Loss of Ethanol Conditioned Taste Aversion and Motor Stimulation in Knockin Mice with Ethanol-Insensitive α2-Containing GABA_AReceptors

Abstract

184 -191, 2008). The goal of our study was to determine the role of receptors containing this subunit in alcohol action. We designed an ␣2 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity in a recombinant expression system. Knockin mice containing this mutant subunit were tested in a range of ethanol behavioral tests. These mutant mice did not develop the typical conditioned taste aversion in response to ethanol and showed complete loss of the motor stimulant effects of ethanol. Conversely, they also demonstrated changes in ethanol intake and preference in multiple tests. The knockin mice showed increased ethanolinduced hypnosis but no difference in anxiolytic effects or recovery from acute ethanol-induced motor incoordination.Overall, these studies demonstrate that the effects of ethanol at GABAergic synapses containing the ␣2 subunit are important for specific behavioral effects of ethanol that may be relevant to the genetic linkage of this subunit with human alcoholism.

Behavioral Characterization of Knockin Mice with Mutations M287L and Q266I in the Glycine Receptor α1 Subunit

“…A significant shortcoming of null mutant mice is that extensive compensation may occur in response to the deletion and may involve genes that are distinct from the deletion. One assumption underlying construction and use of KI mice is that they will display either no or limited compensation compared with knockout mice, thus providing an advantage over null mutants (Werner et al, 2006;Blednov et al, 2011;Harris et al, 2011). However, the mutations used in this study clearly impair the function of the GlyR, and we asked whether some of the changes in behavior that we observed were the result of compensation occurring during development or from the acute impairment in GlyR function.…”

Seeking Structural Specificity: Direct Modulation of Pentameric Ligand-Gated Ion Channels by Alcohols and General Anesthetics

“…Remarkably, the knock-in approach has nonetheless linked specific GABA A and glycine receptors to behavioral actions of alcohol (Boehm et al, 2006;Crabbe et al, 2006;Blednov et al, 2012). In particular, action of ethanol on the a2 subunit of the GABA A receptor appears important for the stimulating and aversive effects of ethanol, but not for other alcohol-related behaviors (Blednov et al, 2011). An important contribution of the approach is the ability to rule out potential targets.…”

Glycine and GABAAUltra-Sensitive Ethanol Receptors as Novel Tools for Alcohol and Brain Research

“…However, these studies involving functional deletion or reduction in receptor sensitivity to ethanol require the use of relatively high ethanol concentrations (10-50 mM) Blednov et al, 2010Blednov et al, , 2011) that may affect other native receptor systems and signaling pathways that modulate additional physiologic processes Harris et al, 2008;Liang et al, 2008;Kumar et al, 2009;Howard et al, 2011;Kelm et al, 2011). In comparison, 17 mM ethanol is equivalent to the 0.08% blood ethanol concentration (BEC) legal driving limit in the United States (Wallner et al, 2003;Ogden and Moskowitz, 2004).…”