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.

  • Original Article
  • Published:

Drosophila modifier screens to identify novel neuropsychiatric drugs including aminergic agents for the possible treatment of Parkinson’s disease and depression

Molecular Psychiatry volume 19, pages 235–242 (2014)Cite this article

Subjects

Abstract

Small molecules that increase the presynaptic function of aminergic cells may provide neuroprotection in Parkinson’s disease (PD) as well as treatments for attention deficit hyperactivity disorder (ADHD) and depression. Model genetic organisms such as Drosophila melanogaster may enhance the detection of new drugs via modifier or ‘enhancer/suppressor’ screens, but this technique has not been applied to processes relevant to psychiatry. To identify new aminergic drugs in vivo, we used a mutation in the Drosophila vesicular monoamine transporter (dVMAT) as a sensitized genetic background and performed a suppressor screen. We fed dVMAT mutant larvae ∼1000 known drugs and quantitated rescue (suppression) of an amine-dependent locomotor deficit in the larva. To determine which drugs might specifically potentiate neurotransmitter release, we performed an additional secondary screen for drugs that require presynaptic amine storage to rescue larval locomotion. Using additional larval locomotion and adult fertility assays, we validated that at least one compound previously used clinically as an antineoplastic agent potentiates the presynaptic function of aminergic circuits. We suggest that structurally similar agents might be used to development treatments for PD, depression and ADHD, and that modifier screens in Drosophila provide a new strategy to screen for neuropsychiatric drugs. More generally, our findings demonstrate the power of physiologically based screens for identifying bioactive agents for select neurotransmitter systems.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Chaudhry FA, Boulland JL, Jenstad M, Bredahl MK, Edwards RH . Pharmacology of neurotransmitter transport into secretory vesicles. Handb Exp Pharmacol 2008; 184: 77–106.

    Article  CAS  Google Scholar 

  2. Hastings TG, Lewis DA, Zigmond MJ . Reactive dopamine metabolites and neurotoxicity: implications for Parkinson’s disease. Adv Exp Med Biol 1996; 387: 97–106.

    Article  CAS  Google Scholar 

  3. Guillot TS, Miller GW . Protective actions of the vesicular monoamine transporter 2 (VMAT2) in monoaminergic neurons. Mol Neurobiol 2009; 39: 149–170.

    Article  CAS  Google Scholar 

  4. Caudle WM, Richardson JR, Wang MZ, Taylor TN, Guillot TS, McCormack AL et al. Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration. J Neurosci 2007; 27: 8138–8148.

    Article  CAS  Google Scholar 

  5. Sang TK, Chang HY, Lawless GM, Ratnaparkhi A, Mee L, Ackerson LC et al. A Drosophila model of mutant human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine. J Neurosci 2007; 27: 981–992.

    Article  CAS  Google Scholar 

  6. Lawal HO, Chang HY, Terrell AN, Brooks ES, Pulido D, Simon AF et al. The Drosophila vesicular monoamine transporter reduces pesticide-induced loss of dopaminergic neurons. Neurobiol Dis 2010; 40: 102–112.

    Article  CAS  PubMed Central  Google Scholar 

  7. Freis ED . Mental depression in hypertensive patients treated for long periods with high doses of reserpine. N Engl J Med 1954; 251: 1006–1008.

    Article  CAS  Google Scholar 

  8. Fukui M, Rodriguiz RM, Zhou J, Jiang SX, Phillips LE, Caron MG et al. Vmat2 heterozygous mutant mice display a depressive-like phenotype. J Neurosci 2007; 27: 10520–10529.

    Article  CAS  PubMed Central  Google Scholar 

  9. Chang H-Y, Grygoruk A, Brooks ES, Ackerson LC, Maidment NT, Bainton RJ et al. Over-expression of the Drosophila vesicular monoamine transporter increases motor activity and courtship but decreases the behavioral response to cocaine. Mol Psychiatry 2006; 11: 99–113.

    Article  CAS  PubMed Central  Google Scholar 

  10. Sulzer D, Sonders MS, Poulsen NW, Galli A . Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol 2005; 75: 406–433.

    Article  CAS  PubMed Central  Google Scholar 

  11. Bier E . Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet 2005; 6: 9–23.

    Article  CAS  Google Scholar 

  12. Simon AF, Daniels R, Romero-Calderón R, Grygoruk A, Chang HY, Najibi R et al. Drosophila vesicular monoamine transporter mutants can adapt to reduced or eliminated vesicular stores of dopamine and serotonin. Genetics 2009; 181: 525–541.

    Article  CAS  PubMed Central  Google Scholar 

  13. Monastirioti M, Linn CEJ, White K . Characterization of Drosophila tyramine beta-hydroxylase gene and isolation of mutant flies lacking octopamine. J Neurosci 1996; 16: 3900–3911.

    Article  CAS  Google Scholar 

  14. Fox LE, Soll DR, Wu CF . Coordination and modulation of locomotion pattern generators in Drosophila larvae: effects of altered biogenic amine levels by the tyramine Beta hydroxlyase mutation. J Neurosci 2006; 26: 1486–1498.

    Article  CAS  PubMed Central  Google Scholar 

  15. Suo S, Kimura Y, Van Tol HH . Starvation induces cAMP response element-binding protein-dependent gene expression through octopamine-Gq signaling in Caenorhabditis elegans. J Neurosci 2006; 26: 10082–10090.

    Article  CAS  Google Scholar 

  16. Pizzo AB, Karam CS, Zhang Y, Yano H, Freyberg RJ, Karam DS et al. The membrane-raft protein Flotillin-1 is essential in dopamine neurons for amphetamine-induced behavior in Drosophila. Mol Psychiatry, advance online publication, 19 June 2012; doi:10.1038/mp.2012.82 (e-pub ahead of print).

    Article  Google Scholar 

  17. Gorczyca MG, Budnik V, White K, Wu CF . Dual muscarinic and nicotinic action on a motor program in Drosophila. J Neurobiol 1991; 22: 391–404.

    Article  CAS  Google Scholar 

  18. Rohrbough J, O'Dowd DK, Baines RA, Broadie K . Cellular bases of behavioral plasticity: establishing and modifying synaptic circuits in the Drosophila genetic system. J Neurobiol 2003; 54: 254–271.

    Article  CAS  Google Scholar 

  19. Bonfante V, Santoro A, Viviani S, Valagussa P, Bonadonna G . ABVD in the treatment of Hodgkin's disease. Semin Oncol 1992; 19 (2 Suppl 5): 38–44, discussion 44-35.

    CAS  PubMed  Google Scholar 

  20. Monastirioti M . Distinct octopamine cell population residing in the CNS abdominal ganglion controls ovulation in Drosophila melanogaster. Dev Biol 2003; 264: 38–49.

    Article  CAS  Google Scholar 

  21. Middleton A, Nongthomba U, Parry K, Sweeney ST, Sparrow JC, Elliott CJ . Neuromuscular organization and aminergic modulation of contractions in the Drosophila ovary. BMC Biol 2006; 4: 17.

    Article  PubMed Central  Google Scholar 

  22. Lee HG, Seong CS, Kim YC, Davis RL, Han KA . Octopamine receptor OAMB is required for ovulation in Drosophila melanogaster. Dev Biol 2003; 264: 179–190.

    Article  CAS  Google Scholar 

  23. Lee HG, Rohila S, Han KA . The octopamine receptor OAMB mediates ovulation via Ca2+/calmodulin-dependent protein kinase II in the Drosophila oviduct epithelium. PLoS One 2009; 4: e4716.

    Article  PubMed Central  Google Scholar 

  24. Willard SS, Koss CM, Cronmiller C . Chronic cocaine exposure in Drosophila: life, cell death and oogenesis. Dev Biol 2006; 296: 150–163.

    Article  Google Scholar 

  25. Unoki S, Matsumoto Y, Mizunami M . Participation of octopaminergic reward system and dopaminergic punishment system in insect olfactory learning revealed by pharmacological study. Eur J Neurosci 2005; 22: 1409–1416.

    Article  Google Scholar 

  26. Ohtani A, Arai Y, Ozoe F, Ohta H, Narusuye K, Huang J et al. Molecular cloning and heterologous expression of an alpha-adrenergic-like octopamine receptor from the silkworm Bombyx mori. Insect Mol Biol 2006; 15: 763–772.

    Article  Google Scholar 

  27. Radad K, Gille G, Rausch WD . Short review on dopamine agonists: insight into clinical and research studies relevant to Parkinson’s disease. Pharmacol Rep 2005; 57: 701–712.

    CAS  PubMed  Google Scholar 

  28. Saraswati S, Fox LE, Soll DR, Wu CF . Tyramine and octopamine have opposite effects on the locomotion of Drosophila larvae. J Neurobiol 2004; 58: 425–441.

    Article  CAS  PubMed Central  Google Scholar 

  29. Pourahmad J, Amirmostofian M, Kobarfard F, Shahraki J . Biological reactive intermediates that mediate dacarbazine cytotoxicity. Cancer Chemother Pharmacol 2009; 65: 89–96.

    Article  CAS  Google Scholar 

  30. Gaidhu MP, Fediuc S, Ceddia RB . 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside-induced AMP-activated protein kinase phosphorylation inhibits basal and insulin-stimulated glucose uptake, lipid synthesis, and fatty acid oxidation in isolated rat adipocytes. J Biol Chem 2006; 281: 25956–25964.

    Article  CAS  Google Scholar 

  31. Stork T, Engelen D, Krudewig A, Silies M, Bainton RJ, Klambt C . Organization and function of the blood-brain barrier in Drosophila. J Neurosci 2008; 28: 587–597.

    Article  CAS  Google Scholar 

  32. Greer CL, Grygoruk A, Patton DE, Ley B, Romero-Calderón R, Chang H-Y et al. A splice variant of the Drosophila vesicular monoamine transporter contains a conserved trafficking domain and functions in the storage of dopamine, serotonin and octopamine. J Neurobiol 2005; 64: 239–258.

    Article  CAS  Google Scholar 

  33. Cubeddu LX, Hoffmann IS, Fuenmayor NT, Malave JJ . Changes in serotonin metabolism in cancer patients: its relationship to nausea and vomiting induced by chemotherapeutic drugs. Br J Cancer 1992; 66: 198–203.

    Article  CAS  PubMed Central  Google Scholar 

  34. Cubeddu LX . Serotonin mechanisms in chemotherapy-induced emesis in cancer patients. Oncology 1996; 53 (Suppl 1): 18–25.

    Article  Google Scholar 

  35. Boon H, Bosselaar M, Praet SF, Blaak EE, Saris WH, Wagenmakers AJ et al. Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients. Diabetologia 2008; 51: 1893–1900.

    Article  CAS  Google Scholar 

  36. Mosharov EV, Larsen KE, Kanter E, Phillips KA, Wilson K, Schmitz Y et al. Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 2009; 62: 218–229.

    Article  CAS  PubMed Central  Google Scholar 

  37. Glatt CE, Wahner AD, White DJ, Ruiz-Linares A, Ritz B . Gain-of-function haplotypes in the vesicular monoamine transporter promoter are protective for Parkinson disease in women. Hum Mol Genet 2006; 15: 299–305.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Institute of Mental Health [MH076900], the National Institute of Environmental Health and Safety [ES015747] and NARSAD ‘The Brain and Behavior Research Foundation’ (to DEK), additional funding from a National Institute of Environmental Health and Safety program project grant [ES016732, MF Chesselet, PI) and training fellowships from the National Institute of Environmental Health and Safety (to HOL and AT). The authors thank Drs Lori Altshuler and Roland Bainton for helpful suggestions on the manuscript.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Biobehavioral Sciences, Gonda Center for Neuroscience and Genetics Research, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    H O Lawal, A Terrell, H A Lam, C Djapri, J Jang, R Hadi, L Roberts, V Shahi, M-T Chou, T Biedermann, B Huang, G M Lawless, N T Maidment & D E Krantz

Authors
  1. H O Lawal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Terrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H A Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Djapri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Hadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V Shahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M-T Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T Biedermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. B Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. G M Lawless
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. N T Maidment
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. D E Krantz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D E Krantz.

Ethics declarations

Competing interests

The authors declare no conflict of interests.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lawal, H., Terrell, A., Lam, H. et al. Drosophila modifier screens to identify novel neuropsychiatric drugs including aminergic agents for the possible treatment of Parkinson’s disease and depression. Mol Psychiatry 19, 235–242 (2014). https://doi.org/10.1038/mp.2012.170

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2012.170

Keywords

This article is cited by

Search

Advanced search

Quick links