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


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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Figure 1: hang AE10 flies have abnormal ethanol tolerance development.
Figure 2: The hang AE10 mutation disrupts a gene encoding a zinc-finger protein.
Figure 3: hang AE10 results in impaired heat–ethanol cross-tolerance.

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We thank R. Threlkeld for the northern blot, N. Funk and I. Schwenkert for the production of rescue constructs and anti-HANG antibody, H.Saumweber and G.Krohne for gifts of antibodies, and B. Poeck, A. Corl, A. Rothenfluh, D. Guarnieri, F. Wolf and C. Kenyon for comments on the manuscript. This work was supported by the NIH/NIAAA (U.H.), ABMRF (U.H.), the Sandler Foundation (U.H.), the Wheeler Center (H.S. and U.H.) and the German Science Foundation DFG (H.S.)

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Correspondence to Henrike Scholz or Ulrike Heberlein.

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Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Figure S1

a, hangAE10 flies show normal ethanol absorption and metabolism. b, The hangAE10 phenotype is reverted to wild type after excision of the P-element. (JPG 201 kb)

Supplementary Figure 2

hang is expressed ubiquitously in the nervous system. (JPG 459 kb)

Supplementary Figure S3

Hang flies show reduced lifespan but no obvious neurodegeneration. (JPG 406 kb)

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Scholz, H., Franz, M. & Heberlein, U. The hangover gene defines a stress pathway required for ethanol tolerance development. Nature 436, 845–847 (2005).

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