This study aims to elucidate the molecular target(s) of anesthetic action by creating knockout mice and examining the progeny for sensitivity to inhaled anesthetics. Six genetically altered mouse lines carrying mutations at GABAA receptor loci are proposed, specifically null alleles of a6, b3, g2, d subtypes, as well as point mutations of a6 and g2 subunits. These specific alleles have been chosen since inbred mice missing these alleles or carrying specific mutations have been shown previously to have altered sensitivity to anesthetic agents. After creation of the mouse strains, each will be tested for anesthetic sensitivity (5 volatile GAs on tail clamp/withdrawal MAC, loss of righting reflex), chloride flux experiments from brains of bred mice, and finally electrophysiologic studies to determine if single mutations change other neurons as well as characteristics of the channel with and without anesthetics. Hence behavioral and electrophysiology data are the endpoints of this project.
| June Sr, Harry L; Foster, Katrina L; Eiler 2nd, William J A et al. (2007) Dopamine and benzodiazepine-dependent mechanisms regulate the EtOH-enhanced locomotor stimulation in the GABAA alpha1 subunit null mutant mice. Neuropsychopharmacology 32:137-52 |
| Ferguson, Carolyn; Hardy, Steven L; Werner, David F et al. (2007) New insight into the role of the beta3 subunit of the GABAA-R in development, behavior, body weight regulation, and anesthesia revealed by conditional gene knockout. BMC Neurosci 8:85 |
| Sonner, James M; Cascio, Mike; Xing, Yilei et al. (2005) Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear. Mol Pharmacol 68:61-8 |
| Chandra, Dev; Korpi, Esa R; Miralles, Celia P et al. (2005) GABAA receptor gamma 2 subunit knockdown mice have enhanced anxiety-like behavior but unaltered hypnotic response to benzodiazepines. BMC Neurosci 6:30 |
