Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Abstract

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Tabakoff, B., Cornell, N. & Hoffman, P. L. Alcohol tolerance. Ann. Emerg. Med. 15, 1005–1012 (1986)

    Article  CAS  Google Scholar 

  2. Lê, A. D. & Mayer, J. M. in Pharmacological Effects of Ethanol on the Nervous System (eds Deitrich, R. A. & Erwin, V. G.) 251–268 (CRC Press, Boca Raton, 1996)

    Google Scholar 

  3. Fadda, F. & Rossetti, Z. L. Chronic ethanol consumption: from neuroadaptation to neurodegeneration. Prog. Neurobiol. 56, 385–431 (1998)

    Article  CAS  Google Scholar 

  4. Scholz, H., Ramond, J., Singh, C. M. & Heberlein, U. Functional ethanol tolerance in Drosophila. Neuron 28, 261–271 (2000)

    Article  CAS  Google Scholar 

  5. Weber, K. E. & Diggins, L. T. Increased selection response in larger populations. II. Selection for ethanol vapor resistance in Drosophila melanogaster at two population sizes. Genetics 125, 585–597 (1990)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Moore, M. S. et al. Ethanol intoxication in Drosophila: genetic and pharmacological evidence for regulation by the cAMP signalling pathway. Cell 93, 997–1007 (1998)

    Article  CAS  Google Scholar 

  7. Singh, C. M. & Heberlein, U. Genetic control of acute ethanol-induced behaviors in Drosophila. Alcohol. Clin. Exp. Res. 24, 1127–1136 (2000)

    Article  CAS  Google Scholar 

  8. Legrain, P. & Choulika, A. The molecular characterization of PRP6 and PRP9 yeast genes reveals a new cysteine/histidine motif common to several splicing factors. EMBO J. 9, 2775–2781 (1990)

    Article  CAS  Google Scholar 

  9. Torroja, L., Chu, H., Kotovsky, I. & White, K. Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport. Curr. Biol. 9, 489–492 (1999)

    Article  CAS  Google Scholar 

  10. Wilke, N., Sganga, M., Barhite, S. & Miles, M. F. Effects of alcohol on gene expression in neural cells. EXS 71, 49–59 (1994)

    CAS  PubMed  Google Scholar 

  11. Piper, P. W. The heat shock and ethanol stress responses of yeast exhibit extensive similarity and functional overlap. FEMS Microbiol. Lett. 134, 121–127 (1995)

    Article  CAS  Google Scholar 

  12. Monastirioti, M., Linn, C. E. J. & White, K. Characterization of Drosophila tyramine β-hydroxylase gene and isolation of mutant flies lacking octopamine. J. Neurosci. 16, 3900–3911 (1996)

    Article  CAS  Google Scholar 

  13. Arking, R., Buck, S., Berrios, A., Dwyer, S. & Baker, G. T. III Elevated paraquat resistance can be used as a bioassay for longevity in a genetically based long-lived strain of Drosophila. Dev. Genet. 12, 362–370 (1991)

    Article  CAS  Google Scholar 

  14. Finkel, T. & Holbrook, N. J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000)

    Article  ADS  CAS  Google Scholar 

  15. Min, K. T. & Benzer, S. Spongecake and eggroll: two hereditary diseases in Drosophila resemble patterns of human brain degeneration. Curr. Biol. 7, 885–888 (1997)

    Article  CAS  Google Scholar 

  16. Suzuki, Y. J., Forman, H. J. & Sevanian, A. Oxidants as stimulators of signal transduction. Free Radic. Biol. Med. 22, 269–285 (1997)

    Article  CAS  Google Scholar 

  17. Walter, H. J. & Messing, R. O. Regulation of neuronal voltage-gated calcium channels by ethanol. Neurochem. Int. 35, 95–101 (1999)

    Article  CAS  Google Scholar 

  18. Sun, A. Y. et al. Ethanol and oxidative stress. Alcohol. Clin. Exp. Res. 25, 237S–243S (2001)

    Article  CAS  Google Scholar 

  19. Schwaerzel, M. et al. Dopamine and octopamine differentiate between aversive and appetitive olfactory memories in Drosophila. J. Neurosci. 23, 10495–10502 (2003)

    Article  CAS  Google Scholar 

  20. Hyman, S. E. & Malenka, R. C. Addiction and the brain: the neurobiology of compulsion and its persistence. Nature Rev. Neurosci. 2, 695–703 (2001)

    Article  CAS  Google Scholar 

  21. Nestler, E. J. Molecular basis of long-term plasticity underlying addiction. Nature Rev. Neurosci. 2, 119–128 (2001)

    Article  ADS  CAS  Google Scholar 

  22. Mlodzik, M. & Hiromi, Y. Enhancer trap method in Drosophila: Its application to neurobiology. Methods Neurosci. 9, 397–414 (1992)

    Article  CAS  Google Scholar 

  23. Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993)

    CAS  Google Scholar 

Download references

Acknowledgements

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.)

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Henrike Scholz or Ulrike Heberlein.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. 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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Scholz, H., Franz, M. & Heberlein, U. The hangover gene defines a stress pathway required for ethanol tolerance development. Nature 436, 845–847 (2005). https://doi.org/10.1038/nature03864

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03864

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing