BACKGROUND: Increased ethanol intake, a major predictor for the development of alcohol use disorders, is facilitated by the development of tolerance to both the aversive and pleasurable effects of the drug. The molecular mechanisms underlying ethanol tolerance development are complex and are not yet well understood. METHODS: To identify genetic mechanisms that contribute to ethanol tolerance, we examined the time course of gene expression changes elicited by a single sedating dose of ethanol in Drosophila, and completed a behavioral survey of strains harboring mutations in ethanol-regulated genes. RESULTS: Enrichment for genes in metabolism, nucleic acid binding, olfaction, regulation of signal transduction, and stress suggests that these biological processes are coordinately affected by ethanol exposure. We also detected a coordinate up-regulation of genes in the Toll and Imd innate immunity signal transduction pathways. A multi-study comparison revealed a small set of genes showing similar regulation, including increased expression of 3 genes for serine biosynthesis. A survey of Drosophila strains harboring mutations in ethanol-regulated genes for ethanol sensitivity and tolerance phenotypes revealed roles for serine biosynthesis, olfaction, transcriptional regulation, immunity, and metabolism. Flies harboring deletions of the genes encoding the olfactory co-receptor Or83b or the sirtuin Sir2 showed marked changes in the development of ethanol tolerance. CONCLUSIONS: Our findings implicate novel roles for these genes in regulating ethanol behavioral responses.
BACKGROUND: Increased ethanol intake, a major predictor for the development of alcohol use disorders, is facilitated by the development of tolerance to both the aversive and pleasurable effects of the drug. The molecular mechanisms underlying ethanol tolerance development are complex and are not yet well understood. METHODS: To identify genetic mechanisms that contribute to ethanol tolerance, we examined the time course of gene expression changes elicited by a single sedating dose of ethanol in Drosophila, and completed a behavioral survey of strains harboring mutations in ethanol-regulated genes. RESULTS: Enrichment for genes in metabolism, nucleic acid binding, olfaction, regulation of signal transduction, and stress suggests that these biological processes are coordinately affected by ethanol exposure. We also detected a coordinate up-regulation of genes in the Toll and Imd innate immunity signal transduction pathways. A multi-study comparison revealed a small set of genes showing similar regulation, including increased expression of 3 genes for serine biosynthesis. A survey of Drosophila strains harboring mutations in ethanol-regulated genes for ethanol sensitivity and tolerance phenotypes revealed roles for serine biosynthesis, olfaction, transcriptional regulation, immunity, and metabolism. Flies harboring deletions of the genes encoding the olfactory co-receptorOr83b or the sirtuin Sir2 showed marked changes in the development of ethanol tolerance. CONCLUSIONS: Our findings implicate novel roles for these genes in regulating ethanol behavioral responses.
Authors: B P Riley; G Kalsi; P-H Kuo; V Vladimirov; D L Thiselton; J Vittum; B Wormley; M S Grotewiel; D G Patterson; P F Sullivan; E van den Oord; D Walsh; K S Kendler; C A Prescott Journal: Mol Psychiatry Date: 2006-08-29 Impact factor: 15.992
Authors: David A Kareken; Eric D Claus; Merav Sabri; Mario Dzemidzic; Ann E K Kosobud; Alexander J Radnovich; Dwight Hector; Vijay A Ramchandani; Sean J O'Connor; Mark Lowe; Ting-Kai Li Journal: Alcohol Clin Exp Res Date: 2004-04 Impact factor: 3.455
Authors: Julie A Mustard; Elaina A Edgar; Reece E Mazade; Chen Wu; Joshua L Lillvis; Geraldine A Wright Journal: Neurobiol Learn Mem Date: 2008-09-07 Impact factor: 2.877
Authors: Nathan Salomonis; Nathalie Cotte; Alexander C Zambon; Katherine S Pollard; Karen Vranizan; Scott W Doniger; Gregory Dolganov; Bruce R Conklin Journal: Genome Biol Date: 2005-01-28 Impact factor: 13.583
Authors: Kathryn Moynihan Ramsey; Jun Yoshino; Cynthia S Brace; Dana Abrassart; Yumiko Kobayashi; Biliana Marcheva; Hee-Kyung Hong; Jason L Chong; Ethan D Buhr; Choogon Lee; Joseph S Takahashi; Shin-Ichiro Imai; Joseph Bass Journal: Science Date: 2009-03-19 Impact factor: 47.728
Authors: Anita V Devineni; Kimberly D McClure; Douglas J Guarnieri; Ammon B Corl; Fred W Wolf; Mark Eddison; Ulrike Heberlein Journal: Fly (Austin) Date: 2011-07-01 Impact factor: 2.160
Authors: Eric C Kong; Katherine Woo; Haiyan Li; Tim Lebestky; Nasima Mayer; Melissa R Sniffen; Ulrike Heberlein; Roland J Bainton; Jay Hirsh; Fred W Wolf Journal: PLoS One Date: 2010-04-01 Impact factor: 3.240