This proposal is focused on determination of the molecular mechanisms of general anesthetics using transgenic techniques. The investigators will focus on the type A-aminobutryic acid receptor. Mouse lines that ubiquitously lack either the beta3, 26, or delta subunits of the GABAA-R have been produced and studies are underway in these cells/animals. In addition, the researchers proposed to create four further novel mouse lines that harbor tissue-specific knockouts of the GABAA-R2 or beta3 subunits. This conditional knockout approach has major advantages in that untoward developmental effects of the genetic alteration are avoided and the technique permits analysis of the putative neuroanatomic site of action of the anesthetic agents. Finally, the investigators will examine the anesthetic response of three additional genetically altered mouse lines: a) ubiquitous knockout of the alpha1, subunit of the GABAA-R; b) a transgene that expresses an Ala291 Trp point mutation in the alpha1 subunit; c) a knockin mutation of the Ala291 Trp mutation that replaces the endogenous alpha1 gene.
| 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 |
