DEFINITION OF INHALED ANESTHETIC SITES OF ACTIONS

University Of California San Francisco, San Francisco CA

Investigators

Linked publications & trials

Abstract

Despite the broad use of inhaled anesthetics, their mechanisms of action remain unknown. The present project hypothesizes that specific proteins/receptors mediate two primary effects of inhaled anesthetics: (a) suppression of movement, and (b) production of amnesia. The former will be measured as MAC, the minimum alveolar concentration of anesthetic that eliminates movement in 50% of mice in response to a noxious stimulus. The latter will be measured as the ED50 at which an anesthetic will interfere with learning and memory, as determined in mice using fear conditioning. The project will assess the relative importance of GABAA, glycine, glutamate, and neuronal nicotinic acetylcholine receptors to each of the two actions, focusing on these receptors, because in vitro evidence suggests (but does not prove) their relevance to the actions of inhaled anesthetics. Aim 1 of the project is to establish anesthetic dose-response relationships for MAC and for fear conditioning for a panel of five inhaled compounds having diverse properties. We will use commonly studied mouse strains, including those that provide the genetic background for the mutant mice tested in Aim 3 studies. These investigations examine the hypothesis that a constant potency relationship does not exist for the two anesthetic effects. Aim 2 broadens the panel of inhaled compounds but tests in vivo potency (for immobilization and fear conditioning) only in C57BL/6J mice, a strain that supplies the genetic background for most mice used in Aim 3. Compounds will be selected from those previously shown useful in studies of anesthetic-receptor interactions. This will test the working hypotheses (a) that a constant potency relationship does not exist for anesthetic partial pressures for MAC versus fear conditioning, (b) that two sites separated by 5 carbons mediate the immobilizing effects of anesthetics, and (c) that these two sites may not mediate interference with fear conditioning. Aim 3 will examine anesthetic potency in mutant mice lacking specific receptor subunits (null mutant mice) or bearing altered subunits (transgenic or knock in mice), and will compare these results with those for control (wild-type) mice. These results will test the hypotheses that specific receptors and specific receptor regions mediate the capacity of anesthetics to produce immobility or to interfere with fear conditioning. Finally, the data will provide a test of the relevance of the hypotheses proposed in the in vitro molecular studies of the rest of the Program Project Grant to the production of anesthesia.