Lmo genes regulate behavioral responses to ethanol in Drosophila melanogaster and the mouse

Background: Previous work from our laboratory demonstrated a role for the Drosophila Lim‐only (dLmo) gene in regulating behavioral responses to cocaine. Herein, we examined whether dLmo influences the flies’ sensitivity to ethanol’s sedating effects. We also investigated whether 1 of the mammalian homologs of dLmo, Lmo3, is involved in behavioral responses to ethanol in mice. Methods: To examine dLmo function in ethanol‐induced sedation, mutant flies with reduced or increased dLmo expression were tested using the loss of righting (LOR) assay. To determine whether mouse Lmo3 regulates behavioral responses to ethanol, we generated transgenic mice expressing a short‐hairpin RNA targeting Lmo3 for RNA interference‐mediated knockdown by lentiviral infection of single cell embryos. Adult founder mice, expressing varying amounts of Lmo3 in the brain, were tested using ethanol loss‐of‐righting‐reflex (LORR) and 2‐bottle choice ethanol consumption assays. Results: We found that in flies, reduced dLmo activity increased sensitivity to ethanol‐induced sedation, whereas increased expression of dLmo led to increased resistance to ethanol‐induced sedation. In mice, reduced levels of Lmo3 were correlated with increased sedation time in the LORR test and decreased ethanol consumption in the 2‐bottle choice protocol. Conclusions: These data describe a novel and conserved role for Lmo genes in flies and mice in behavioral responses to ethanol. These studies also demonstrate the feasibility of rapidly translating findings from invertebrate systems to mammalian models of alcohol abuse by combining RNA interference in transgenic mice and behavioral testing.