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Selective serotonin re-uptake inhibitors in the environment: Effects of citalopram on fish behaviour
Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Environmental Science. Södertörn University, Centre for Baltic and East European Studies (CBEES), Baltic & East European Graduate School (BEEGS).
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Selective serotonin re-uptake inhibitors (SSRIs) are a class of anxiolytic and anti-depressant drugs. SSRIs act on the evolutionarily ancient serotonergic system which is virtually identical throughout the vertebrate phylum. Serotonin is involved in a wide range of processes ranging from neuronal and craniofacial embryonic development to regulation of behaviour. However, SSRIs are also emerging pollutants, mainly entering the environment via sewage treatment plants. Since the serotonergic system is virtually identical in humans and other animals, exposed animals will be affected in similar ways as humans and suspicions are rising that ecologically important behaviours may be affected in subtle ways. Using the three-spined stickleback (Gasterosteus aculeatus) and zebrafish (Danio rerio) as model organisms, this thesis focuses on the behavioural effects of SSRIs in fish. The SSRI used throughout this thesis is citalopram, which has been found in fish in coastal areas of the Baltic Sea and other parts of the world.

Effects on behaviour were investigated using several different tests measuring stress response, feeding behaviour, aggression and locomotor activity. Anxiolytic effects of 0.1 μg/l, 1.5 μg/l 15 μg/l were investigated as well as effects of 0.15 μg/l and 1.5 μg/l on feeding behaviour. Because serotonin is involved in the development of the nervous system, the effects of developmental exposure to 1.5 μg/l was studied after 100 days of remediation. Finally, because SSRIs rarely occur alone in natural waters, the effects on zebrafish of citalopram in a cocktail scenario, with the anxiogenic compound 17α-ethinyl estradiol (EE2 ) was also investigated. Citalopram was found to have anxiolytic effects on the three-spined stickleback at 0.1 μg/l, 1.5 μg/l and 15 μg/l.

Citalopram also suppressed feeding behaviour within a week of exposure and at concentrations as low as 0.15 μg/l. Developmental exposure to 1.5 μg/l for 30 days was found to increase aggression and feeding behaviour and to reduce locomotor activity. The changes were persistent and remained in adult fish. In the cocktail scenario, citalopram in single-substance exposure had anxiolytic effects on one parameter in the novel tank test at 0.1 μg/l. Citalopram enhanced the anxiogenic effects of EE2 in the novel tank test, but in the scototaxis test citalopram appeared to counteract the effects of EE2. It is concluded that citalopram has the potential to affect behaviour in fish at concentrations that have been found in close proximity of sewage treatment plants.

Abstract [sv]

Det serotonerga systemet är i stort sett identiskt hos människor och övriga vertebrater. Serotonin är inblandat i ett stort antal kroppsliga funktioner, bland annat stressreaktioner, reglering av födobeteende och aggression. Vidare är serotonin med och reglerar nervsystemets tillväxt under embryonalutvecklingen. Selektiva serotoninåterupptagshämmare (SSRI) är en grupp antidepressiva och lugnande läkemedel vars användning har ökat snabbt på senare år då de är effektiva och har få allvarliga bieffekter. SSRI verkar på det serotonerga systemet, genom att blockera återupptaget av serotonin i den presynaptiska nervänden. SSRI har tilldragit sig en viss uppmärksamhet som potentiella miljöhot då de visats kunna påverka ekologiskt relevanta beteenden hos fisk och andra akvatiska organismer vid relativt låga koncentrationer i miljön samtidigt som de bryts ned dåligt i avloppsreningsverk. Avhandlingen fokuserar på ekologiskt relevanta beteendeeffekter av SSRI på fisk, med storspigg (Gasterosteus aculeatus) och zebrafisk (Danio rerio) som modellorganismer. Citalopram har använts som försökssubstans då det anses vara den SSRI som har minst antal sidoeffekter på till exempel det dopaminerga systemet. Citalopram förekommer i utloppsvatten från reningsverk i alla industrialiserade länder och har även hittats i abborre i Östersjön.

Effekter av exponering för SSRI har påvisats med hjälp av olika beteendetest. Skototaxi-test och novel tank diving test mäter stressresponsen genom att kvantifiera preferensen för närhet till botten och mörka omgivningar. Ätbeteende har mätts som antal utfall mot en matbit under en given tidsperiod och aggression har mätts genom att räkna antal bett mot en spegel. Anxiolytiska effekter undersöktes vid koncentrationer på 0,1 µg/l, 15 µg/l och 1,5 µg/l. Effekter på ätbeteende undersöktes vid 0,15 µg/l och 1,5 µg/l. Eftersom serotonin är inblandat i embryonalutvecklingen testades de beteendemässiga effekterna av exponering för 1,5 µg/l under utvecklingen. Då citalopram sällan förekommer ensamt i miljön testades ett cocktailscenario där zebrafisk samtidigt exponerades för citalopram och den anxiogena substansen 17α-etinylestradiol (EE2).

Citalopram befanns ha anxiolytisk verkan på storspigg samt undertrycka ätbeteendet. Effekter på ätbeteendet uppstod inom en vecka efter exponering och vid den minsta testade dosen vilken var 0,15 µg/l. Storspigg som exponerats under embryonalutvecklingen var mer aggressiva, hade lägre lokomotoraktivitetoch gjorde fler utfall mot mat då de testades 100 dagar efter att exponeringen avslutats. Samtidigt exponering för citalopram och den anxiogena substansen 17α-etinylestradiol (EE2) gav tvetydiga resultat. Citalopram ensamt hade ingen signifikant påverkan på beteendet i detta försök. I skototaxitestet motverkade citalopram den anxiogena effekten av EE2 medan det förstärkte den anxiogena effekten i novel tank. Sammanfattningsvis har citalopram effekter på ekologiskt relevanta beteenden hos fisk i koncentrationer som förekommer i ytvatten. Det har också permanenta effekter på beteende om exponeringen sker under embryonalutvecklingen. Dessa resultat gör det sannolikt att citalopram och andra SSRI har ekologiska effekter i påverkade vattendrag.

Place, publisher, year, edition, pages
Huddinge: Södertörns högskola, 2017. , 63 p.
Series
Södertörn Doctoral Dissertations, ISSN 1652-7399 ; 137
Keyword [en]
Citalopram, SSRI, stickleback, Baltic, behaviour, fish, feeding, anxiety, boldness, serotonin, development
Keyword [sv]
Storspigg, serotonin, östersjön, SSRI, läkemedel, miljö, citalopram, ätbeteende, beteende, utveckling
National Category
Environmental Sciences
Research subject
Environmental Studies; Baltic and East European studies
Identifiers
URN: urn:nbn:se:sh:diva-32422ISBN: 978-91-87843-96-9 (print)ISBN: 978-91-87843-97-6 (electronic)OAI: oai:DiVA.org:sh-32422DiVA: diva2:1089319
Public defence
2017-06-01, MA624, Alfred Nobels allé 7, Huddinge, 13:00 (English)
Opponent
Supervisors
Funder
Stockholm County Council, 806/3.1.1/2014The Foundation for Baltic and East European Studies, 1352/3.1.1/2015
Available from: 2017-05-10 Created: 2017-04-19 Last updated: 2017-09-25Bibliographically approved
List of papers
1. Environmentally relevant concentrations of citalopram partially inhibit feeding in the three-spine stickleback (Gasterosteus aculeatus)
Open this publication in new window or tab >>Environmentally relevant concentrations of citalopram partially inhibit feeding in the three-spine stickleback (Gasterosteus aculeatus)
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2015 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 158, 165-170 p.Article in journal (Refereed) Published
Abstract [en]

Selective Serotonin Re-uptake Inhibitors (SSRI) are mood-altering, psychotropic drugs commonly used in the treatment of depression and other psychological illnesses. Many of them are poorly degraded in sewage treatment plants and enter the environment unaltered. In laboratory studies, they have been demonstrated to affect a wide range of behaviours in aquatic organisms. In this study we investigated the effect of a three-week exposure to 0.15 and 1.5 μg/l of the SSRI citalopram dissolved in the ambient water on the feeding behaviour in three-spine stickleback (Gasterosteus aculeatus). Feeding, measured as the number of attacks performed on a piece of frozen bloodworms during a 10-min period, was reduced by 30–40% in fish exposed to both 0.15 and 1.5 μg/l citalopram. The effects of the environmentally relevant concentration 0.15 μg/l on feeding, an important fitness characteristic, suggests that the ecological significance of environmental SSRI exposure may be pronounced.

Place, publisher, year, edition, pages
Elsevier, 2015
Keyword
SSRI, citalopram, fish, stickleback, feeding, antidepressant
National Category
Environmental Sciences
Research subject
Environmental Studies
Identifiers
urn:nbn:se:sh:diva-25351 (URN)10.1016/j.aquatox.2014.11.003 (DOI)000348888400018 ()25438122 (PubMedID)2-s2.0-84912082657 (Scopus ID)
Funder
The Foundation for Baltic and East European Studies
Available from: 2014-12-02 Created: 2014-12-02 Last updated: 2017-04-19Bibliographically approved
2. Waterborne citalopram has anxiolytic effects and increases locomotor activity in the three-spine stickleback (Gasterosteus aculeatus)
Open this publication in new window or tab >>Waterborne citalopram has anxiolytic effects and increases locomotor activity in the three-spine stickleback (Gasterosteus aculeatus)
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2016 (English)In: Aquatic Toxicology, ISSN 0166-445X, E-ISSN 1879-1514, Vol. 173, 19-28 p.Article in journal (Refereed) Published
Abstract [en]

Citalopram is an antidepressant drug, which acts by inhibiting the re-uptake of serotonin from the synaptic cleft into the pre-synaptic nerve ending. It is one of the most common drugs used in treatment of depression, it is highly lipophilic and frequently found in sewage treatment plant effluents and surface waters around the world. Citalopram and other selective serotonin re-uptake inhibitors have, at concentrations that occur in nature, been shown to have behavioural as well as physiological effects on fish and other animals. This study is the result of several different experiments, intended to analyse different aspects of behavioural effects of chronic citalopram exposure in fish. Our model species the three-spine stickleback is common in the entire northern hemisphere and is considered to be a good environmental sentinel species. Female three-spine sticklebacks were exposed to 0, 1.5 and 15μg/l nominal concentrations of citalopram for 21 days and subjected to the novel tank (NT) diving test. In the NT test, the fish exposed to 1.5μg/l, but not the 15μg/l fish made a significantly higher number of transitions to the upper half and stayed there for significantly longer time than the fish exposed to 0μg/l. The 15μg/l group, however, displayed a significantly lower number of freeze bouts and a shorter total freezing time. The test for locomotor activity included in the NT test showed that fish treated with 1.5 and 15μg/l displayed a significantly higher swimming activity than control fish both 5-7 and 15-17min after the start of the experiment. In the next experiment we compared fish exposed to 1.5μg/l and 0.15μg/l to pure water controls with regard to shoaling intensity and found no effect of treatment. In the final experiment the propensity of fish treated with 1.5μg/l to approach an unknown object and aggressive behaviour was investigated using the Novel Object test and a mirror test, respectively. The exposed fish ventured close to the unknown object significantly more often and stayed there for significantly longer time than unexposed fish. The aggression test yielded no statistically significant effects. It is concluded that citalopram changes the behaviour of the three-spine stickleback in a way that is likely to have ecological consequences and that it must not be considered an environmentally safe pharmaceutical.

Keyword
Call centre, identity, membership categorization analysis (MCA), multilingualism, omnirelevance, outsourcing, relational talk, transactional talk
National Category
Environmental Sciences Biological Sciences
Research subject
Environmental Studies; Baltic and East European studies
Identifiers
urn:nbn:se:sh:diva-29453 (URN)10.1016/j.aquatox.2015.12.026 (DOI)000372689900003 ()26827268 (PubMedID)2-s2.0-84955596941 (Scopus ID)
Funder
The Foundation for Baltic and East European StudiesStockholm County Council
Available from: 2016-02-05 Created: 2016-02-05 Last updated: 2017-04-19Bibliographically approved
3. Developmental exposure to the SSRI citalopram causes persistent behavioural effects in the three-spined stickleback (Gasterosteus aculeatus)
Open this publication in new window or tab >>Developmental exposure to the SSRI citalopram causes persistent behavioural effects in the three-spined stickleback (Gasterosteus aculeatus)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Selective Serotonin Re-uptake Inhibitors (SSRIs) are a class of psychotropic drugs used to treat depression in both adolescents and pregnant or breast-feeding mothers as well as in the general population. Recent research on rodents points to persistent behavioural effects of pre- and perinatal exposure to SSRI which last into adulthood. To study effects of developmental exposure in fish, three-spine sticklebacks were exposed to 1.5 µg/l of the SSRI citalopram in the ambient water for 30 days, starting two days post-fertilisation. After 100 days of remediation in clean water the fish were put through an extensive test battery. Feeding behaviour was tested as the number of bites against a piece of food and found to be increased in the exposed fish. Aggression levels were measured as the number of bites against a mirror image during 10 minutes and was also found to be significantly increased in the exposed fish. Novel tank behaviour and locomotor activity was tested in an aquarium that had a horizontal line drawn half-way between the bottom and the surface. Neither the latency to the first transition to the upper half, nor the number of transitions or the total time spent in the upper half was affected by treatment. Locomotor activity was significantly reduced in the exposed fish. The light/dark preference was tested in an aquarium where the bottom and walls were black on one side and white on the other. The number of transitions to the white side was significantly reduced in the exposed fish but there was no effect on the latency to the first transition or the total time spent in the white half. The results in the current study indicate that developmental SSRI exposure causes persistent behavioural effects in fish and contribute to the existing knowledge about SSRIs as environmental pollutants.

National Category
Environmental Sciences
Research subject
Environmental Studies
Identifiers
urn:nbn:se:sh:diva-32426 (URN)
Funder
The Foundation for Baltic and East European Studies, 1352/3.1.1/2015Stockholm County Council, 806/3.1.1/2014
Note

As manuscript in dissertation.

Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2017-04-20Bibliographically approved
4. Combinatory effects of low-dose 17alpha-etinyl estradiol and citalopram on behavior in adult zebrafish (Danio rerio)
Open this publication in new window or tab >>Combinatory effects of low-dose 17alpha-etinyl estradiol and citalopram on behavior in adult zebrafish (Danio rerio)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Sewage treatment plant effluents contain a complex mixture of pharmaceuticals, personal care products and industrial chemicals, thus exposing aquatic organisms. Still, the consequences of exposure to combinations of different classes of drugs is largely unknown. In this study, we expose adult zebrafish (Danio rerio) males and females to low, environmentally relevant concentrations of the endocrine disrupting chemical 17α-ethinyl estradiol (EE2) and the selective serotonin re-uptake inhibitor (SSRI) citalopram, alone and in combination, and analyse three non-reproductive behaviours of importance for population fitness.

Two weeks exposure to 0.1 and 0.5 ng/LEE2 resulted in increased anxiety in males in the scototaxis (light/dark preference) test. Significantly longer latency periods before entering the white zone and fewer visits in the white zone were observed in males exposed to both 0.1 and 0.5 ng/LEE2 compared to unexposed males. No significant effects of citalopram alone (0.1 and 0.5 µg/L) were observed in the scototaxis test. The combined exposures (0.1 ng/L EE2 + 0.1 µg/L citalopram and 0.5 ng/L EE2 + 0.5 µg/L citalopram) resulted in abolishment of the anxiogenic effects of EE2, with significantly shorter latency period (low dose) and more transitions to white (high and low dose) than in fish exposed to EE2 alone. No significant effects of either EE2, citalopramor the combination of the two were observed in females. In the novel tank test, significantly more transitions to the upper half of the tank were observed in males exposed to 0.1 µg/L citalopram alone compared to unexposed males while males exposed to 0.1 ng/lEE2 had significantly shorter latency period to enter the upper half. Exposure to the combination of the two low concentrations did, however, result in a significantly longer latency and fewer transitions to upper half compared to both control, EE2- and citalopram-exposed males. These males also spent significantly less time in the upper half than the fish exposed to 0.1 ng/l EE2 or 0.1 µg/l citalopram alone. No significant effects on novel tank behaviour were observed in females or males exposed to the higher concentrations. In the shoaling test, males exposed to 0.1 µg/L citalopram and females exposed to 0.5 ng/l EE2 made significantly fewer transitions away from peers while males exposed to 0.1 µg/L citalopram + 0.1 ng/l EE2 performed significantly more transitions than the fish exposed to 0.1 µg/L citalopram alone.

In conclusion, this study shows that very low concentrations ofEE2, at or slightly above the predicted noeffect concentration (NOEC), affects anxiety in zebrafish males. Furthermore, citalopram, in spite of marginal effect of its own at such low levels, counteracts the response to EE2. This study represents an initial effort to understand the effects on water-living organisms of the cocktails of anthropogenic substances contaminating aquatic environments.

National Category
Environmental Sciences
Research subject
Environmental Studies
Identifiers
urn:nbn:se:sh:diva-32427 (URN)
Funder
Stockholm County Council, 806/3.1.1/2014The Foundation for Baltic and East European Studies, 1352/3.1.1/2015
Note

As manuscript in dissertation.

Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2017-04-20Bibliographically approved

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  • ieee
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