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Time flies like an arrow. Fruit flies like crack?

The Pharmacogenomics Journal volume 1, pages 97–100 (2001)Cite this article

As opposed to the human population, addiction to drugs of abuse is not a great problem in insects, at least as far as we are aware. Nonetheless, the fruit fly, Drosophila melanogaster, has recently shown potential as a model organism for molecular genetic studies of response pathways to several human drugs of abuse, including cocaine, alcohol, and nicotine.1,2,3 These studies are possible since these drugs induce motor behaviors in insects that are strikingly similar to those induced in higher animals. In addition, repeated drug exposures result in plastic changes in responsiveness; tolerance to alcohol,4 and reverse tolerance, or sensitization, to repeated exposures to cocaine.1 Sensitization is of interest in that it represents an animal model for a long-lasting behavioral change that appears linked to the long-lasting drug craving in animals and humans,5 and also has potential links to mental disorders such as schizophrenia.6 Here we will focus on studies of sensitization in Drosophila, emphasizing an unexpected link between sensitization and the circadian gene family.

The real strength of the Drosophila model is in the potential for identification of novel pathways that would be much more difficult to uncover in vertebrates. Recent studies have identified two additional pathways required for cocaine sensitization in Drosophila. First, the trace amine tyramine is essential for sensitization, as shown by a mutant line, inactive (iav), that is defective in sensitization. This line shows reduced tyramine levels, and sensitization can be restored to iav by selective feeding of tyramine.13 An active role for tyramine is inferred from the finding that activity of the tyramine biosynthetic enzyme, tyrosine decarboxylase (TDC), is induced subsequent to a single cocaine exposure, with kinetics that closely match the time course for induction of sensitization following a single cocaine exposure. Tyramine can cause vertebrate and Drosophila amine transporters to reverse polarity,14,15 dumping amines into the synaptic cleft, giving a potential mechanism by which tyramine could lead to transient increases in released dopamine associated with sensitization in vertebrates.

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References

  1. McClung C, Hirsh J . Stereotypic behavioral responses to free-base cocaine and the development of behavioral sensitization in Drosophila melanogaster Curr Biol 1998 8: 109–112

    Article  CAS  Google Scholar 

  2. Moore MS et al . Ethanol intoxication in Drosophila: genetic and pharmacological evidence for regulation by the cAMP signaling pathway Cell 1998 93: 997–1007

    Article  CAS  Google Scholar 

  3. Bainton RJ et al . Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila Curr Biol 2000 10: 187–194

    Article  CAS  Google Scholar 

  4. Scholz H, Ramond J, Singh CM, Heberlein U . Functional ethanol tolerance in Drosophila Neuron 2000 28: 261–271

    Article  CAS  Google Scholar 

  5. Robinson TE, Berridge KE . The psychology and neurobiology of addiction: an incentive-sensitization view Addiction 2000 (Suppl 2) 95: S91–S117

    PubMed  Google Scholar 

  6. Lieberman JA, Sheitman BB, Kinon BJ . Neurochemical sensitization in the pathophysiology of schizophrenia: deficits and dysfunction in neuronal regulation and plasticity Neuropsychopharmacology 1997 17: 205–229

    Article  CAS  Google Scholar 

  7. Wolf ME . The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants Prog Neurobiol 1998 54: 679–720

    Article  CAS  Google Scholar 

  8. White FJ, Hu X-T, Henry DJ, Zhang S-F . In: Hammer RP (ed) The Neurobiology of Cocaine: Cellular and Molecular Mechanisms CRC Press: Boca Raton 1995 pp 81–98

  9. Vanderschuren LJ, Kalivas PW . Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies Psychopharmacology (Berl) 2000 151: 99–120

    Article  CAS  Google Scholar 

  10. Nestler EJ, Aghajanian GK . Molecular and cellular basis of addiction Science 1997 278: 58–63

    Article  CAS  Google Scholar 

  11. 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 2000 10: 211–214

    Article  CAS  Google Scholar 

  12. Park S, Sedore S, Cronmiller C, Hirsh J . PKAII-deficient Drosophila are viable but show developmental, circadian and drug response phenotypes J Biol Chem 2000 275: 20588–20596

    Article  CAS  Google Scholar 

  13. McClung C, Hirsh J . The trace amine tyramine is essential for sensitization to cocaine in Drosophila Curr Biol 1999 9: 853–860

    Article  CAS  Google Scholar 

  14. Bönisch H, Trendelenburg U. In: Trendelenburg U, Weiner N (eds) Catecholamines. Handbook of Experimental Pharmacology Springer-Verlag: Berlin 1988 pp 247–248

  15. Porzgen P, Park SK, Hirsh J, Sonders MS, Amara SG . The antidepressant-sensitive dopamine transporter in Drosophila melanogaster: a primordial carrier for catecholamines Mol Pharmacol 2001 59: 83–95

    Article  CAS  Google Scholar 

  16. Andretic R, Chaney S, Hirsh J . Circadian genes are required for cocaine sensitization in Drosophila Science 1999 285: 1066–1068

    Article  CAS  Google Scholar 

  17. Scully AL, Kay SA . Time flies for Drosophila Cell 2000 100: 297–300

    Article  CAS  Google Scholar 

  18. Gaytan O, Swann A, Dafny N . Diurnal differences in rat’s motor response to amphetamine Eur J Pharmacol 1998 345: 119–128

    Article  CAS  Google Scholar 

  19. Gaytan O, Swann A, Dafny N . Time-dependent differences in the rat’s motor response to amphetamine Pharmacol Biochem Behav 1998 59: 459–467

    Article  CAS  Google Scholar 

  20. Gaytan O, Lewis C, Swann A, Dafny N . Diurnal differences in amphetamine sensitization Eur J Pharmacol 1999 374: 1–9

    Article  CAS  Google Scholar 

  21. Baird TJ, Gauvin D . Characterization of cocaine self-administration and pharmacokinetics as a function of time of day in the rat Pharmacol Biochem Behav 2000 65: 289–99

    Article  CAS  Google Scholar 

  22. White W, Feldon J, Heidbreder CA, White IM . Effects of administering cocaine at the same versus varying times of day on circadian activity patterns and sensitization in rats Behav Neurosci 2000 114: 972–982

    Article  CAS  Google Scholar 

  23. Honma K, Honma S, Hiroshige T . Disorganization of the rat activity rhythm by chronic treatment with methamphetamine Physiol Behav 1986 38: 687–695

    Article  CAS  Google Scholar 

  24. Honma K, Honma S, Hiroshige T . Activity rhythms in the circadian domain appear in suprachiasmatic nuclei lesioned rats given methamphetamine Physiol Behav 1987 40: 767–774

    Article  CAS  Google Scholar 

  25. Honma S, Honma K . Phase-dependent phase shift of methamphetamine-induced circadian rhythm by haloperidol in SCN-lesioned rats Brain Res 1995 674: 283–290

    Article  CAS  Google Scholar 

  26. Andretic R, Hirsh J . Circadian modulation of dopamine receptor responsiveness in Drosophila melanogaster Proc Natl Acad Sci USA 2000 97: 1873–1878

    Article  CAS  Google Scholar 

  27. Gekakis N et al . Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL Science 1995 270: 811–815

    Article  CAS  Google Scholar 

  28. Myers MP, Wager-Smith K, Wesley CS, Young MW, Sehgal A . Positional cloning and sequence analysis of the Drosophila clock gene, timeless Science 1995 270: 805–808

    Article  CAS  Google Scholar 

  29. Sehgal A, Price JL, Man B, Young MW . Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless Science 1994 263: 1603–1606

    Article  CAS  Google Scholar 

  30. Vosshall LB, Price JL, Sehgal A, Saez L, Young, MW . Block in nuclear localization of period protein by a second clock mutation, timeless Science 1994 263: 1606–1609

    Article  CAS  Google Scholar 

  31. Saez L, Young MW . Regulation of nuclear entry of the Drosophila clock proteins period and timeless Neuron 1996 17: 911–920

    Article  CAS  Google Scholar 

  32. Rothenfluh A, Young MW, Saez L . A TIMELESS-independent function for PERIOD proteins in the Drosophila clock Neuron 2000 26: 505–514

    Article  CAS  Google Scholar 

  33. Burnette WB et al . Human norepinephrine transporter kinetics using rotating disk electrode voltammetry Anal Chem 1996 68: 2932–2938

    Article  CAS  Google Scholar 

  34. Chen N, Trowbridge CG, Justice JB Jr . Voltammetric studies on mechanisms of dopamine efflux in the presence of substrates and cocaine from cells expressing human norepinephrine transporter J Neurochem 1998 71: 653–665

    Article  CAS  Google Scholar 

  35. Buckley KM, Melikian HE, Provoda CJ, Waring MT . Regulation of neuronal function by protein trafficking: a role for the endosomal pathway J Physiol (Lond) 2000 525 Pt 1: 11–19

    Article  Google Scholar 

  36. Blakely RD, Bauman AL . Biogenic amine transporters: regulation in flux Curr Opin Neurobiol 2000 10: 328–336

    Article  CAS  Google Scholar 

  37. Arakawa S et al . Cloning, localization, and permanent expression of a Drosophila octopamine receptor Neuron 1990 4: 343–354

    Article  CAS  Google Scholar 

  38. Robb S et al . Agonist-specific coupling of a cloned Drosophila octopamine/tyramine receptor to multiple second messenger systems EMBO J 1994 13: 1325–1330

    Article  CAS  Google Scholar 

  39. Sidiropoulou K et al . Basal hyperactivity and behavioral sensitization to cocaine in clock mutant mice SFN Abstracts 2000 26: 525.

    Google Scholar 

Download references

Acknowledgements

Work from my laboratory mentioned in this review is supported by NIH grant GM/DA 27813. I thank the current members of my laboratory and Colleen McClung for helpful comments on this manuscript.

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  1. Department of Biology, University of Virginia, Charlottesville, VA, USA

    J Hirsh

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Hirsh, J. Time flies like an arrow. Fruit flies like crack?. Pharmacogenomics J 1, 97–100 (2001). https://doi.org/10.1038/sj.tpj.6500020

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