receptors in anesthesia and may aid in the development of novel anesthetic agents specifically targeted to receptor sites mediating anesthesia.