Zebrafish in Drug Discovery: Safety Assessment

  • Adrian Hill


Included in this review are a series of the more common larval and adult zebrafish safety screens that have been developed over the past decade. As such, this is not a comprehensive list but aims to highlight benefits, advances, and pitfalls of key screens related solely to the cardiovascular system and CNS, as well as provide comparisons to earlier models and alternative in vitro and in vivo screens.


Conditioned Place Preference Danio Rerio Adult Zebrafish hERG Channel Zebrafish Larva 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References and Further Reading

  1. Aizenberg M, Schuman EM (2011) Cerebellar-dependent learning in larval zebrafish. J Neurosci 31(24):8708–8712PubMedCrossRefGoogle Scholar
  2. Alderton W, Berghmans S, Butler P, Chassaing H, Fleming A, Golder Z, Richards F, Gardner I (2010) Accumulation and metabolism of drugs and CYP probe substrates in zebrafish larvae. Xenobiotica 40(8):547–557PubMedCrossRefGoogle Scholar
  3. Anichtchik O, Sallinen V, Peitsaro N, Panula P (2006) Distinct structure and activity of monoamine oxidase in the brain of zebrafish (Danio rerio). J Comp Neurol 498(5):593–610PubMedCrossRefGoogle Scholar
  4. Animals Scientific Procedures Act (1986) Chapter 14. Her majesty’s stationary office. The National Archieves. See Scholar
  5. Annilo T, Chen ZQ, Shulenin S, Costantino J, Thomas L, Lou H, Stefanov S, Dean M (2006) Evolution of the vertebrate ABC gene family: analysis of gene birth and death. Genomics 88(1):1–11PubMedCrossRefGoogle Scholar
  6. Antzelevitch C (2004) Arrhythmogenic mechanisms of QT prolonging drugs: is QT prolongation really the problem? J Electrocardiol 37(Suppl):15–24PubMedCrossRefGoogle Scholar
  7. Archer A, Lauter G, Hauptmann G, Mode A, Gustafsson JA (2008) Transcriptional activity and developmental expression of liver X receptor (lxr) in zebrafish. Dev Dyn 237(4):1090–1098PubMedCrossRefGoogle Scholar
  8. Arnaout R, Ferrer T, Huisken J, Spitzer K, Stainier DY, Tristani-Firouzi M, Chi NC (2007) Zebrafish model for human long QT syndrome. Proc Natl Acad Sci USA 104:11316–11321PubMedCrossRefGoogle Scholar
  9. Arthur D, Levin ED (2001) Spatial and non-spatial visual discrimination learning in zebrafish (Danio rerio). Anim Cogn 4:125–131CrossRefGoogle Scholar
  10. Aylott M, Bate S, Collins S, Jarvis P, Saul J (2011) Review of the statistical analysis of the dog telemetry study. Pharm Stat 10(3):236–249PubMedCrossRefGoogle Scholar
  11. Bagatto B, Burggren W (2006) A three-dimensional functional assessment of heart and vessel development in the larva of the zebrafish (Danio rerio). Physiol Biochem Zool 79:194–201PubMedCrossRefGoogle Scholar
  12. Baker K, Warren KS, Yellen G, Fishman MC (1997) Defective “pacemaker” current (Ih) in a zebrafish mutant with a slow heart rate. Proc Natl Acad Sci USA 94(9):4554–4559PubMedCrossRefGoogle Scholar
  13. Baraban SC, Taylor MR, Castro PA, Baier H (2005) Pentylenetetrazole induced changes in zebrafish behavior, neural activity and c-fos expression. Neuroscience 131:759–768PubMedCrossRefGoogle Scholar
  14. Barros TP, Alderton WK, Reynolds HM, Roach AG, Berghmans S (2008) Zebrafish: an emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery. Br J Pharmacol 154:1400–1413PubMedCrossRefGoogle Scholar
  15. Bate J, Diekmann H, Hill A (2010) Zebrafish as an alternative model system to identify compounds with anti-epileptic activity. In: Forty-ninth annual meeting of the society of toxicology, Salt Lake City, 7–11 March 2010Google Scholar
  16. Berghmans S, Barros T, Golder Z, Gardner I, Butler P, Hill A, Fleming A, Alderton W, Roach A (2007a) The future of in vivo safety pharmacology screening. J Pharmacol Toxicol Methods 58(2):177–178CrossRefGoogle Scholar
  17. Berghmans S, Hunt J, Roach A, Goldsmith P (2007b) Zebrafish offer the potential for a primary screen to identify a wide variety of potential anticonvulsants. Epilepsy Res 75(1):18–28PubMedCrossRefGoogle Scholar
  18. Berghmans S, Butler B, Goldsmith P, Waldron G, Gardner I, Golder Z, Richards FM, Kimber G, Roach A, Alderton W, Fleming A (2008) Early drug safety assessment for the cardiac, visual and gut functions using the zebrafish. J Pharmacol Toxicol Methods 58:59–68PubMedCrossRefGoogle Scholar
  19. Best JD, Berghmans S, Hunt JJ, Clarke SC, Fleming A, Goldsmith P, Roach AG (2008) Non-associative learning in larval zebrafish. Neuropsychopharmacology 33:1206–1215PubMedCrossRefGoogle Scholar
  20. Brannen KC, Panzica-Kelly JM, Danberry TL, Augustine-Rauch KA (2010) Development of a zebrafish embryo teratogenicity assay and quantitative prediction model. Birth Defects Res 89:66–77CrossRefGoogle Scholar
  21. Bresolin T, de Freitas RM, Celso Dias Bainy A (2005) Expression of PXR, CYP3A and MDR1 genes in liver of zebrafish. Comp Biochem Physiol C Toxicol Pharmacol 140(3–4):403–407PubMedCrossRefGoogle Scholar
  22. Brookshire KH, Hognander OC (1968) Conditioned fear in the fish. Psychol Rep 22:75–81PubMedCrossRefGoogle Scholar
  23. Burns CG, Milan DJ, Grande EJ, Rottbauer W, MacRae CA, Fishman MC (2005) High-throughput assay for small molecules that modulate zebrafish embryonic heart rate. Nat Chem Biol 1:263–264PubMedCrossRefGoogle Scholar
  24. Cachat J, Canavello P, Elegante M, Bartels B, Hart P, Bergner C, Egan R, Duncan A, Tien D, Chung A, Wong K, Goodspeed J, Tan J, Grimes C, Elkhayat S, Suciu C, Rosenberg M, Chung KM, Kadri F, Roy S, Gaikwad S, Stewart A, Zapolsky I, Gilder T, Mohnot S, Beeson E, Amri H, Zukowska Z, Soignier RD, Kalueff AV (2010) Modeling withdrawal syndrome in zebrafish. Behav Brain Res 208(2):371–376PubMedCrossRefGoogle Scholar
  25. Cahill GM (2002) Clock mechanisms in zebrafish. Cell Tissue Res 309:27–34PubMedCrossRefGoogle Scholar
  26. Cahill GM, Hurd MW, Batchelor MM (1998) Circadian rhythmicity in the locomotor activity of larval zebrafish. Neuroreport 9:3445–3449PubMedCrossRefGoogle Scholar
  27. Carvan MJ III, Loucks E, Weber DN, Williams FE (2004) Ethanol effects on the developing zebrafish: neurobehavior and skeletal morphogenesis. Neurotoxicol Teratol 26:757–768PubMedCrossRefGoogle Scholar
  28. Chapin R, Augustine-Rauch KA, Beyer B, Daston G, Finnell R, Flynn T, Hunter S, Mirkes P, O’Shea KS, Piersma A, Sandler D, Vanparys P, Van Maele-Fabry G (2008) State of the art in developmental toxicity screening methods and a way forward: a meeting report addressing embryonic stem cells, whole embryo culture, and zebrafish. Birth Defects Res 83:446–456CrossRefGoogle Scholar
  29. Colwill RM, Raymond MP, Ferreira L, Escudero H (2005) Visual discrimination learning in zebrafish (Danio rerio). Behav Processes 70:19–31PubMedCrossRefGoogle Scholar
  30. Darland T, Dowling JE (2001) Behavioral screening for cocaine sensitivity in mutagenized zebrafish. Proc Natl Acad Sci USA 98:11691–11696PubMedCrossRefGoogle Scholar
  31. Darpö B (2001) Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes. Eur Heart J 3(Suppl K):K70–K80Google Scholar
  32. Dasmahapatra AK, Doucet HL, Bhattacharyya C, Carvan MJ 3rd (2001) Developmental expression of alcohol dehydrogenase (ADH3) in zebrafish (Danio rerio). Biochem Biophys Res Commun 286(5):1082–1086PubMedCrossRefGoogle Scholar
  33. Davis RE, Klinger PD (1994) NMDA receptor antagonist MK-801 blocks learning of conditioned stimulus-unconditioned stimulus contiguity but not fear of conditioned stimulus in goldfish (Carassius auratus L.). Behav Neurosci 108:935–940PubMedCrossRefGoogle Scholar
  34. DiMasi JA, Hansen RW, Grabowski HG (2003) The price of innovation: new estimates of drug development costs. J Health Econ 22(2):151–185PubMedCrossRefGoogle Scholar
  35. Doshna C, Benbow J, DePasquale M, Okerberg C, Turnquist S, Stedman D, Chapin R, 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. Toxicol Sci 108(S-1):78, #377Google Scholar
  36. Dou Y, Andersson-Lendahl M, Arner A (2008) Structure and function of skeletal muscle in zebrafish early larvae. J Gen Physiol 131(5):445–453PubMedCrossRefGoogle Scholar
  37. Drapeau P, Saint-Amant L, Buss RR, Chong M, McDearmid JR, Brustein E (2002) Development of the locomotor network in zebrafish. Prog Neurobiol 68:85–111PubMedCrossRefGoogle Scholar
  38. Easter A, Bell ME, Damewood JR Jr, Redfern WS, Valentin JP, Winter MJ, Fonck C, Bialecki RA (2009) Approaches to seizure risk assessment in preclinical drug discovery. Drug Discov Today 14(17–18):876–884PubMedCrossRefGoogle Scholar
  39. Egan RJ, Bergner CL, Hart PC, Cachat JM, Canavello PR, Elegante MF, Elkhayat SI, Bartels BK, Tien AK, Tien DH, Mohnot S, Beeson E, Glasgow E, Amri H, Zukowska Z, Kalueff AV (2009) Understanding behavioral and physiological phenotypes of stress and anxiety in zebrafish. Behav Brain Res 205(1):38–44PubMedCrossRefGoogle Scholar
  40. Egorouchkina K, Braecklein M, Pang L, Tchoudovski I, Kellermann W, Bolz A (2005) Comparison of two different methods for coherent averaging in online ECG analysis. Comput Cardiol 32:463–466Google Scholar
  41. FDA (2005) ICH guidance for industry: S7B nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. HHS, FDA, CDER and CBERGoogle Scholar
  42. Forouhar AS, Hove JR, Calvert C, Flores J, Jadvar H, Gharib M (2004) Electrocardiographic characterization of embryonic zebrafish. Conf Proc IEEE Eng Med Biol Soc 5:3615–3617PubMedGoogle Scholar
  43. Foster FS, Zhang MY, Zhou YQ, Liu G, Mehi J, Cherin E, Harasiewicz KA, Starkoski BG, Zan L, Knapik DA, Adamson SL (2002) A new ultrasound instrument for in vivo microimaging of mice. Ultrasound Med Biol 28:1165–1172PubMedCrossRefGoogle Scholar
  44. Friedrichs GS, Patmore L, Bass A (2005) Non-clinical evaluation of ventricular repolarization (ICH S7B): results of an interim survey of international pharmaceutical companies. J Pharmacol Toxicol Methods 52:6–11PubMedCrossRefGoogle Scholar
  45. Fung M, Thornton A, Mybeck K, Hsiao-Hui W, Hornbuckle K, Muniz E (2001) Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceutical markets—1960–1999. Drug Inf J 35:293–317CrossRefGoogle Scholar
  46. George SG, Taylor B (2002) Molecular evidence for multiple UDP-glucuronosyltransferase gene families in fish. Mar Environ Res 54(3–5):253–257PubMedCrossRefGoogle Scholar
  47. Glassman AH, Bigger JT (2001) Antipsychotic drugs: prolonged Qtc interval, torsades de pointes, and sudden death. Am J Psychiatry 158:1774–1782PubMedCrossRefGoogle Scholar
  48. Goldsmith P (2004) Zebrafish as a pharmacological tool: the how, why and when. Curr Opin Pharmacol 4(5):504–512PubMedCrossRefGoogle Scholar
  49. Goldsmith P, Fleming A (2007) Screening methods employing zebrafish and the blood brain barrier. Granted Patent EP1644733Google Scholar
  50. Goldstone JV, McArthur AG, Kubota A, Zanette J, Parente T, Jönsson ME, Nelson DR, Stegeman JJ (2010) Identification and developmental expression of the full complement of cytochrome P450 genes in zebrafish. BMC Genomics 11:643PubMedCrossRefGoogle Scholar
  51. Grunwald DJ, Eisen JS (2002) Headwaters of the zebrafish—emergence of a new model vertebrate. Nat Rev Genet 3:717–724PubMedCrossRefGoogle Scholar
  52. Guo S (2004) Linking genes to brain, behavior and neurological diseases: what can we learn from zebrafish? Genes Brain Behav 3:63–74PubMedCrossRefGoogle Scholar
  53. Hall D, Suboski MD (1995) Visual and olfactory stimuli in learned release of alarm reactions by zebra danio fish (Brachydanio rerio). Neurobiol Learn Mem 63:229–240PubMedCrossRefGoogle Scholar
  54. Hill AJ (2008a) Zebrafish in drug discovery: bridging the gap between in vitro and in vivo methodologies. Preclin World 121–123Google Scholar
  55. Hill AJ (2008b) Zebrafish use in drug discovery. Toxicol Sci 102(S-1):407, #1977Google Scholar
  56. Hill AJ, Teraoka H, Heideman W, Peterson RE (2005) Zebrafish as a model vertebrate for investigating chemical toxicity. Toxicol Sci 86(1):6–19PubMedCrossRefGoogle Scholar
  57. Hill A, Albert S, Richards B, Tinsley J (2007) Zebrafish as a model vertebrate for cardiotoxicity. J Pharmacol Toxicol Methods 56(2):e10CrossRefGoogle Scholar
  58. Hill AJ, Dumotier B, Traebert M (2009) Cardiotoxicity testing in zebrafish: relevance of bioanalysis. J Pharmacol Toxicol Methods 62(2):e22–e23CrossRefGoogle Scholar
  59. Hill A, Mesens N, Steemans M, Xu JJ, Aleo MD (2012) Comparisons between in vitro whole cell imaging and in vivo Zebrafish-based approaches for identifying potential human hepatotoxicants earlier in pharmaceutical development. Drug Metab Rev 44(1):127–140Google Scholar
  60. Ho Y-L, Shau Y-W, Tsai H-J, Lin LC, Huang PJ, Hsieh FJ (2002) Assessment of zebrafish cardiac performance using Doppler echocardiography and power angiography. Ultrasound Med Biol 28:1137–1143PubMedCrossRefGoogle Scholar
  61. Hove JR (2004) In vivo biofluid dynamic imaging in the developing zebrafish. Birth Defects Res C Embryo Today 72:277–289PubMedCrossRefGoogle Scholar
  62. Huebner T, Goernig M, Schuepbach M, Sanz E, Pilgram R, Seeck A, Voss A (2010) Electrocardiologic and related methods of noninvasive detection and risk stratification in myocardial ischemia: state of the art and perspectives. GMS Ger Med Sci 8:Doc27. doi:10.3205/000116, URN: urn:nbn:de:0183–0001164Google Scholar
  63. Huisken J, Swoger J, Del Bene F, Wittbrodt J, Stelzer EH (2004) Optical sectioning deep inside live embryos by selective plane illumination microscopy. Science 305:1007–1009PubMedCrossRefGoogle Scholar
  64. Iannelli MA, Marcucci I, Vittozzi L (1994) Xenobiotic-metabolizing enzyme systems in test fish. V. Comparative studies of liver microsomal glucuronyltransferases. Ecotoxicol Environ Saf 28(2):172–180PubMedCrossRefGoogle Scholar
  65. Iftimia NV, Hammer DX, Ferguson RD, Mujat M, Vu D, Ferrante AA (2008) Dual-beam Fourier domain optical Doppler tomography of zebrafish. Opt Express 16(18):13624–13636PubMedCrossRefGoogle Scholar
  66. Janaitis C, Steger-Hartmann T, Hill A, Albert S, Weiser T, Clemann N, Bluemel J (2007) Use of the zebrafish for embryotoxicity screening. Toxicol Sci 96(S-1):94, #450Google Scholar
  67. Jensen JA (1996) Estimation of blood velocities using ultrasound. Cambridge University Press, New YorkGoogle Scholar
  68. Jeong JY, Kwon HB, Ahn JC, Kang D, Kwon SH, Park JA, Kim KW (2008) Functional and developmental analysis of the blood-brain barrier in zebrafish. Brain Res Bull 75(5):619–628PubMedCrossRefGoogle Scholar
  69. Jones M, Ball JS, Dodd A, Hill AJ (2009) Comparison between zebrafish and Hep G2 assays for the predictive identification of hepatotoxins. Toxicology 262(1):13–14CrossRefGoogle Scholar
  70. Joshi A, Dimino T, Vohra Y, Cui C, Yan G-X (2004) Preclinical strategies to assess QT liability and torsadogenic potential of new drugs: the role of experimental models. J Electrocardiol 37:7–14PubMedCrossRefGoogle Scholar
  71. Kastenhuber E, Kratochwil CF, Ryu S, Schweitzer J, Driever W (2010) Genetic dissection of dopaminergic and noradrenergic contributions to catecholaminergic tracts in early larval zebrafish. J Comp Neurol 518:439–458PubMedCrossRefGoogle Scholar
  72. Kily LJ, Cowe YC, Hussain O, Patel S, McElwaine S, Cotter FE, Brennan CH (2008) Gene expression changes in a zebrafish model of drug dependency suggest conservation of neuro-adaptation pathways. J Exp Biol 211(10):1623–1634PubMedCrossRefGoogle Scholar
  73. Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF (1995) Stages of embryonic development of the zebrafish. Dev Dyn 203(3):253–310PubMedCrossRefGoogle Scholar
  74. Kinter LB, Siegl PKS, Bass AS (2004) New preclinical guidelines on drug effects on ventricular repolarization: safety pharmacology comes of age. J Pharmacol Toxicol Methods 49:153–158PubMedCrossRefGoogle Scholar
  75. Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715PubMedCrossRefGoogle Scholar
  76. Kung H-C, Hoyert DL, Xu J, Murphy SL (2008) Deaths: final data for 2005. National Vital Statistics Reports, vol 56, number 10, 24 April 2008. US Department of Health and Human Services, Centers for Disease Control and Prevention, AtlantaGoogle Scholar
  77. Laming PR, Ennis P (1982) Habituation of fright and arousal responses in the teleosts Carassius auratus and Rutilus rutilus. J Comp Physiol Psychol 96:460–466PubMedCrossRefGoogle Scholar
  78. Langheinrich U, Vacun G, Wagner T (2003) Zebrafish embryos express an orthologue of HERG and are sensitive toward a range of QT-prolonging drugs inducing severe arrhythmia. Toxicol Appl Pharmacol 193:370–382PubMedCrossRefGoogle Scholar
  79. Lassen N, Estey T, Tanguay RL, Pappa A, Reimers MJ, Vasiliou V (2005) Molecular cloning, baculovirus expression, and tissue distribution of the zebrafish aldehyde dehydrogenase 2. Drug Metab Dispos 33(5):649–656PubMedCrossRefGoogle Scholar
  80. Lawrence CL, Pollard CE, Hammond TG, Valentin JP (2005) Nonclinical proarrhythmia models: predicting torsades de pointes. J Pharmacol Toxicol Methods 52:46–59PubMedCrossRefGoogle Scholar
  81. Lieschke GJ, Currie PD (2007) Animal models of human disease: zebrafish swim into view. Nat Rev Genet 8:353–367PubMedCrossRefGoogle Scholar
  82. Lillesaar C (2011) The serotonergic system in fish. J Chem Neuroanat. 41(4):294–308Google Scholar
  83. Liu TA, Bhuiyan S, Liu MY, Sugaham T, Sakakibata Y, Suiko M, Yasuda S, Katuta Y, Kumura M, Willams FE, Liu MC (2010) Zebrafish as a model for the study of the phas II cytosolic sulfotransferases. Curr Drug Metab 11(6):538–546Google Scholar
  84. Lockwood B, Bjerke S, Kobayashi K, Guo S (2004) Acute effects of alcohol on larval zebrafish: a genetic system for large-scale screening. Pharmacol Biochem Behav 77:647–654PubMedCrossRefGoogle Scholar
  85. Lopez-Patino MA, Yu L, Cabral H, Zhdanova IV (2008) Anxiogenic effects of cocaine withdrawal in zebrafish. Physiol Behav 93:160–171PubMedCrossRefGoogle Scholar
  86. Malone MH, Sciaky N, Stalheim L, Hahn KM, Linney E, Johnson GL (2007) Laser-scanning velocimetry: a confocal microscopy method for quantitative measurement of cardiovascular performance in zebrafish embryos and larvae. BMC Biotechnol 7:40PubMedCrossRefGoogle Scholar
  87. Mathur P, Guo S (2010) Use of zebrafish as a model to understand mechanisms of addiction and complex neurobehavioral phenotypes. Neurobiol Dis 40(1):66–72PubMedCrossRefGoogle Scholar
  88. Mattingly CJ, McLachlan JA, Toscano WA Jr (2001) Green fluorescent protein (GFP) as a marker of aryl hydrocarbon receptor (AhR) function in developing zebrafish (Danio rerio). Environ Health Perspect 109(8):845–849PubMedCrossRefGoogle Scholar
  89. Maximino C, Herculano AM (2010) A review of monoaminergic neuropsychopharmacology in zebrafish. Zebrafish 7(4):359–378PubMedCrossRefGoogle Scholar
  90. Mehta V, Peterson RE, Heideman W (2008) 2,3,7,8-Tetrachlorodibenzo-p-dioxin exposure prevents cardiac valve formation in developing zebrafish. Toxicol Sci 104(2):303–311PubMedCrossRefGoogle Scholar
  91. Meuldermans W, Hendrickx J, Lauwers W, Hurkmans R, Mostmans E, Swysen E, Bracke J, Knaeps A, Heykants J (1988a) Excretion and biotransformation of cisapride in rats after oral administration. Drug Metab Dispos 16(3):410–419PubMedGoogle Scholar
  92. Meuldermans W, Van Peer A, Hendrickx J, Lauwers W, Swysen E, Bockx M, Woestenborghs R, Heykants J (1988b) Excretion and biotransformation of cisapride in dogs and humans after oral administration. Drug Metab Dispos 16(3):403–409PubMedGoogle Scholar
  93. Milan DJ, Peterson TA, Ruskin JN, Peterson RT, MacRae CA (2003) Drugs that induce repolarization abnormalities cause bradycardia in zebrafish. Circulation 107:1355–1358PubMedCrossRefGoogle Scholar
  94. Milan DJ, Jones IL, Ellinor PT, MacRae CA (2006) In vivo recording of adult zebrafish electrocardiogram and assessment of drug-induced QT prolongation. Am J Physiol Heart Circ Physiol 291:H269–H273PubMedCrossRefGoogle Scholar
  95. Milan DJ, Kim AM, Winterfield JR, Jones IL, Pfeufer A, Sanna S, Arking DE, Amsterdam AH, Sabeh KM, Mably JD, Rosenbaum DS, Peterson RT, Chakravarti A, Kaab S, Roden DM, MacRae CA (2009) Drug-sensitized zebrafish screen identifies multiple genes, including gins3, as regulators of myocardial repolarization. Circulation 120:553–559PubMedCrossRefGoogle Scholar
  96. Nakai J, Okhura M, Imoto K (2001) A high signal-to-noise Ca(2+) probe composed of a single green fluorescent protein. Nat Biotechnol 19:137–141PubMedCrossRefGoogle Scholar
  97. Ninkovic J, Folchert A, Makhankov YV, Neuhauss SC, 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 66:463–475PubMedCrossRefGoogle Scholar
  98. Ohnishi K (1997) Effects of telencephalic ablation on short-term memory and attention in goldfish. Behav Brain Res 86:191–199PubMedCrossRefGoogle Scholar
  99. Olson RD, Kastin AJ, Michell GF, Olson GA, Coy DH, Montalbano DM (1978) Effects of endorphin and enkephalin analogs on fear habituation in goldfish. Pharmacol Biochem Behav 9:111–114PubMedCrossRefGoogle Scholar
  100. Orger MB, Gahtan E, Muto A, Page-McCaw P, Smear MC, Baier H (2004) Behavioral screening assays in zebrafish. Methods Cell Biol 77:53–68PubMedCrossRefGoogle Scholar
  101. Peal DS, Mills RW, Lynch SN, Mosley JM, Lim E, Ellinor PT, January CT, Peterson RT, Milan DJ (2011) Novel chemical suppressors of long QT syndrome identified by an in vivo functional screen. Circulation 123(1):23–30PubMedCrossRefGoogle Scholar
  102. Postlethwait JH, Woods IG, Ngo-Hazelett P, Yan YL, Kelly PD, Chu F, Huang H, Hill-Force A, Talbot WS (2000) Zebrafish comparative genomics and the origins of vertebrate chromosomes. Genome Res 10:1890–1902PubMedCrossRefGoogle Scholar
  103. Pradel G, Schachner M, Schmidt R (1999) Inhibition of memory consolidation by antibodies against cell adhesion molecules after active avoidance conditioning in zebrafish. J Neurobiol 39:197–206PubMedCrossRefGoogle Scholar
  104. Pradel G, Schmidt R, Schachner M (2000) Involvement of L1.1 in memory consolidation after active avoidance conditioning in zebrafish. J Neurobiol 43:389–403PubMedCrossRefGoogle Scholar
  105. Raehl CL, Patel AK, LeRoy M (1985) Drug-induced torsade de pointes. Clin Pharm 4:675–690PubMedGoogle Scholar
  106. Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG (2003) Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 58:32–45PubMedCrossRefGoogle Scholar
  107. Redfern WS, Waldron G, Writer MJ, Butler P, Holbrook M, Wallis R, Valentin JP (2008) Zebrafish assays as early safety pharmacology screens: paradigm shift or red herning? J Pharmacol Toxicol Method 58(2):110–117Google Scholar
  108. Reimers MJ, Hahn ME, Tanguay RL (2004) Two zebrafish alcohol dehydrogenases share common ancestry with mammalian class I, II, IV, and V alcohol dehydrogenase genes but have distinct functional characteristics. J Biol Chem 279(37):38303–38312PubMedCrossRefGoogle Scholar
  109. Rink E, Wullimann MF (2004) Connections of the ventral telencephalon (subpallium) in the zebrafish (Danio rerio). Brain Res 1011:206–220PubMedCrossRefGoogle Scholar
  110. Rinkwitz S, Mourrain P, Becker TS (2011) Zebrafish: an integrative system for neurogenomics and neurosciences. Prog Neurobiol 93(2):231–243PubMedCrossRefGoogle Scholar
  111. Saglio P, Trijasse S (1998) Behavioral responses to atrazine and diuron in goldfish. Arch Environ Contam Toxicol 35:484–491PubMedCrossRefGoogle Scholar
  112. Schachter AD, Ramoni MF (2007) Clinical forecasting in drug development. Nat Rev Drug Discov 6(2):107–108PubMedCrossRefGoogle Scholar
  113. Schwerte T, Pelster B (2000) Digital motion analysis as a tool for analysing the shape and performance of the circulatory system in transparent animals. J Exp Biol 203:1659–1669PubMedGoogle Scholar
  114. Shin JT, Pomerantsev EV, Mably JD, MacRae CA (2010) High-resolution cardiovascular function confirms functional orthology of myocardial contractility pathways in zebrafish. Physiol Genomics 42(2):300–309PubMedCrossRefGoogle Scholar
  115. Song W, Zou Z, Xu F, Gu X, Xu X, Zhao Q (2006) Molecular cloning and expression of a second zebrafish aldehyde dehydrogenase 2 gene (aldh2b). DNA Seq 17(4):262–269PubMedGoogle Scholar
  116. Spieler RE, Nelson CA, Huston JP, Mattioli R (1999) Post-trial administration of H1 histamine receptor blocker improves appetitive reversal learning and memory in goldfish, Carassius auratus. Neurosci Lett 277:5–8PubMedCrossRefGoogle Scholar
  117. Stewart A, Wong K, Cachat J, Gaikwad S, Kyzar E, Wu N, Hart P, Piet V, Utterback E, Elegante M, Tien D, Kalueff AV (2011) Zebrafish models to study drug abuse-related phenotypes. Rev Neurosci 22(1):95–105PubMedGoogle Scholar
  118. Sun L, Lien CL, Xu X, Shung KK (2008) In vivo cardiac imaging of adult zebrafish using high frequency ultrasound (45–75 MHz). Ultrasound Med Biol 34(1):31–39PubMedCrossRefGoogle Scholar
  119. Suzuki T, Takagi Y, Osanai H, Li L, Takeuchi M, Katoh Y, Kobayashi M, Yamamoto M (2005) Pi class glutathione S-transferase genes are regulated by Nrf 2 through an evolutionarily conserved regulatory element in zebrafish. Biochem J 388(Pt 1):65–73PubMedGoogle Scholar
  120. Thompson ED, Burwinkel KE, Chava AK, Notch EG, Mayer GD (2010) Activity of Phase I and Phase II enzymes of the benzo[a]pyrene transformation pathway in zebrafish (Danio rerio) following waterborne exposure to arsenite. Comp Biochem Physiol C Toxicol Pharmacol 152(3):371–378PubMedCrossRefGoogle Scholar
  121. Tseng HP, Hseu TH, Buhler DR, Wang WD, Hu CH (2005) Constitutive and xenobiotics-induced expression of a novel CYP3A gene from zebrafish larva. Toxicol Appl Pharmacol 205:247–258PubMedCrossRefGoogle Scholar
  122. Van den Bulck K, Hill A, Mesens N, Diekmann H, De Schaepdrijver L, Lammens L (2011) Zebrafish developmental toxicity assay: a fishy solution to reproductive toxicity screening, or just a red herring? J Reprod Toxicol 32(2):213–219CrossRefGoogle Scholar
  123. Westerfield M (1995) The zebrafish book: a guide for the laboratory use of zebrafish (Danio rerio), 3rd edn. University of Oregon Press, EugeneGoogle Scholar
  124. Williams FE, Messer WS Jr (1998) Memory function and muscarinic receptors in zebrafish. Soc Neurosci Abstr 24:182Google Scholar
  125. Williams FE, White D, Messer WS (2002) A simple spatial alternation task for assessing memory function in zebrafish. Behav Processes 58:125–132PubMedCrossRefGoogle Scholar
  126. Winter MJ, Redfern WS, Hayfield AJ, Owen SF, Valentin JP, Hutchinson TH (2008) Validation of a larval zebrafish locomotor assay for assessing the seizure liability of early-stage development drugs. J Pharmacol Toxicol Methods 57:176–187PubMedCrossRefGoogle Scholar
  127. Woosley RL (1996) Cardiac actions of antihistamines. Annu Rev Pharmacol Toxicol 36:233–252PubMedCrossRefGoogle Scholar
  128. Wullimann MF, Mueller T (2004) Teleostean and mammalian forebrains contrasted: evidence from genes to behavior. J Comp Neurol 475:143–162PubMedCrossRefGoogle Scholar
  129. Xu X (1997) NMDA receptor antagonist MK-801 selectively impairs learning of the contiguity of the conditioned stimulus and unconditioned stimulus in goldfish. Pharmacol Biochem Behav 58:491–496PubMedCrossRefGoogle Scholar
  130. Xu X, Davis RE (1992) N-methyl-d-aspartate receptor antagonist MK-801 impairs learning but not memory fixation or expression of classical fear conditioning in goldfish (Carassius auratus). Behav Neurosci 106:307–314PubMedCrossRefGoogle Scholar
  131. Xu X, Scott-Scheiern T, Kempker L, Simons K (2007) Active avoidance conditioning in zebrafish (Danio rerio). Neurobiol Learn Mem 87:72–77PubMedCrossRefGoogle Scholar
  132. Yang T, Snyders D, Roden DM (2001) Drug block of I(kr): model systems and relevance to human arrhythmias. J Cardiovasc Pharmacol 38:737–744PubMedCrossRefGoogle Scholar
  133. Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M, Murray KT, Norris K, George AL Jr, Roden DM (2002) Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 105:1943–1948PubMedCrossRefGoogle Scholar
  134. Yap YG, Camm AJ (1999) Arrhymogenic mechanisms of non-sedating antihistamines. Clin Exp Allergy 29(3):174–181PubMedCrossRefGoogle Scholar
  135. Zhdanova IV, Wang SY, Leclair OU, Danilova NP (2001) Melatonin promotes sleep-like state in zebrafish. Brain Res 903:263–268PubMedCrossRefGoogle Scholar
  136. Zok S, Görge G, Kalsch W, Nagel R (1991) Bioconcentration, metabolism and toxicity of substituted anilines in the zebrafish (Brachydanio rerio). Sci Total Environ 109–110:411–421PubMedCrossRefGoogle Scholar
  137. Zon LI, Peterson RT (2005) In vivo drug discovery in the zebrafish. Nat Rev Drug Discov 4:35–44PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Business Engagement & Innovation ServicesUniversity of NottinghamNottinghamUnited Kingdom

Personalised recommendations