Behavioral sensitivity to ethanol is a complex trait that appears to depend upon a number of different genes that all contribute to the behavioral phenotype. We will use electrophysiological techniques to study the actions of ethanol at the cellular level in animals that have been selected on the basis of behavioral responses to ethanol, in order to identify the cellular bases for differences in behavior. One mechanism that we hypothesize is an important determinant of behavioral ethanol sensitivity is the acute neuronal tolerance that we observe in electro- physiological experiments, which is maximal within 5-7 minutes following methanol application, and occurs rapidly enough that this type of tolerance could occur even before blood ethanol concentrations have reached their peak levels. We have observed this form of tolerance at the single cell level in animals selectively bred for ethanol sensitivity (short sleep mice and low alcohol sensitivity rats), but not in animals selected for increased ethanol sensitivity (long sleep mice and high alcohol sensitivity rats). We propose to compare this very rapid phase of tolerance between brain regions (hippocampus and cerebellum), and in other lines of mice that have been selected specifically for the rapid acquisition of behavioral ethanol tolerance. We also propose to determine whether there are cellular mechanisms that can account for the behavioral phenomenon of acute functional tolerance, which develops more slowly ( greater than 30 minutes), and for which no electrophysiological correlates have been identified. A second series of experiments will examine congenic mice that isolate individual quantitative trait loci (QTLs) for behavioral sensitivity to ethanol on a ethanol insensitive short sleep or ethanol sensitive long sleep background. We hypothesize that some of the QTLs will be associated with differences that we have previously observed in electrophysiological responses to ethanol in hippocampus and cerebellum. We will determine whether the same QTL-associated genes control initial ethanol sensitivity in the cerebellum and in the hippocampus, and whether there are separate and distinct QTLs associated with differences in acute neuronal tolerance and initial sensitivity. A final set of experiments will examine differences in GABAergic responses at the cellular level in lines of transgenic mice that overexpress either the gamma2L or gamma2S subunit of the GABAa receptor, which has been hypothesized to play a role in the ethanol sensitivity of this receptor.
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