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A Drosophila model for alcohol reward

Nature Neuroscience volume 14, pages 612–619 (2011)Cite this article

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Abstract

The rewarding properties of drugs contribute to the development of abuse and addiction. We developed a new assay for investigating the motivational properties of ethanol in the genetically tractable model Drosophila melanogaster. Flies learned to associate cues with ethanol intoxication and, although transiently aversive, the experience led to a long-lasting attraction for the ethanol-paired cue, implying that intoxication is rewarding. Temporally blocking transmission in dopaminergic neurons revealed that flies require activation of these neurons to express, but not develop, conditioned preference for ethanol-associated cues. Moreover, flies acquired, consolidated and retrieved these rewarding memories using distinct sets of neurons in the mushroom body. Finally, mutations in scabrous, encoding a fibrinogen-related peptide that regulates Notch signaling, disrupted the formation of memories for ethanol reward. Our results thus establish that Drosophila can be useful for understanding the molecular, genetic and neural mechanisms underling the rewarding properties of ethanol.

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Figure 1: Ethanol is both aversive and rewarding to flies.
Figure 2: Pharmacological properties of ethanol induce preference.
Figure 3: Dopamine is required for conditioned preference.
Figure 4: Dopamine is required for expression of ethanol reward.
Figure 5: The mushroom body is required for aversion and preference.
Figure 6: Sequential use of mushroom body neurons.
Figure 7: sca affects memories for ethanol reward.

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References

  1. Hyman, S.E., Malenka, R.C. & Nestler, E.J. Neural mechanisms of addiction: The role of reward-related learning and memory. Annu. Rev. Neurosci. 29, 565–598 (2006).

    Article  CAS  Google Scholar 

  2. Tzschentke, T.M. Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict. Biol. 12, 227–462 (2007).

    Article  CAS  Google Scholar 

  3. Rodan, A.R. & Rothenfluh, A. The genetics of behavioral alcohol responses in Drosophila. Int. Rev. Neurobiol. 91, 25–51 (2010).

    Article  CAS  Google Scholar 

  4. Baker, N.E., Mlodzik, M. & Rubin, G.M. Spacing differentiation in the developing Drosophila eye: a fibrinogen-related lateral inhibitor encoded by scabrous. Science 250, 1370–1377 (1990).

    Article  CAS  Google Scholar 

  5. Powell, P.A., Wesley, C., Spencer, S. & Cagan, R.L. Scabrous complexes with Notch to mediate boundary formation. Nature 409, 626–630 (2001).

    Article  CAS  Google Scholar 

  6. Nehring, L.C., Miyamoto, A., Hein, P.W., Weinmaster, G. & Shipley, J.M. The extracellular matrix protein MAGP-2 interacts with Jagged1 and induces its shedding from the cell surface. J. Biol. Chem. 280, 20349–20355 (2005).

    Article  CAS  Google Scholar 

  7. Miyamoto, A., Lau, R., Hein, P.W., Shipley, J.M. & Wienmaster, G. Microfibrillar proteins MAGP-1 and MAGP-2 induce Notch1 extracellular domain dissociation and receptor activation. J. Biol. Chem. 281, 10089–10097 (2006).

    Article  CAS  Google Scholar 

  8. Louvi, A. & Artavanis-Tsakonas, S. Notch signaling in vertebrate neural development. Nat. Rev. Neurosci. 7, 93–102 (2006).

    Article  CAS  Google Scholar 

  9. Wang, Y. et al. Involvement of Notch signaling in hippocampal synaptic plasticity. Proc. Natl. Acad. Sci. USA 101, 9458–9462 (2004).

    Article  CAS  Google Scholar 

  10. Costa, R.M., Honjo, T. & Silva, A.J. Learning and memory deficits in Notch mutant mice. Curr. Biol. 13, 1348–1354 (2003).

    Article  CAS  Google Scholar 

  11. Presente, A., Boyles, R.S., Serway, C.N., de Belle, S. & Andres, A. Notch is required for long-term memory in Drosophila. Proc. Natl. Acad. Sci. USA 101, 1764–1768 (2004).

    Article  CAS  Google Scholar 

  12. Ge, X. et al. Notch signaling in Drosophila long-term memory formation. Proc. Natl. Acad. Sci. USA 101, 10172–10176 (2004).

    Article  CAS  Google Scholar 

  13. Phillips, T.J. & Shen, E.H. Neurochemical basis of locomotion and ethanol stimulant effects. Int. Rev. Neurobiol. 39, 243–282 (1996).

    Article  CAS  Google Scholar 

  14. Deadwyler, S.A. Electrophysiological correlates of abused drugs: relation to natural rewards. Ann. NY Acad. Sci. 1187, 140–147 (2010).

    Article  CAS  Google Scholar 

  15. Bainton, R.J. et al. Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila. Curr. Biol. 10, 187–194 (2000).

    Article  CAS  Google Scholar 

  16. Kong, E.C. et al. A pair of dopamine neurons target the D1-like dopamine receptor DopR in the central complex to promote ethanol-stimulated locomotion in Drosophila. PLoS ONE 5, e9954 (2010).

    Article  Google Scholar 

  17. Kitamoto, T. Targeted expression of temperature-sensitive dynamin to study neural mechanisms of complex behavior in Drosophila. J. Neurogenet. 16, 205–228 (2002).

    Article  CAS  Google Scholar 

  18. Friggi-Grelin, F. et al. Targeted expression in Drosophila dopaminergic cells using regulatory sequences from tyrosine hydroxylase. J. Neurobiol. 54, 618–627 (2003).

    Article  CAS  Google Scholar 

  19. Li, H., Chaney, S., Forte, M. & Hirsh, J. Ectopic G-protein expression in dopamine and serotonin neurons blocks cocaine sensitization in Drosophila melanogaster. Curr. Biol. 10, 211–214 (2000).

    Article  CAS  Google Scholar 

  20. Dhonnchadha, B.A.N. & Cunningham, K.A. Serotonergic mechanisms in addiction-related memories. Behav. Brain Res. 195, 29–52 (2008).

    Google Scholar 

  21. Krashes, M.J., Keene, A.C., Leung, B., Armstrong, J.D. & Waddell, S. Sequential use of mushroom body neuron subsets during Drosophila odor memory processing. Neuron 53, 103–115 (2007).

    Article  CAS  Google Scholar 

  22. Krashes, M.J. et al. A neural circuit mechanism integrating motivational state with memory expression in Drosophila. Cell 139, 416–427 (2009).

    Article  CAS  Google Scholar 

  23. Claridge-Chang, A. et al. Writing memories with light-addressable reinforcement circuitry. Cell 139, 405–415 (2009).

    Article  CAS  Google Scholar 

  24. LaFerriere, H. et al. Genetic dissociation of ethanol sensitivity and memory formation in Drosophila melanogaster. Genetics 178, 1895–1902 (2008).

    Article  CAS  Google Scholar 

  25. Hu, X., Lee, E.C. & Baker, N.E. Molecular analysis of scabrous mutant alleles from Drosophila melanogaster indicates a secreted protein with two functional domains. Genetics 141, 607–617 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Devineni, A.V. & Heberlein, U. Preferential ethanol consumption in Drosophila models features of addiction. Curr. Biol. 19, 2126–2132 (2009).

    Article  CAS  Google Scholar 

  27. Laviolette, S.R. & van der Kooy, D. The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nat. Rev. Neurosci. 5, 55–65 (2004).

    Article  CAS  Google Scholar 

  28. Pautassi, R.M., Molina, J.C. & Spear, N. Infant rats exhibit aversive learning mediated by ethanol's orosensory effects but are positively reinforced by ethanol's post-ingestive effects. Pharmacol. Biochem. Behav. 88, 393–402 (2008).

    Article  CAS  Google Scholar 

  29. Cunningham, C.L. et al. Ethanol-conditioned place preference reduced in dopamine D2 receptor–deficient mice. Pharmacol. Biochem. Behav. 67, 693–699 (2000).

    Article  CAS  Google Scholar 

  30. Risinger, F.O., Freeman, P.A., Greengard, P. & Fienberg, A.A. Motivational effects of ethanol in DARPP-32 knock-out mice. J. Neurosci. 21, 340–348 (2001).

    Article  CAS  Google Scholar 

  31. Walker, B.M. & Ettenberg, A. Intracerebroventricular ethanol-induced conditioned place preference are prevented by fluphenazine infusions into the nucleus accumbens of rats. Behav. Neurosci. 121, 401–410 (2007).

    Article  CAS  Google Scholar 

  32. Gremel, C.M. & Cunningham, C.L. Involvement of amygdala dopamine and nucleus accumbens NMDA receptors in ethanol-seeking behavior in mice. Neuropsychopharmacology 34, 1443–1453 (2008).

    Article  Google Scholar 

  33. Schultz, W. Getting formal with dopamine and reward. Neuron 36, 241–263 (2002).

    Article  CAS  Google Scholar 

  34. 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 

  35. Kim, Y.C., Lee, H.G. & Han, K.A. D1 dopamine receptor dDA1 is required in the mushroom body neurons for aversive and appetitive learning in Drosophila. J. Neurosci. 27, 7640–7647 (2007).

    Article  CAS  Google Scholar 

  36. Zars, T., Fischer, M., Schultz, R. & Heisenberg, M. Localization of a short-term memory in Drosophila. Science 288, 672–675 (2000).

    Article  CAS  Google Scholar 

  37. Dubnau, J., Grady, L., Kitamoto, T. & Tully, T. Disruption of neurotransmission in Drosophila mushroom body blocks retrieval but not acquisition of memory. Nature 411, 476–480 (2001).

    Article  CAS  Google Scholar 

  38. McGuire, S.E., Le, P.T. & Davis, R.L. The role of Drosophila mushroom body signaling in olfactory memory. Science 293, 1330–1333 (2001).

    Article  CAS  Google Scholar 

  39. King, I. et al. Drosophila tao controls mushroom body development and ethanol-stimulated behavior through par-1. J. Neurosci. 31, 1139–1148 (2011).

    Article  CAS  Google Scholar 

  40. Akalal, D.B., Yu, D. & Davis, R.L. A late-phase, long-term memory trace forms in the γ neurons of Drosophila mushroom bodies after olfactory classical conditioning. J. Neurosci. 30, 16699–166708 (2010).

    Article  CAS  Google Scholar 

  41. Isabel, G., Pascual, A. & Preat, T. Exclusive consolidated memory phases in Drosophila. Science 304, 1024–1027 (2004).

    Article  CAS  Google Scholar 

  42. Brand, A.H., Manuokian, A.S. & Perrimon, N. Ectopic expression in Drosophila. Methods Cell Biol. 44, 635–654 (1994).

    Article  CAS  Google Scholar 

  43. Berger, K.H. et al. Ethanol sensitivity and tolerance in long-term memory mutants of Drosophila melanogaster. Alcohol. Clin. Exp. Res. 32, 895–908 (2008).

    Article  CAS  Google Scholar 

  44. Hardie, S.L. & Hirsh, J. An improved method for the separation and detection of biogenic amines in adult Drosophila brain extract by high performance liquid chromatography. J. Neurosci. Methods 153, 243–249 (2006).

    Article  CAS  Google Scholar 

  45. Aso, Y. et al. The mushroom body of adult Drosophila characterized by GAL4 drivers. J. Neurogenet. 23, 156–172 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Waddell, J. Levine, M. Sokolowski, A. Barron and members of the Heberlein laboratory for reagents, input and advice, and S. Birman (Developmental Biology Institute of Marseilles-Luminy), F. Wolf (Gallo Institute), S. Sweeney (University of York), K. Kaiser (Glasgow University), N. Baker (Albert Einstein College of Medicine) and the Bloomington Stock Center for flies. Funding was provided by a Heart and Stroke Foundation of Canada Research Fellowship to K.R.K. and the US National Institutes of Health to U.H.

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Authors and Affiliations

  1. Department of Anatomy, University of California, San Francisco, California, USA

    Karla R Kaun, Reza Azanchi, Zaw Maung & Ulrike Heberlein

  2. Department of Biology, University of Virginia, Charlottesville, Virginia, USA

    Jay Hirsh

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  1. Karla R Kaun
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  2. Reza Azanchi
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Contributions

K.R.K. conceived, conducted and interpreted the experiments, performed data analysis, and co-wrote the paper. R.A. assisted with the behavior experiments. Z.M. conducted control experiments. J.H. performed high-performance liquid chromatography experiments. U.H. conceived and interpreted experiments and co-wrote the paper.

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Correspondence to Karla R Kaun or Ulrike Heberlein.

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Kaun, K., Azanchi, R., Maung, Z. et al. A Drosophila model for alcohol reward. Nat Neurosci 14, 612–619 (2011). https://doi.org/10.1038/nn.2805

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