, Volume 27, Issue 4, pp 485–497 | Cite as

The psychoactive drug Escitalopram affects swimming behaviour and increases boldness in zebrafish (Danio rerio)

  • Sebastian V. Nielsen
  • Martin Kellner
  • Per G. Henriksen
  • Håkan Olsén
  • Steen H. Hansen
  • Erik Baatrup


Selective serotonin re-uptake inhibitors are pharmaceuticals used to treat a range of psychological disorders. They are frequently found in surface waters in populated areas. In recent years, they have been shown to affect the behaviour of various aquatic organisms in a way that can have ecological effects. In this study, we exposed zebrafish of both sexes to nominally 0.00, 0.15 and 1.50 µg L−1 Escitalopram in flow-through tanks for three weeks. Subsequently, ten swimming behaviour parameters were quantified using high-resolution video tracking. There were noticeable gender differences in the behaviour responses to Escitalopram. Female fish exposed to 1.50 µg L−1 Escitalopram had a lower maximum swimming velocity, stopped less often and exhibited increased boldness (reduced thigmotaxis) compared to controls. Male fish exposed to 1.50 µg L−1 had a lower maximum swimming velocity compared to control fish. At the end of exposures, both length and weight of the females exposed to 1.50 µg L−1 Escitalopram were significantly less than the group of control fish. In addition, males exposed to 1.50 µg L−1 Escitalopram were significantly shorter than control fish. The behaviour, weight and body length of the fish exposed to nominally 0.15 µg L−1 was not significantly different from control fish in either sex. The results of this study demonstrate that Escitalopram can affect subtle but ecologically important aspects of fish behaviour and lends further credibility to the assumption that Escitalopram is an environmentally active pharmaceutical.


Psychoactive drug SSRI Escitalopram Zebrafish Altered swimming behaviour Increased boldness 



This work was supported by the Faculty of Science and Technology, Aarhus University, Denmark.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The experiments were conducted in accordance with the guidelines by The Danish Animal Experiments Inspectorate (permission 2012-15-2934-00246).

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. Abbing-Karahagopian V, Huerta C, Souverein PC, de Abajo F, Leufkens HGM, Slattery J et al. (2014) Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications. Eur J Clin Pharmacol 70(7):849–857CrossRefGoogle Scholar
  2. Ansai S, Hosokawa H, Maegawa S, Kinoshita M (2016) Chronic fluoxetine treatment induces anxiolytic responses and altered social behaviors in medaka, Oryzias latipes. Behav Brain Res 303:126–136. CrossRefGoogle Scholar
  3. Baatrup E, Bayley M (1993) Quantitative analysis of spider locomotion employing computer-aided video tracking. Physiol Behav 54(1):83–90CrossRefGoogle Scholar
  4. Baiamonte M, Parker MO, Vinson G, Brennan CH (2016) Sustained effects of developmental exposure to ethanol on Zebrafish anxiety-like behaviour. PLoS ONE 11(2):e0148425. CrossRefGoogle Scholar
  5. Barbosa Junior A, Alves FL, ASP Pereira, Ide LM, Hoffmann A (2012) Behavioral characterization of the alarm reaction and anxiolytic-like effect of acute treatment with fluoxetine in Piauçu fish Physiol Behav 105(3):784–790. CrossRefGoogle Scholar
  6. Bell AM (2005) Behavioural differences between individuals and two populations of stickleback (Gasterosteus aculeatus). J Evol Biol 18:464–473. CrossRefGoogle Scholar
  7. Benotti MJ, Brownawell BJ (2009) Microbial degradation of pharmaceuticals in estuarine and coastal seawater. Environ Pollut 157(3):994–1002. CrossRefGoogle Scholar
  8. Brion F, Tyler CR, Palazzi X, Laillet B, Porcher JM, Garric J, Flammarion P (2004) Impacts of 17β-estradiol, including environmentally relevant concentrations, on reproduction after exposure during embryo-larval-, juvenile- and adult-life stages in zebrafish (Danio rerio). Aquat Toxicol 68(3):193–217CrossRefGoogle Scholar
  9. Brooks BW, Chambliss CK, Stanley JK, Ramirez A, Banks KE, Johnson RD et al. (2005) Determination of select antidepressants in fish from an effluent-dominated stream. Environ Toxicol Chem 24(2):464Google Scholar
  10. Chakraborty T, Shibata Y, Zhou LY, Katsu Y, Iguchi T, Nagahama Y (2011) Differential expression of three estrogen receptor subtype mRNAs in gonads and liver from embryos to adults of the medaka, Oryzias latipes. Mol Cell Endocrinol 333:47–54. CrossRefGoogle Scholar
  11. Clements S, Schreck CB (2007) Chronic administration of fluoxetine alters locomotor behavior, but does not potentiate the locomotor stimulating effects of CRH in Juvenile Chinook Salmon (Oncorhynchus Tshawytscha). Comp Biochem Physiol Part A 147(1):43–49. CrossRefGoogle Scholar
  12. Dahlbom SJ, Lagman D, Lundstedt-Enkel K, Sundström LF, Winberg S (2011) Boldness predicts social status in Zebrafish (Danio rerio). PLoS ONE 6(8):e23565. CrossRefGoogle Scholar
  13. Daughton CG, Ternes TA (1999) Pharmaceuticals and personal care products in the environment: agents of subtle change? Environ Health Perspect 107(Suppl 6):907–938CrossRefGoogle Scholar
  14. Dugatkin LA (1992) Tendency to inspect predators predicts mortality risk in the guppy (Poecilia reticulata). Behav Ecol 3(2):124–127. CrossRefGoogle Scholar
  15. Eaton RC, Farley RD (1974) Spawning cycle and egg-production of Zebrafish, Brachydanio rerio, in laboratory. Copeia 1:195–204. CrossRefGoogle Scholar
  16. Egan RJ, Bergner CL, Hart PC, Cachat JM, Canavello PR, Elegante MF, Elkhayat SI et al. (2009) Understanding behavioral and physiological phenotypes of stress and anxiety in Zebrafish. Behav Brain Res 205(1):38–44. CrossRefGoogle Scholar
  17. Fick J, Lindberg RH, Tysklind M, Larsson DGJ (2010) Predicted critical environmental concentrations for 500 pharmaceuticals. Reg Toxicol Pharmacol 58(3):516–523. CrossRefGoogle Scholar
  18. Fick J, Lindberg RH, Kaj L, Brorström-Lundén E (2011) Results from the Swedish National Screening Pro-gramme 2010 (No. Subreport 3. Pharmaceuticals). Swedish Environmental Research InstituteGoogle Scholar
  19. Fick J, Soederstrom H, Lindberg RH, Phan C, Tysklind M, Larsson DGJ (2009) Contamination of surface, ground, and drinking water from pharmaceutical production. Environ Toxicol Chem 28(12):2522–2527. CrossRefGoogle Scholar
  20. Foran CM, Weston J, Slattery M, Brooks BW, Duane B, Huggett DB (2004) Reproductive assessment of Japanese Medaka (Oryzias Latipes) Following a Four-Week Fluoxetine (SSRI) exposure. Arch Environ Cont Toxicol 46(4):511–517. CrossRefGoogle Scholar
  21. Forsatka MN, Nematollahi MA, Amiri BM, Huang W-B (2014) Fluoxetine inhibits aggressive behaviour during parental care I male fighting fish (Betta splendens, Regan). Ecotoxicology 23:1794–1802. CrossRefGoogle Scholar
  22. Gaworecki KM, Klaine SJ (2008) Behavioral and biochemical responses of hybrid striped bass during and after fluoxetine exposure. Aquat Toxicol 88:207–213. CrossRefGoogle Scholar
  23. Giacomini ACVV, Abreu MS, Giacomini LV, Siebe AMl, Zimerman FF, Rambo CL, Mocelin R, Bonan CD, Piato AL, Barcellos LJG (2016) Fluoxetine and Diazepam acutely modulate stress induced-behavior. Behav Brain Res 296:301–310. CrossRefGoogle Scholar
  24. Giebułtowicz J, Nałęcz-Jawecki G (2014) Occurrence of antidepressant residues in the sewage-impacted Vistula and Utrata rivers and in tap water in Warsaw (Poland). Ecotoxicol Environ Saf 104:103–9. JuneCrossRefGoogle Scholar
  25. Grabicova K, Lindberg RH, Östman M, Grabic R, Randak T, Larsson DGJ et al. (2014) Tissue-specific bioconcentration of antidepressants in fish exposed to effluent from a municipal sewage treatment plant. Sci Total Environ 488–489:46–50CrossRefGoogle Scholar
  26. Grabicova K, Grabic R, Blaha M, Kumar V, Cerveny D, Fedorova G et al. (2015) Presence of pharmaceuticals in benthic fauna living in a small stream affected by effluent from a municipal sewage treatment plant. Water Res 72:145–153CrossRefGoogle Scholar
  27. Henriksen PG, Beedholm K, Baatrup E (2016) Differences in reproductive behavior between spawning and non-spawning zebrafish pairs and the effects of 17α-Ethinylestradiol (EE2). Toxics 4:22–33. CrossRefGoogle Scholar
  28. Hiemke C, Härtter S (2000) Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther 85(1):11–28. CrossRefGoogle Scholar
  29. Huntingford FA (1976) The relationship between anti-predator behaviour and aggression among conspecifics in the three-spined stickleback, Gasterosteus Aculeatus. Anim Behav 24(2):245–260. CrossRefGoogle Scholar
  30. Jantzen CE, Annunziato KM, Cooper KR (2016) Behavioral, morphometric, and gene expression effects in adult zebrafish (danio rerio) embryonically exposed to PFOA, PFOS, and PFNA. Aquat Toxicol 180:123–30. CrossRefGoogle Scholar
  31. Krog JS, Hansen MS, Holm E, Hjulsager CK, Chriél M, Pedersen K et al. (2015) Influenza A(H10N7) Virus in Dead Harbor Seals, Denmark. Emerg Infect Dis 21(4):684–687CrossRefGoogle Scholar
  32. Kragelund C, Litty K, Lindholst S, Langerhuus AT, Møller T, Rasmussen HU et al. (2015) Miljø-og energieffektiv rensning af miljøfremmede stoffer i særligt be-lastet spildevand. Miljøministeriet, NaturstyrelsenGoogle Scholar
  33. Kellner M, Porseryd T, Hallgren S, Porsch-Hällström I, Hansen SH, Olsén KH (2016) Waterborne citalopram has anxiolytic effects and increases locomotor activity in the three-spine stickleback (Gasterosteus Aculeatus). Aquat Toxicol 173:19–28. CrossRefGoogle Scholar
  34. Kellner M, Porseryd T, Porsch-Hällström I, Hansen SH, Olsén KH (2015) Environmentally relevant concentrations of Citalopram partially inhibit feeding in the three-spine stickleback (Gasterosteus Aculeatus). Aquat Toxicol 158:165–70. CrossRefGoogle Scholar
  35. Kohlert JG, Mangan BP, Kodra C, Drako L, Long E, Simpson H (2012) Decreased aggressive and locomotor behaviors in Betta splendens after exposure to fluoxetine. Psychol Rep 110(1):51–62. CrossRefGoogle Scholar
  36. Kreke N, Dietrich DR (2008) Physiological endpoints for potential SSRI interactions in fish. Crit Rev Toxicol 38(3):215–47. CrossRefGoogle Scholar
  37. Kwon J-W, Armbrust KL (2005) Degradation of citalopram by simulated sunlight. Environ Toxicol Chem 24(7):1618. CrossRefGoogle Scholar
  38. Kwon J-W, Armbrust KL (2008) Aqueous solubility, N-octanol–water partition coefficient, and sorption of five selective serotonin reuptake inhibitors to sediments and soils. Bull Environ Contam Toxicol 81(2):128–35. CrossRefGoogle Scholar
  39. Lahti M, Oikari A (2012) Vertical distribution of pharmaceuticals in lake sediments-citalopram as potential chemomarker. Environ Toxicol Chem 31(8):1738–44. CrossRefGoogle Scholar
  40. Lam MW, Young CJ, Brain RA, Johnson DJ, Hanson MA, Wilson CJ, Richards SM, Solomon KR, Mabury SA (2004) Aquatic persistence of eight pharmaceuticals in a microcosm study. Environ Toxicol Chem 23(6):1431. CrossRefGoogle Scholar
  41. Lawrence C (2007) The husbandry of Zebrafish (Danio rerio): a review. Aquaculture 269(1):1–20. CrossRefGoogle Scholar
  42. Lepage O, Larson ET, Mayer I, Winberg S (2005) Serotonin, but not melatonin, plays a role in shaping dominant–subordinate relationships and aggression in Rainbow Trout. Horm Behav 48(2):233–42. CrossRefGoogle Scholar
  43. Lister A, Regan C, Van Zwol J, Van Der Kraak G (2009) Inhibition of egg production in Zebrafish by Fluoxetine and municipal effluents: a mechanistic evaluation. Aquat Toxicol 95(4):320–29. CrossRefGoogle Scholar
  44. Mennigen JA, Martyniuk CJ, Crump K, Xiong H, Zhao E, Popesku J, Anisman H, Cossin AR, Xia X, Trudeau VL (2008) Effects of fluoxetine on the reproductive axis of Female Goldfish (Carassius Auratus). Physiol Genom 35(3):273–82. CrossRefGoogle Scholar
  45. Mennigen JA, Harris EA, Chang JP, Moon TW, Trudeau VL (2009) Fluoxetine affects weight gain and expression of feeding peptides in the female Goldfish Brain. Regul Pept 155(1–3):99–104. CrossRefGoogle Scholar
  46. Mennigen JA, Sassine J, Trudeau VL, Moon TW (2010) Waterborne fluoxetine disrupts feeding and energy metabolism in the Goldfish Carassius Auratus. Aquat Toxicol 100(1):128–37. CrossRefGoogle Scholar
  47. Menuet A, Le Page Y, Torres O, Kern L, Kah O, Pakdel F (2004) Analysis of the estrogen regulation of the zebrafish estrogen receptor (ER) reveals distinct effects of ERalpha, ERbeta1 and ERbeta2. J Mol Endocrinol 32:975–86CrossRefGoogle Scholar
  48. Moretz JA, Martins EP, Robison BD (2007) Behavioral syndromes and the evolution of correlated behavior in Zebrafish. Behav Ecol 18(3):556–62. CrossRefGoogle Scholar
  49. Nakamura Y, Yamamoto H, Sekizawa J, Kondo T, Hirai N, Tatarazako N (2008) The effects of pH on fluoxetine in Japanese medaka (Oryzias latipes): Acute toxicity in fish larvae and bioaccumulation in juvenile fish. Chemosphere 70(5):865–873CrossRefGoogle Scholar
  50. Nash JP, Kime DE, Van der Ven LTM, Wester PW, Brion F, Maack G et al. (2004) Long-term exposure to environmental concentrations of the pharmaceutical ethynylestradiol causes reproductive failure in fish. Environ Health Perspect 112(17):1725–1733. CrossRefGoogle Scholar
  51. Nema S, Hasan W, Bhargava A, Bhargava Y (2016) A novel method for automated tracking and quantification of adult Zebrafish behaviour during anxiety. J Neurosci Met 271:65–75. Scholar
  52. Olsén KH, Ask K, Olsén H, Porsch-Hällström I, Hallgren S (2014) Effects of the SSRI citalopram on behaviours connected to stress and reproduction in Endler guppy. Poecilia wingei Aquat Toxicol 151:97–104. CrossRefGoogle Scholar
  53. Organisation for Economic Cooperation and Development (OECD) (1992) Fish, Early Life Stage Toxicity Test. Guideline No. 210. OECD, Paris, FranceGoogle Scholar
  54. Pawlowski L, Nowak G, Górka Z, Mazela H (1985) Ro 11-2465 (Cyan-Imipramine), Citalopram and Their N-Desmethyl metabolites: effects on the uptake of 5-Hydroxytryptamine and Noradrenaline in vivo and related pharmacological activities. Psychopharmacology 86(1–2):156–63. CrossRefGoogle Scholar
  55. Pérez Maceira JJ, Mancebo MJ, Aldegunde M (2014) The involvement of 5-HT-like receptors in the regulation of food intake in rainbow trout (Oncorhynchus mykiss). Comp Biochem Physiol C Toxicol Pharmacol 161:1–6CrossRefGoogle Scholar
  56. Porseryd T, Kellner M, Caspillo NR, Volkova K, Elabbas L, Ullah S, Olsén H, Dinnétz P, Hällström IP (2017) Combinatory effects of low concentrations of 17α-etinylestradiol and citalopram on non-reproductive behaviour in adult zebrafish (Danio rerio). Aquat Toxicol 193:9–17. CrossRefGoogle Scholar
  57. Pottegård A, Zoëga H, Hallas J, Damkier P (2014) Use of SSRIs among Danish children: a nationwide study. Eur Child Adolesc Psychiatry 23(12):1211–1218CrossRefGoogle Scholar
  58. Prasad P, Ogawa S, Parhar IS (2015) Role of serotonin in fish reproduction. Frontiers in Neuroscience 9Google Scholar
  59. Rani KV, Sehgal N, Goswami SV, Prakash O (2010) Relative potencies of natural estrogens on vitellogenin and choriogenin levels in the Indian freshwater spotted snakehead, Channa punctata: in vivo and in vitro studies. Fish Physiol Biochem 36:587–595. CrossRefGoogle Scholar
  60. Sánchez C, Hyttel J (1999) Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 19(4):467–89. CrossRefGoogle Scholar
  61. Santos LHMLM, Araújo AN, Fachini A, Pena A, Delerue-Matos C, Montenegro MCBSM (2010) Ecotoxicological aspects related to the presence of pharmaceuticals in the aquatic environment. J Hazard Mater 175(1–3):45–95CrossRefGoogle Scholar
  62. Schlüsener MP, Hardenbicker P, Nilson E, Schulz M, Viergutz C, Ternes TA (2015) Occurrence of Venlafaxine, other antidepressants and selected metabolites in the Rhine Catchment in the face of climate change. Environ Pollut 196:247–56. CrossRefGoogle Scholar
  63. Schultz MM, Furlong ET, Kolpin DW, Werner SL, Schoenfuss HL, Barber LB, Blazer VS, Norris DO, Vajda AM (2010) Antidepressant pharmaceuticals in two U.S. Effluent-Impacted Streams: occurrence and fate in water and sediment, and selective uptake in fish neural tissue. Environ Sci Technol 44(6):1918–25. CrossRefGoogle Scholar
  64. Sharma S, Coombs S, Patton P, Perera TBde (2009) The function of wall-following behaviors in the Mexican blind cavefish and a sighted relative, the Mexican tetra (Astyanax). J Comp Physiol A 195(3):225–240. CrossRefGoogle Scholar
  65. Sih A, Bell A, Johnson JC (2004) Behavioral syndromes: an ecological and evolutionary overview. Trends Ecol Evol 19(7):372–378. CrossRefGoogle Scholar
  66. Silva LJG, Pereira AMPT, Meisel LM, Lino CM, Pena A (2015) Reviewing the serotonin reuptake inhibitors (SSRIs) footprint in the aquatic biota: uptake, bioaccumulation and ecotoxicology. Environ Pollut 197:127–143. CrossRefGoogle Scholar
  67. Singer ML, Oreschak K, Rhinehart Z, Robison BD (2016) Anxiolytic effects of fluoxetine and nicotine exposure on exploratory behavior in Zebrafish. PeerJ 4:e2352. CrossRefGoogle Scholar
  68. Stahl SM (1998) Basic psychopharmacology of antidepressants: Part 1. Antidepressants have seven dis-tinct mechanisms of action. J Clin Psychiatry 59:5–14Google Scholar
  69. Toufexis D, Rivarola MA, Lara H, Viau V (2014) Stress and the reproductive axis. J Neuroendocrinol 26(9):573–86. CrossRefGoogle Scholar
  70. Valenti TW, Gould GG, Berninger JP, Connors KA, Keele NB, Prosser KN, Brooks BW (2012) Human therapeutic plasma levels of the selective serotonin reuptake inhibitor (ssri) sertraline decrease serotonin reuptake transporter binding and shelter-seeking behavior in adult male fathead minnows. Environ Sci Technol 46(4):2427–2435. CrossRefGoogle Scholar
  71. Vasskog T, Anderssen T, Pedersen-Bjergaard S, Kallenborn R, Jensen E (2008) Occurrence of selective serotonin reuptake inhibitors in sewage and receiving waters at Spitsbergen and in Norway. J Chromatogr A 1185(2):194–205. CrossRefGoogle Scholar
  72. Vasskog T, Berger U, Samuelsen P-J, Kallenborn R, Jensen E (2006) Selective serotonin reuptake inhibitors in sewage influents and effluents from Tromsø, Norway. J Chromatogr A 1115(1–2):187–95. CrossRefGoogle Scholar
  73. Vaswani M, Linda FK, Ramesh S (2003) Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry 27(1):85–102CrossRefGoogle Scholar
  74. Wahlberg C, Sverige Naturvårdsverket, Stockholm vatten and IVL Svenska miljöinstitutet (2008) Avloppsreningsverkens förmåga att ta hand om läkemedelsrester och andra farliga ämnen: redovisning av regeringsuppdrag: 512-386-06 Rm. Stockholm: NaturvårdsverketGoogle Scholar
  75. Way GP, Kiesel AL, Ruhl N, Snekser JL, McRobert SP (2015) Sex differences in a shoaling-boldness behavioral syndrome, but no link with aggression. Behav Proc 113:7–12. CrossRefGoogle Scholar
  76. Weinberger J, Klaper R (2014) Environmental concentrations of the selective serotonin reuptake inhibitor fluoxetine impact specific behaviors involved in reproduction, feeding and predator avoidance in the Fish Pimephales Promelas (Fathead Minnow). Aquat Toxicol 151:77–83. CrossRefGoogle Scholar
  77. Wilson DS, Clark AB, Coleman K, Dearstyne T (1994) Shyness and boldness in humans and other animals. Trends Ecol Evol 9(11):442–446. CrossRefGoogle Scholar
  78. Winberg S, Thörnqvist P-O (2016) Role of brain serotonin in modulating fish behavior. Curr Zool 62(3):317–323. CrossRefGoogle Scholar
  79. Woldegiorgis A (2011) SSLs Mätningar Av Läkemedel I Vatten Och Korresponderande Regional Försäljning Av Läkemedel I StorstockholmGoogle Scholar
  80. Yuan S, Jiang X, Xia X, Zhang H, Zheng S (2013) Detection, occurrence and fate of 22 psychiatric pharmaceuticals in psychiatric hospital and municipal wastewater treatment plants in Beijing, China. Chemosphere 90(10):2520–25. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Sebastian V. Nielsen
    • 1
  • Martin Kellner
    • 2
  • Per G. Henriksen
    • 1
  • Håkan Olsén
    • 2
  • Steen H. Hansen
    • 3
  • Erik Baatrup
    • 1
  1. 1.Department of Bioscience, ZoophysiologyAarhus UniversityAarhusDenmark
  2. 2.Natural Science, Technology and Environmental StudiesSödertörn UniversityHuddingeSweden
  3. 3.Department of Pharmacy, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations