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Mammalian Genome

, Volume 19, Issue 2, pp 77–84 | Cite as

A phenotype-driven ENU mutagenesis screen for the identification of dominant mutations involved in alcohol consumption

  • Cornelius R. Pawlak
  • Carles Sanchis-Segura
  • Dian Soewarto
  • Sibylle Wagner
  • Martin Hrabé de Angelis
  • Rainer Spanagel
Article

Abstract

The aim of this study was the application of a phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis screen in mice for the identification of dominant mutations involved in the regulation and modulation of alcohol-drinking behavior. The chemical mutagen ENU was utilized in the generation of 131 male ENU-mutant C57BL/6J mice (G0). These ENU-treated mice were paired with wild-type C57BL/6J mice to generate G1 and subsequent generations. In total, 3327 mice were generated. Starting with G1, mice were screened for voluntary oral self-administration of 10% (v/v) alcohol vs. water in a two-bottle paradigm. From these mice, after a total period of 5 weeks of drinking, 43 mutants fulfilled the criteria of an “alcohol phenotype,” that is, high or low ethanol intake. They were then selected for breeding and tested in a “confirmation cross” (G2–G4) for inheritance. Although we did not establish stable high or low drinking lines, several results were obtained in the context of alcohol consumption. First, female mice drank more alcohol than their male counterparts. Second, the former demonstrated greater infertility. Third, all animals displayed relatively stable alcohol intake, although significantly different in two different laboratories. Finally, seasonal and monthly variability was observed, with the highest alcohol consumption occurring in spring and the lowest in autumn. In conclusion, it seems difficult to identify dominant mutations involved in the modulation or regulation of voluntary alcohol consumption via a phenotype-driven ENU mutagenesis screen. In accordance with the findings from knockout studies, we suggest that mainly recessive mutations contribute to an alcohol-drinking or alcohol-avoiding phenotype.

Keywords

Alcohol Consumption Alcohol Intake Ethanol Consumption Dominant Mutation Spermatogonal Stem Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank Mark Lathrop for initiating this project, and Martina Herforth, Sabrina Koch, Stefanie Frank, and Peter Siegel for excellent technical assistance. This work was supported by BMBF grants FKZ 01GS0475 and 01 EB 0410 and the Centre National de Génotypage, Evry, France.

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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Cornelius R. Pawlak
    • 1
  • Carles Sanchis-Segura
    • 1
  • Dian Soewarto
    • 2
  • Sibylle Wagner
    • 2
  • Martin Hrabé de Angelis
    • 2
  • Rainer Spanagel
    • 1
  1. 1.Department of PsychopharmacologyCentral Institute of Mental Health (CIMH)MannheimGermany
  2. 2.Institute of Experimental GeneticsGSF Research CenterNeuherbergGermany

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