Zebrafish Biogenic Amine Transporters and Behavior in Novel Environments: Targets of Reuptake Inhibitors and Pesticide Action as Tools for Neurotoxicology Research

  • Georgianna G. Gould
Part of the Neuromethods book series (NM, volume 52)


Central monoamine systems (e.g., dopamine, serotonin, norepinephrine) are associated with motivation, locomotion, social behavior, emotion, and mood. Biogenic amine transporters regulate neurotransmission by removing neurotransmitters from synapses and extracellular fluid. Despite evolutionary divergence, teleost fish and mammalian transporter proteins appear similar, particularly at active binding sites. However, it is not clear if the similarities extend to functional responses, reuptake-inhibiting drugs, or involvement in delayed neurotoxic responses to pesticide exposures. Under certain exposure conditions, alterations in expression and function of these transporters may be more sensitive biomarkers of pesticide exposure or neurodegenerative disease risk than acetylcholinesterase inhibition. Zebrafish (Danio rerio) behavioral assays targeting associative responses such as anxiety are useful as pharmacological and toxicological screens, or for studying modulation of behavior by central neurotransmitter systems. In novel environments, zebrafish go to tank bottoms and dark backgrounds, a stereotypical behavior (attributed to predator anxiety) forming the basis of the novel light/dark aquatic plus maze characterized in this chapter. Such behavioral paradigms are an essential component to establish zebrafish as pharmacological and toxicological research models. Herein adult zebrafish are exposed to reuptake inhibitors and representative organochloride, organophosphate, or pyrethroid pesticides at 1 μg day−1 for 21 days, tested for anxious response in the light/dark plus maze, then assayed for dopamine and serotonin transporter density by radioligand binding. Exposures to these compounds variably affect dopamine and serotonin transporter density and alter behavior in the maze as compared to controls.

Key words

Dopamine serotonin norepinephrine monoamine systems amine transporters acetylcholinesterase inhibition mammalian homology SERT DAT transporter mechanisms Parkinson’s disease pesticide light-dark plus-maze expression regulation toxicology 



This study was funded by a NIOSH ERC Pilot Project research training grant awarded by the Southwest Center for Occupational and Environmental Health at the University of Texas School of Public Health in Houston (Grant No. T42CCT610417 from NIOSH/CDC to SWCOEH). I would like to thank Dr. Alan Frazer for sponsoring this research in his laboratory at UTHSCSA, Ezra Scientific LLC for technical assistance in developing and building the zebrafish offset cross maze, and Jim Sackerman, Ngoc Nhung Nguyen, Adam Long, Kelly Lawless, and Dr. Bob Benno at William Paterson University, New Jersey, for their technical assistance and intellectual input in validating the dive tank and light/dark plus maze tests.


  1. 1.
    Baldereschi, M., Di Carlo, A., Vanni, P., Ghetti, A., Carbonin, P., Amaducci, L. & Inzitari, D. (2003) Lifestyle-related risk factors for Parkinson’s disease: a population-based study. Acta Neurol Scand 108, 239–244.PubMedCrossRefGoogle Scholar
  2. 2.
    Hubble, J. P., Cao, T., Hassanein, R. E., Neuberger, J. S. & Koller, W. C. (1993) Risk factors for Parkinson’s disease. Neurology 43, 1693–1697.PubMedCrossRefGoogle Scholar
  3. 3.
    Kanthasamy, A. G., Kitazawa, M., Kanthasamy, A. & Anantharam, V. (2005) Dieldrin-induced neurotoxicity: relevance to Parkinson’s disease pathogenesis. Neurotoxicology 26, 701–719.PubMedCrossRefGoogle Scholar
  4. 4.
    Petrovitch, H., Ross, G. W., Abbott, R. D., Sanderson, W. T., Sharp, D. S., Tanner, C. M., Masaki, K. H., Blanchette, P. L., Popper, J. S., Foley, D., Launer, L. & White, L. R. (2002) Plantation work and risk of Parkinson disease in a population-based longitudinal study. Arch Neurol 59, 1787–1792.PubMedCrossRefGoogle Scholar
  5. 5.
    Ascherio, A., Chen, H., Weisskopf, M. G., O’Reilly, E., McCullough, M. L., Calle, E. E., Schwarzschild, M. A. & Thun, M. J. (2006) Pesticide exposure and risk for Parkinson’s disease. Ann Neurol 60, 197–203.PubMedCrossRefGoogle Scholar
  6. 6.
    Brown, T. P., Rumsby, P. C., Capleton, A. C., Rushton, L. & Levy, L. S. (2006) Pesticides and Parkinson’s disease – is there a link? Environ Health Perspect 114(2), 156–164, Feb.PubMedCrossRefGoogle Scholar
  7. 7.
    Hatcher, J. M., Pennell, K. D. & Miller, G. W. (2008) Parkinson’s disease and pesticides: a toxicological perspective. Trends Pharmacol Sci 29, 322–329.PubMedCrossRefGoogle Scholar
  8. 8.
    Shepherd, K. R., Lee, E. S., Schmued, L., Jiao, Y., Ali, S. F., Oriaku, E. T., Lamango, N. S., Soliman, K. F. & Charlton, C. G. (2006) The potentiating effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on paraquat-induced neurochemical and behavioral changes in mice. Pharmacol Biochem Behav 83, 349–359.PubMedCrossRefGoogle Scholar
  9. 9.
    Gorell, J. M., Johnson, C. C., Rybicki, B. A., Peterson, E. L. & Richardson, R. J. (1998) The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50, 1346–1350.PubMedCrossRefGoogle Scholar
  10. 10.
    Alexander, B. H., Burns, C. J., Bartels, M. J., Acquavella, J. F., Mandel, J. S., Gustin, C. & Baker, B. (2006) Chlorpyrifos exposure in farm families: results from the farm family exposure study. J Exp Sci Environ Epidemiol 16, 447–456.CrossRefGoogle Scholar
  11. 11.
    Bouvier, G., Blanchard, O., Momas, I. & Seta, N. (2006a) Environmental and biological monitoring of exposure to organophosphorus pesticides: application to occupationally and non-occupationally exposed adult populations. J Exp Sci Environ Epidemiol 16(5), 417–426.CrossRefGoogle Scholar
  12. 12.
    Bouvier, G., Blanchard, O., Momas, I. & Seta, N. (2006b) Pesticide exposure of non-occupationally exposed subjects compared to some occupational exposure: a French pilot study. Sci Total Environ 366, 74–91.PubMedCrossRefGoogle Scholar
  13. 13.
    Fenske, R. A., Lu, C., Curl, C. L., Shirai, J. H. & Kissel, J. C. (2005) Biologic monitoring to characterize organophosphorus pesticide exposure among children and workers: an analysis of recent studies in Washington State. Environ Health Perspect 113, 1651–1657.PubMedCrossRefGoogle Scholar
  14. 14.
    Jirachaiyabhas, V., Visuthismajarn, P., Hore, P. & Robson, M. G. (2004) Organophosphate pesticide exposures of traditional and integrated pest management farmers from working air conditions: a case study in Thailand. Int J Occup Environ Health 10, 289–295.PubMedGoogle Scholar
  15. 15.
    Coghlan, A. (2005) Exposure to pesticides can cause Parkinson’s. New Scientist 2501, 14.Google Scholar
  16. 16.
    Costello, S., Cockburn, M., Bronstein, J., Zhang, X. & Ritz, B. (2009) Parkinson’s disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. Am J Epidemiol 169(8), 919–926, Apr 15.PubMedCrossRefGoogle Scholar
  17. 17.
    Kamel, F., Tanner, C., Umbach, D., Hoppin, J., Alavanja, M., Blair, A., Comyns, K., Goldman, S., Korell, M., Langston, J., Ross, G. & Sandler, D. (2006) Pesticide exposure and self-reported Parkinson’s disease in the agricultural health study. Am J Epidemiol 165, 364–374.PubMedCrossRefGoogle Scholar
  18. 18.
    Kamel, F. & Hoppin, J. A. (2004) Association of pesticide exposure with neurologic dysfunction and disease. Environ Health Perspect 112, 950–958.PubMedCrossRefGoogle Scholar
  19. 19.
    Seidler, A., Hellenbrand, W., Robra, B. P., Vieregge, P., Nischan, P., Joerg, J., Oertel, W. H., Ulm, G. & Schneider, E. (1996) Possible environmental, occupational, and other etiologic factors for Parkinson’s disease: a case-control study in Germany. Neurology 46, 1275–1284.PubMedCrossRefGoogle Scholar
  20. 20.
    Abou-Donia, M. B., Wilmarth, K. R., Jensen, K. F., Oehme, F. W. & Kurt, T. L. (1996) Neurotoxicity resulting from coexposure to pyridostigmine bromide, deet, and permethrin: implications of Gulf War chemical exposures. J Toxicol Environ Health 48, 35–56.PubMedCrossRefGoogle Scholar
  21. 21.
    Chen, C. & Lu, C. (2002) An analysis of the combined effects of organic toxicants. Sci Total Environ 289, 123–132.PubMedCrossRefGoogle Scholar
  22. 22.
    Betarbet, R., Sherer, T. B., MacKenzie, G., Garcia-Osuna, M., Panov, A. V. & Greenamyre, J. I. (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3, 1301–1306.PubMedCrossRefGoogle Scholar
  23. 23.
    Betarbet, R., Sherer, T. B. & Greenamyre, J. T. (2002) Animal models of Parkinson’s disease. Bioessays 24, 308–318.PubMedCrossRefGoogle Scholar
  24. 24.
    Cory-Slechta, D. A., Thiruchelvam, M., Richfield, E. K., Barlow, B. K. & Brooks, A. I. (2005) Developmental pesticide exposures and the Parkinson’s disease phenotype. Birth Defects Res A Clin Mol Teratol 73, 136–139.PubMedCrossRefGoogle Scholar
  25. 25.
    Beseler, C. L., Stallones, L., Hoppin, J. A., Alavanja, M. C., Blair, A., Keefe, T. & Kamel, F. (2008) Depression and pesticide exposures among private pesticide applicators enrolled in the Agricultural Health Study. Environ Health Perspect 116, 1713–1719.PubMedCrossRefGoogle Scholar
  26. 26.
    Salvi, R. M., Lara, D. R., Ghisolfi, E. S., Portela, L. V., Dias, R. D. & Souza, D. O. (2003) Neuropsychiatric evaluation in subjects chronically exposed to organophosphate pesticides. Toxicol Sci 72, 267–271.PubMedCrossRefGoogle Scholar
  27. 27.
    Stallones, L. & Beseler, C. (2002) Pesticide poisoning and depressive symptoms among farm residents. Ann Epid 12, 389–394.CrossRefGoogle Scholar
  28. 28.
    Aldridge, J. E., Levin, E. D., Seidler, F. J. & Slotkin, T. A. (2005a) Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression. Environ Health Perspect 113, 527–531.PubMedCrossRefGoogle Scholar
  29. 29.
    Alavanja, M. C., Hoppin, J. A. & Kamel, F. (2004) Health effects of chronic pesticide exposure: cancer and neurotoxicity. Annu Rev Public Health 25, 155–197.PubMedCrossRefGoogle Scholar
  30. 30.
    Sánchez-Santed, F., Cañadas, F., Flores, P., López-Grancha, M. & Cardona, D. (2004) Long-term functional neurotoxicity of paraoxon and chlorpyrifos: behavioural and pharmacological evidence. Neurotoxicol Teratol 26, 305–317.PubMedCrossRefGoogle Scholar
  31. 31.
    Bradman, A., Eskenazi, B., Barr, D. B., Bravo, R., Castorina, R., Chevrier, J., Kogut, K., Harnly, M. E. & McKone, T. E. (2005) Organophosphate urinary metabolite levels during pregnancy and after delivery in women living in an agricultural community. Environ Health Perspect 113, 1802–1807.PubMedCrossRefGoogle Scholar
  32. 32.
    Crisostomo, L. & Molina, V. V. (2002) Pregnancy outcomes among farming households of Nueva Ecija with conventional pesticide use versus integrated pest management. Int J Occup Environ Health 8, 232–242.PubMedGoogle Scholar
  33. 33.
    Curl, C. L., Fenske, R. A., Kissel, J. C., Shirai, J. H., Moate, T. F., Griffith, W., Coronado, G. & Thompson, B. (2002) Evaluation of take-home organophosphorus pesticide exposure among agricultural workers and their children. Environ Health Perspect 110, A787–A792.PubMedCrossRefGoogle Scholar
  34. 34.
    Fenske, R. A. (1997) Pesticide exposure assessment of workers and their families. Occup Med 12, 221–237.PubMedGoogle Scholar
  35. 35.
    Shipp, E. M., Cooper, S. P., Burau, K. D. & Bolin, J. N. (2005) Pesticide safety training and access to field sanitation among migrant farmworker mothers from Starr County, Texas. J Agric Saf Health 11, 51–60.PubMedGoogle Scholar
  36. 36.
    Elwan, M. A., Richardson, J. R., Guillot, T. S., Caudle, W. M. & Miller, G. W. (2006) Pyrethroid pesticide-induced alterations in dopamine transporter function. Toxicol Appl Pharmacol 211, 188–197.PubMedCrossRefGoogle Scholar
  37. 37.
    Gillette, J. S. & Bloomquist, J. R. (2003) Differential up-regulation of striatal dopamine transporter and alpha-synuclein by the pyrethroid insecticide permethrin. Toxicol Appl Pharmacol 192, 287–293.PubMedCrossRefGoogle Scholar
  38. 38.
    Miller, G. W., Gainetdinov, R. R., Levey, A. I. & Caron, M. G. (1999) Dopamine transporters and neuronal injury. Trends Pharmacol Sci 20, 424–429.PubMedCrossRefGoogle Scholar
  39. 39.
    Ossowska, K., Wardas, J., Smialowska, M., Kuter, K., Lenda, T., Wieronska, J. M., Zieba, B., Nowak, P., Dabrowska, J., Bortel, A., Kwiecinski, A. & Wolfarth, S. (2005) A slowly developing dysfunction of dopaminergic nigrostriatal neurons induced by long-term paraquat administration in rats: an animal model of preclinical stages of Parkinson’s disease? Eur J Neurosci 22, 1294–1304.PubMedCrossRefGoogle Scholar
  40. 40.
    Uhl, G. R. (1998) Hypothesis: the role of dopaminergic transporters in selective vulnerability of cells in Parkinson’s disease. Ann Neurol 43, 555–560.PubMedCrossRefGoogle Scholar
  41. 41.
    Aldridge, J. E., Seidler, F. J., Meyer, A., Thillai, I. & Slotkin, T. A. (2003) Serotonergic systems targeted by developmental exposure to chlorpyrifos: effects during different critical periods. Environ Health Perspect 111, 1736–1743.PubMedCrossRefGoogle Scholar
  42. 42.
    Aldridge, J. E., Seidler, F. J. & Slotkin, T. A. (2004) Developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood: critical periods and regional selectivity for effects on the serotonin transporter, receptor subtypes, and cell signaling. Environ Health Perspect 112, 148–155.PubMedCrossRefGoogle Scholar
  43. 43.
    Richardson, J. R., Caudle, W. M., Wang, M., Dean, E. D., Pennell, K. D. & Miller, G. W. (2006) Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson’s disease. FASEB J 20, 1695–1697.PubMedCrossRefGoogle Scholar
  44. 44.
    Slotkin, T. A. & Seidler, F. J. (2005) The alterations in CNS serotonergic mechanisms caused by neonatal chlorpyrifos exposure are permanent. Brain Res Dev Brain Res 158, 115–119.PubMedCrossRefGoogle Scholar
  45. 45.
    Carvey, P. M., Punati, A. & Newman, M. B. (2006) Progressive dopamine neuron loss in Parkinson’s disease: the multiple hit hypothesis. Cell Transplant 15, 239–250.PubMedCrossRefGoogle Scholar
  46. 46.
    Sulzer, D. (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci 30, 244–250.PubMedCrossRefGoogle Scholar
  47. 47.
    McKinley, E. T., Baranowski, T. C., Blavo, D. O., Cato, C., Doan, T. N. & Rubinstein, A. L. (2005) Neuroprotection of MPTP-induced toxicity in zebrafish dopaminergic neurons. Brain Res Mol Brain Res 141, 128–137.PubMedCrossRefGoogle Scholar
  48. 48.
    Doshna, C., Benbow, J., DePasquale, M., Okerberg, C., Turnquist, S., Stedman, D., Chapin, B., Sivaraman, L., Waldron, G., Navetta, K., Brady, J., Banker, M., Casimiro-Garcia, A., Hill, A., Jones, M., Ball, J. & Aleo, M. (2009) Multi-phase analysis of uptake and toxicity in zebrafish: relationship to compound physical-chemical properties. The Toxicologist, Poster Abstract#377, Society of Toxicology 2009 Annual Meeting, Baltimore MD.Google Scholar
  49. 49.
    Panula, P., Sallinen, V., Sundvik, M., Kolehmainen, J., Torkko, V., Tiittula, A., Moshnyakov, M. & Podlasz, P. (2006) Modulatory neurotransmitter systems and behavior: towards zebrafish models of neurodegenerative diseases. Zebrafish 3, 235–247.PubMedCrossRefGoogle Scholar
  50. 50.
    Anichtchik, O. V., Kaslin, J., Pietsaro, N., Scheinin, M. & Panula, P. (2004) Neurochemical and behavioral changes in zebrafish Danio rerio after systematic administration of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 88, 443–453.PubMedCrossRefGoogle Scholar
  51. 51.
    Bretaud, S., Lee, S. & Guo, S. (2004) Sensitivity of zebrafish to environmental toxins implicated in Parkinson’s disease. Neurotox Teratol 26, 857–864.CrossRefGoogle Scholar
  52. 52.
    Sallinen, V., Sundvik, M., Reenilä, I., Peitsaro, N., Khrustalyov, D., Anichtchik, O., Toleikyte, G., Kaslin, J. & Panula, P. (2009a) Hyperserotonergic phenotype after monoamine oxidase inhibition in larval zebrafish. J Neurochem 109, 403–415.PubMedCrossRefGoogle Scholar
  53. 53.
    Aldridge, J. E., Meyer, A., Seidler, F. J. & Slotkin, T. A. (2005b) Alterations in central nervous system serotonergic and dopaminergic synaptic activity in adulthood after prenatal or neonatal chlorpyrifos exposure. Environ Health Perspect 113, 1027–1031.PubMedCrossRefGoogle Scholar
  54. 54.
    Gould, G. G., Brooks, B. W. & Frazer, A. (2007) [3H] citalopram binding to serotonin transporter sites in minnow brains. Basic Clin Pharmacol Toxicol 101, 203–210.PubMedCrossRefGoogle Scholar
  55. 55.
    Levin, E. D., Chrysanthis, E., Yacisin, K. & Linney, E. (2003) Chlorpyrifos exposure of developing zebrafish: effects on survival and long-term effects on response latency and spatial discrimination. Neurotoxicol Teratol 25, 51–57.PubMedCrossRefGoogle Scholar
  56. 56.
    Levin, E. D., Swain, H. A., Donerly, S. & Linney, E. (2004) Developmental chlorpyrifos effects on hatchling zebrafish swimming behavior. Neurotoxicol Teratol 26, 719–723.PubMedCrossRefGoogle Scholar
  57. 57.
    Ciesielski, S., Loomis, D. P., Mims, S. R. & Auer, A. (1994) Pesticide exposures, cholinesterase depression, and symptoms among North Carolina migrant farmworkers. Am J Publ Health 84, 446–451.CrossRefGoogle Scholar
  58. 58.
    Cañadas, F., Cardona, D., Davila, E. & Sanchez-Santed, F. (2005) Long-term neurotoxicity of chlorpyrifos: spatial learning impairment on repeated acquisition in a water maze. Toxicol Sci 85, 944–951.PubMedCrossRefGoogle Scholar
  59. 59.
    Jarvinen, A. W., Nordling, B. R. & Henry, M. E. (1983) Chronic toxicity of Dursban (chlorpyrifos) to the fathead minnow and the resultant acetylcholinesterase inhibition. Ecotoxicol Environ Safety 7, 423–434.PubMedCrossRefGoogle Scholar
  60. 60.
    Roex, E. W., Keijzers, R. & van Gestel, C. A. (2003) Acetylcholinesterase inhibition and increased food consumption rate in the zebrafish, Danio rerio, after chronic exposure to parathion. Aquat Toxicol 64, 451–460.PubMedCrossRefGoogle Scholar
  61. 61.
    Benmansour, S., Cecchi, M., Morilak, D., Gerhardt, G. A., Javors, M. A., Gould, G. G. & Frazer, A. (1999) Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA. J Neurosci 19, 10494–10501.PubMedGoogle Scholar
  62. 62.
    Kunko, P. M., Loeloff, R. J. & Izenwasser, S. (1997) Chronic administration of the selective dopamine uptake inhibitor GBR 12,909, but not cocaine, produces marked decreases in dopamine transporter density. Naunyn Schmiedebergs Arch Pharmacol 356, 562–569.PubMedCrossRefGoogle Scholar
  63. 63.
    Bloomquist, J. R., Barlow, R. L., Gillette, J. S., Li, W. & Kirby, M. L. (2002) Selective effects of insecticides on nigrostriatal dopaminergic nerve pathways. Neurotoxicology 23, 537–544.PubMedCrossRefGoogle Scholar
  64. 64.
    Kitazawa, M., Anantharam, V. & Kanthasamy, A. G. (2003) Dieldrin induces apoptosis by promoting caspase-3-dependent proteolytic cleavage of protein kinase Cgamma in dopaminergic cells: relevance to oxidative stress and dopaminergic degradation. Neuroscience 119, 945–964.PubMedCrossRefGoogle Scholar
  65. 65.
    Purkerson-Parker, S., McDaniel, K. L. & Moser, V. C. (2001) Dopamine transporter binding in the rat striatum is increased by gestational, perinatal, and adolescent exposure to heptachlor. Toxicol Sci 64, 216–223.PubMedCrossRefGoogle Scholar
  66. 66.
    Karen, D. J., Li, W., Harp, P. R., Gillette, J. S. & Bloomquis, J. R. (2001) Striatal dopaminergic pathways as a target for the insecticides permethrin and chlorpyrifos. Neurotoxicology 22, 811–817.PubMedCrossRefGoogle Scholar
  67. 67.
    Braunbeck, T., Boettcher, M., Hollert, H., Kosmehl, T., Lammer, E., Leist, E., Rudolf, M. & Seitz, N. (2005) Towards an alternative for the acute fish LC(50) test in chemical assessment: the fish embryo toxicity test goes multi-species – an update. ALTEX 22, 87–102.PubMedGoogle Scholar
  68. 68.
    Guo, S. (2004) Linking genes to brain, behavior and neurological diseases: what can we learn from zebrafish? Genes Brain Behav 3, 63–74.PubMedCrossRefGoogle Scholar
  69. 69.
    Hinton, D. E., Kullman, S. W., Hardman, R. C., Volz, D. C., Chen, P. J., Carney, M. & Bencic, D. C. (2005) Resolving mechanisms of toxicity while pursuing ecotoxicological relevance? Mar Pollut Bull 51, 635–648.PubMedCrossRefGoogle Scholar
  70. 70.
    Lardelli, M. (2005) Zebrafish – do we need another vertebrate model? Anzccart News 13, 1–3.Google Scholar
  71. 71.
    Linney, E., Upchurch, L. & Donerly, S. (2004) Zebrafish as a neurotoxicological model. Neurotoxicol Teratol 26, 709–718.PubMedCrossRefGoogle Scholar
  72. 72.
    Repetto, G., del Peso, A. & Repetto, M. (2000) Alternative ecotoxicological methods for the evaluation, control and monitoring of environmental pollutants. Ecotoxicol Environ Restor 3, 47–51.Google Scholar
  73. 73.
    Ton, C., Lin, Y. & Willett, C. (2006) Zebrafish as a model for developmental neurotoxicity testing. Birth Defects Res A Clin Mol Teratol 76, 553–567.PubMedCrossRefGoogle Scholar
  74. 74.
    Le Crom, S., Kapsimali, M., Barôme, P. O. & Vernier, P. (2003) Dopamine receptors for every species: gene duplications and functional diversification in Craniates. J Struct Funct Genomics 3, 161–176.PubMedCrossRefGoogle Scholar
  75. 75.
    Ryu, S., Holzschuh, J., Mahler, J. & Driever, W. (2006) Genetic analysis of dopaminergic system development in zebrafish. J Neural Transm Suppl 70, 61–66.PubMedCrossRefGoogle Scholar
  76. 76.
    Caveney, S., Cladman, W., Verellen, L. & Donly, C. (2006) Ancestry of neuronal monoamine transporters in the metazoa. J Exp Biol 209, 4858–4868.PubMedCrossRefGoogle Scholar
  77. 77.
    Huggett, D. B., Cook, J. C., Ericson, J. E. & Williams, R. T. (2003) Theoretical model for prioritizing potential impacts of human pharmaceuticals to fish. J Hum Ecol Risk Assess 9, 1789–1799.CrossRefGoogle Scholar
  78. 78.
    Rink, E. & Wullimann, M. F. (2002) Connections of the ventral telencephalon and tyrosine hydroxylase distribution in the zebrafish brain (Danio rerio) lead to identification of an ascending dopaminergic system in a teleost. Brain Res Bull 57, 385–387.PubMedCrossRefGoogle Scholar
  79. 79.
    Rink, E. & Wullimann, M. F. (2004) Connections of the ventral telencephalon (subpallium) in the zebrafish (Danio rerio). Brain Res 1011, 206–220.PubMedCrossRefGoogle Scholar
  80. 80.
    Salas, C., Broglio, C., Durán, E., Gómez, A., Ocaña, F. M., Jiménez-Moya, F. & Rodríguez, F. (2006) Neuropsychology of learning and memory in teleost fish. Zebrafish 3, 157–171.PubMedCrossRefGoogle Scholar
  81. 81.
    Koutoku, T., Zhang, R., Tachibana, T., Oshima, Y. & Furuse, M. (2003) Effect of acute L-tryptophan exposure on the brain serotonergic system and behavior in the male medaka. Zool Sci 20, 121–124.PubMedCrossRefGoogle Scholar
  82. 82.
    Lepage, O., Larson, E. T., Mayer, I. & Winberg, S. (2005) Serotonin, but not melatonin, plays a role in shaping dominant-subordinate relationships and aggression in rainbow trout. Horm Behav 8, 233–242.CrossRefGoogle Scholar
  83. 83.
    Perreault, H. A., Semsar, K. & Godwin, J. (2003) Fluoxetine treatment decreases territorial aggression in a coral reef fish. Physiol Behav 79, 719–724.PubMedCrossRefGoogle Scholar
  84. 84.
    Winberg, S., Overli, O. & Lepage, O. (2001) Suppression of aggression in rainbow trout (Oncorhynchus mykiss) by dietary L-tryptophan. J Exp Biol 204, 3867–3876.PubMedGoogle Scholar
  85. 85.
    Winberg, S. & Nilsson, G. (1996) Multiple high-affinity binding sites for [3H] serotonin in the brain of a teleost fish, the Arctic charr (Salvelinus alpinus). J Exp Biol 199, 2429–2435.PubMedGoogle Scholar
  86. 86.
    Ferriere, F., Khan, N. A., Meyniel, J. P. & Deschaux, P. (1999) Characterisation of serotonin transport mechanisms in rainbow trout peripheral blood lymphocytes: role in PHA-induced lymphoproliferation. Dev Comp Immunol 23, 37–50.PubMedCrossRefGoogle Scholar
  87. 87.
    Wang, Y., Takai, R., Yoshioka, H. & Shirabe, K. (2006) Characterization and expression of serotonin transporter genes in zebrafish. Tohoku J Exp Med 208, 267–274.PubMedCrossRefGoogle Scholar
  88. 88.
    Norton, W. H., Folchert, A. & Bally-Cuif, L. (2008) Comparative analysis of serotonin receptor (HTR1A/HTR1B families) and transporter (slc6a4a/b) gene expression in the zebrafish brain. J Comp Neurol 511, 521–542.PubMedCrossRefGoogle Scholar
  89. 89.
    Severinsen, K., Sinning, S., Müller, H. K. & Wiborg, O. (2008) Characterisation of the zebrafish serotonin transporter functionally links TM10 to the ligand binding site. J Neurochem 105, 1794–1805.PubMedCrossRefGoogle Scholar
  90. 90.
    Boehmler, W., Obrecht-Pflumio, S., Canfield, V., Thisse, C., Thisse, B. & Levenson, R. (2004) Evolution and expression of D2 and D3 dopamine receptor genes in zebrafish. Dev Dyn 230, 481–493.PubMedCrossRefGoogle Scholar
  91. 91.
    Clements, S. & Schreck, C. B. (2004) Evidence that GABA mediates dopaminergic and serotonergic pathways associated with locomotor activity in juvenile chinook salmon (Oncorhynchus tshawytscha). Behav Neurosci 118, 191–198.PubMedCrossRefGoogle Scholar
  92. 92.
    Johansson, V., Winberg, S. & Bjornsson, B. T. (2005) Growth hormone-induced stimulation of swimming and feeding behaviour of rainbow trout is abolished by the D1 dopamine antagonist SCH23390. Gen Comp Endocrinol 141, 58–65.PubMedCrossRefGoogle Scholar
  93. 93.
    Rink, E. & Wullimann, M. F. (2001) The teleostean (zebrafish) dopaminergic system ascending to the subpallium (striatum) is located in the basal diencephalon (posterior tuberculum). Brain Res 889, 316–330.PubMedCrossRefGoogle Scholar
  94. 94.
    Holzschuh, J., Ryu, S., Aberger, F. & Driever, W. (2001) Dopamine transporter expression distinguishes dopaminergic neurons from other catecholaminergic neurons in the developing zebrafish embryo. Mech Dev 101, 237–243.PubMedCrossRefGoogle Scholar
  95. 95.
    López Patiño, M. A., Yu, L., Yamamoto, B. K. & Zhdanova, I. V. (2008) Gender differences in zebrafish responses to cocaine withdrawal. Physiol Behav 95, 36–47.PubMedCrossRefGoogle Scholar
  96. 96.
    Bretaud, S., Li, Q., Lockwood, B. L., Kobayashi, K., Lin, E. & Guo, S. (2007a) A choice behavior for morphine reveals experience-dependent drug preference and underlying neural substrates in developing larval zebrafish. Neuroscience 146, 1109–1116.PubMedCrossRefGoogle Scholar
  97. 97.
    Kily, L. J., Cowe, Y. C., Hussain, O., Patel, S., McElwaine, S., Cotter, F. E. & Brennan, C. H. (2008) Gene expression changes in a zebrafish model of drug dependency suggest conservation of neuro-adaptation pathways. J Exp Biol 211, 1623–1634.PubMedCrossRefGoogle Scholar
  98. 98.
    Ninkovic, J. & Bally-Cuif, L. (2006) The zebrafish as a model system for assessing the reinforcing properties of drugs of abuse. Methods 39, 262–274.PubMedCrossRefGoogle Scholar
  99. 99.
    Colwill, R. M., Raymond, M. P., Ferreira, L. & Escudero, H. (2005) Visual discrimination learning in zebrafish (Danio rerio). Behav Processes 70, 19–31.PubMedCrossRefGoogle Scholar
  100. 100.
    Darland, T. & Dowling, J. E. (2001) Behavioral screening for cocaine sensitivity in mutagenized zebrafish. Proc Natl Acad Sci USA 98, 11691–11696.PubMedCrossRefGoogle Scholar
  101. 101.
    Lau, B., Bretaud, S., Huang, Y., Lin, E. & Guo, S. (2006) Dissociation of food and opiate preference by a genetic mutation in zebrafish. Genes Brain Behav 5, 497–505.PubMedCrossRefGoogle Scholar
  102. 102.
    Carobrez, A. P. & Bertoglio, L. J. (2005) Ethological and temporal analyses of anxiety-like behavior: the elevated plus-maze model 20 years on. Neurosci Biobehav Rev 29, 1193–1205.PubMedCrossRefGoogle Scholar
  103. 103.
    Bondi, C. O., Rodriguez, G., Gould, G. G., Frazer, A. & Morilak, D. A. (2008) Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment. Neuropsychopharmacology 33, 320–331.PubMedCrossRefGoogle Scholar
  104. 104.
    Bass, S. L. & Gerlai, R. (2008) Zebrafish (Danio rerio) responds differentially to stimulus fish: the effects of sympatric and allopatric predators and harmless fish. Behav Brain Res 186, 107–117.PubMedCrossRefGoogle Scholar
  105. 105.
    Ferrari, M. C., Messier, F. & Chivers, D. P. (2008) Can prey exhibit threat-sensitive generalization of predator recognition? Extending the predator recognition continuum hypothesis. Proc Biol Sci 2008(275), 1811–1816.CrossRefGoogle Scholar
  106. 106.
    Speedie, N. & Gerlai, R. (2008) Alarm substance induced behavioral responses in zebrafish (Danio rerio). Behav Brain Res 188, 168–177.PubMedCrossRefGoogle Scholar
  107. 107.
    Peitsaro, N., Kaslin, J., Anichtchik, O. V. & Panula, P. (2003) Modulation of the histaminergic system and behaviour by alpha-fluoromethylhistidine in zebrafish. J Neurochem 86, 432–441.PubMedCrossRefGoogle Scholar
  108. 108.
    Levin, E. D., Bencan, Z. & Cerutti, D. T. (2007) Anxiolytic effects of nicotine in zebrafish. Physiol Behav 90, 54–58.PubMedCrossRefGoogle Scholar
  109. 109.
    Serra, E. L., Medalha, C. C. & Mattioli, R. (1999) Natural preference of zebrafish (Danio rerio) for a dark environment. Braz J Med Biol Res 32, 1551–1553.PubMedCrossRefGoogle Scholar
  110. 110.
    Office of Laboratory Animal Welfare (2002) Guide for the Care and Use of Laboratory Animals. Bethesda, MD, Public Health Service Policy on Humane Care and Use of Laboratory Animals. National Institutes of Health.Google Scholar
  111. 111.
    Wullimann, M. F., Rupp, B. & Reichert, H. (1996) The Neuroanatomy of the Zebrafish Brain: A Topological Atlas. Boston, MA, Birkhäuser.CrossRefGoogle Scholar
  112. 112.
    Kovachich, G. B., Aronson, C. E., Brunswick, D. J. & Frazer, A. (1988) Quantitative autoradiography of serotonin uptake sites in rat brain using [3H] cyanoimipramine. Brain Res 454, 78–88.PubMedCrossRefGoogle Scholar
  113. 113.
    Galici, R., Galli, A., Jones, D. J., Sanchez, T. A., Saunders, C., Frazer, A., Gould, G. G., Lin, R. Z. & France, C. P. (2003) Selective decreases in amphetamine self-administration and regulation of dopamine transporter function in diabetic rats. Neuroendocrinology 77, 132–140.PubMedCrossRefGoogle Scholar
  114. 114.
    Geary, W. A., Tioga, A. W. & Wooten, G. F. (1985) Quantitative film autoradiography for tritium: methodological considerations. Brain Res 337, 99–108.PubMedCrossRefGoogle Scholar
  115. 115.
    Boja, J. W., Mitchell, W. M., Patel, A., Kopajtic, T. A., Carroll, F. I., Lewin, A. H., Abraham, P. & Kuhar, M. J. (1992) High-affinity binding of [125I] RTI-55 to dopamine and serotonin transporters in rat brain. Synapse 12, 27–36.PubMedCrossRefGoogle Scholar
  116. 116.
    Bradford, M. M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72, 248–254.PubMedCrossRefGoogle Scholar
  117. 117.
    Wheelock, C. E., Eder, K. J., Werner, I., Huang, H., Jones, P. D., Brammell, B. F., Elskus, A. A. & Hammock, B. D. (2005) Individual variability in esterase activity and CYP1A levels in Chinook salmon (Oncorhynchus tshawytscha) exposed to esfenvalerate and chlorpyrifos. Aquat Toxicol 74, 172–192.PubMedCrossRefGoogle Scholar
  118. 118.
    Ellman, G. L., Courtney, K. D., Andres, V., Jr & Feather-Stone, R. M. (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7, 88–95.PubMedCrossRefGoogle Scholar
  119. 119.
    Cui, M., Aras, R., Christian, W. V., Rappold, P. M., Hatwar, M., Panza, J., Jackson-Lewis, V., Javitch, J. A., Ballatori, N., Przedborski, S. & Tieu, K. (2009) The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proc Natl Acad Sci 106, 8043–8048.PubMedCrossRefGoogle Scholar
  120. 120.
    Brooks, B. W., Chambliss, C. K., Stanley, J. K., Ramirez, A., Banks, K. E., Johnson, R. D. & Lewis, R. J. (2005) Determination of select antidepressants in fish from an effluent-dominated stream. Environ Toxicol Chem 24, 464–469.PubMedCrossRefGoogle Scholar
  121. 121.
    Braunbeck, T., Boettcher, M., Hollert, H., Kosmehl, T., Lammer, E., Leist, E., Rudolf, M. & Seitz, N. (2005) Towards an alternative for the acute fish LC(50) test in chemical assessment: the fish embryo toxicity test goes multi-species – an update. ALTEX 22, 87–102.PubMedGoogle Scholar
  122. 122.
    Sandahl, J. F., Baldwin, D. H., Jenkins, J. J. & Scholz, N. L. (2005) Comparative thresholds for acetylcholinesterase inhibition and behavioral impairment in coho salmon exposed to chlorpyrifos. Environ Toxicol Chem 24, 136–145.PubMedCrossRefGoogle Scholar
  123. 123.
    Ninkovic, J., Folchert, A., Makhankov, Y. V., Neuhauss, S. C., Sillaber, I., Straehle, U. & Bally-Cuif, L. (2006) Genetic identification of AChE as a positive modulator of addiction to the psychostimulant D-amphetamine in zebrafish. J Neurobiol 66, 463–475.PubMedCrossRefGoogle Scholar
  124. 124.
    Rico, E. P., Rosemberg, D. B., Dias, R. D., Bogo, M. R. & Bonan, C. D. (2007) Ethanol alters acetylcholinesterase activity and gene expression in zebrafish brain. Toxicol Lett 174, 25–30.PubMedCrossRefGoogle Scholar
  125. 125.
    Beseler, C. & Stallones, L. (2003) Safety practices, neurological symptoms, and pesticide poisoning. J Occup Environ Med 45, 1079–1086.PubMedCrossRefGoogle Scholar
  126. 126.
    Sánchez-Amate, M. C., Flores, P. & Sánchez-Santed, F. (2001) Effects of chlorpyrifos in the plus-maze model of anxiety. Behav Pharmacol 12, 285–292.PubMedCrossRefGoogle Scholar
  127. 127.
    Harmer, C. J., Mackay, C. E., Reid, C. B., Cowen, P. J. & Goodwin, G. M. (2006) Antidepressant drug treatment modifies the neural processing of nonconscious threat cues. Biol Psychiatry 59, 816–820.PubMedCrossRefGoogle Scholar
  128. 128.
    Drapier, D., Bentué-Ferrer, D., Laviolle, B., Millet, B., Allain, H., Bourin, M. & Reymann, J. M. (2007) Effects of acute fluoxetine, paroxetine and desipramine on rats tested on the elevated plus-maze. Behav Brain Res 176, 202–209.PubMedCrossRefGoogle Scholar
  129. 129.
    Kurt, M., Arik, A. C. & Celik, S. (2000) The effects of sertraline and fluoxetine on anxiety in the elevated plus-maze test in mice. J Basic Clin Physiol Pharmacol 11, 173–180.PubMedCrossRefGoogle Scholar
  130. 130.
    Lapiz-Bluhm, M. D., Bondi, C. O., Doyen, J., Rodriguez, G. A., Bédard-Arana, T. & Morilak, D. A. (2008) Behavioural assays to model cognitive and affective dimensions of depression and anxiety in rats. J Neuroendocrinol 20, 1115–1137.PubMedCrossRefGoogle Scholar
  131. 131.
    Finney, J. L., Robertson, G. N., McGee, C. A., Smith, F. M. & Croll, R. P. (2006) Structure and autonomic innervation of the swim bladder in the zebrafish (Danio rerio). J Comp Neurol 495, 587–606.PubMedCrossRefGoogle Scholar
  132. 132.
    Airhart, M. J., Lee, D. H., Wilson, T. D., Miller, B. E., Miller, M. N. & Skalko, R. G. (2007) Movement disorders and neurochemical changes in zebrafish larvae after bath exposure to fluoxetine (PROZAC). Neurotoxicol Teratol 29, 652–664.PubMedCrossRefGoogle Scholar
  133. 133.
    Flinn, L., Mortiboys, H., Volkmann, K., Köster, R. W., Ingham, P. W. & Bandmann, O. (2009) Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio). Brain 132, 1613–1623.PubMedCrossRefGoogle Scholar
  134. 134.
    Anichtchik, O., Diekmann, H., Fleming, A., Roach, A., Goldsmith, P. & Rubinsztein, D. C. (2008) Loss of PINK1 function affects development and results in neurodegeneration in zebrafish. J Neurosci 28, 8199–8207.PubMedCrossRefGoogle Scholar
  135. 135.
    Bai, Q., Mullett, S. J., Garver, J. A., Hinkle, D. A. & Burton, E. A. (2006) Zebrafish DJ-1 is evolutionarily conserved and expressed in dopaminergic neurons. Brain Res 1113, 33–44.PubMedCrossRefGoogle Scholar
  136. 136.
    Bretaud, S., Allen, C., Ingham, P. W. & Bandmann, O. (2007b) p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson’s disease. J Neurochem 100, 1626–1635.PubMedGoogle Scholar
  137. 137.
    Son, O. L., Kim, H. T., Ji, M. H., Yoo, K. W., Rhee, M. & Kim, C. H. (2003) Cloning and expression analysis of a Parkinson’s disease gene, uch-L1, and its promoter in zebrafish. Biochem Biophys Res Commun 2003(312), 601–607.CrossRefGoogle Scholar
  138. 138.
    Rubinstein, A. L. (2003) Zebrafish: from disease modeling to drug discovery. Curr Opin Drug Discov Devel 6, 218–223.PubMedGoogle Scholar
  139. 139.
    Wen, L., Wei, W., Gu, W., Huang, P., Ren, X., Zhang, Z., Zhu, Z., Lin, S. & Zhang, B. (2008) Visualization of monoaminergic neurons and neurotoxicity of MPTP in live transgenic zebrafish. Dev Biol 314(1), 84–92.PubMedCrossRefGoogle Scholar
  140. 140.
    Boehmler, W., Petko, J., Woll, M., Frey, C., Thisse, B., Thisse, C., Canfield, V. A. & Levenson, R. (2009) Identification of zebrafish A2 adenosine receptors and expression in developing embryos. Gene Expr Patterns 9, 144–151.PubMedCrossRefGoogle Scholar
  141. 141.
    Sallinen, V., Torkko, V., Sundvik, M., Reenilä, I., Khrustalyov, D., Kaslin, J. & Panula, P. (2009b) MPTP and MPP+ target specific aminergic cell populations in larval zebrafish. J Neurochem 108, 719–731.PubMedCrossRefGoogle Scholar
  142. 142.
    Qiao, D., Seidler, F. J., Padilla, S. & Slotkin, T. A. (2002) Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period? Environ Health Perspect 110, 1097–1103.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Georgianna G. Gould
    • 1
  1. 1.Department of PhysiologyUniversity of Texas at Health Science Center at San AntonioSan AntonioUSA

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