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Nature 436, 845-847 (11 August 2005) | doi:10.1038/nature03864; Received 15 April 2005; Accepted 27 May 2005

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The hangover gene defines a stress pathway required for ethanol tolerance development

Henrike Scholz1,3, Mirjam Franz3 & Ulrike Heberlein1,2

  1. Department of Anatomy and
  2. Program in Neuroscience, University of California at San Francisco, California 94143-0452, USA
  3. Biozentrum, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany

Correspondence to: Henrike Scholz1,3Ulrike Heberlein1,2 Correspondence and requests for materials should be addressed to H.S. (Email: henrike.scholz@biozentrum.uni-wuerzburg.de) or U.H. (Email: ulrike@itsa.ucsf.edu).

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Repeated alcohol consumption leads to the development of tolerance, simply defined as an acquired resistance to the physiological and behavioural effects of the drug. This tolerance allows increased alcohol consumption, which over time leads to physical dependence and possibly addiction1, 2, 3. Previous studies have shown that Drosophila develop ethanol tolerance, with kinetics of acquisition and dissipation that mimic those seen in mammals. This tolerance requires the catecholamine octopamine, the functional analogue of mammalian noradrenaline4. Here we describe a new gene, hangover, which is required for normal development of ethanol tolerance. hangover flies are also defective in responses to environmental stressors, such as heat and the free-radical-generating agent paraquat. Using genetic epistasis tests, we show that ethanol tolerance in Drosophila relies on two distinct molecular pathways: a cellular stress pathway defined by hangover, and a parallel pathway requiring octopamine. hangover encodes a large nuclear zinc-finger protein, suggesting a role in nucleic acid binding. There is growing recognition that stress, at both the cellular and systemic levels, contributes to drug- and addiction-related behaviours in mammals. Our studies suggest that this role may be conserved across evolution.

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