Behavioral effects of citalopram, tramadol, and binary mixture in zebrafish (Danio rerio) larvae

Raougina-Laouisa Bachour,Oksana Golovko,Martin Kellner,Johannes Pohl

doi:10.1016/j.chemosphere.2019.124587

Raougina-Laouisa Bachour, Oksana Golovko + Show 2 more

Open Access

https://doi.org/10.1016/j.chemosphere.2019.124587

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Abstract

Pharmaceuticals are emerging as environmentally problematic compounds. As they are often not appropriately removed by sewage treatment plants, pharmaceutical compounds end up in surface water environments worldwide at concentrations in the ng to μg L−1 range. There is a need to further explore single compound and mixture effects using e.g. in vivo test model systems. We have investigated, for the first time, behavioral effects in larval zebrafish (Danio rerio) exposed to a binary mixture of an antidepressant drug (citalopram) and a synthetic opioid (tramadol). Citalopram and tramadol have a similar mode of action (serotonin reuptake inhibition) and are known to produce drug-drug interactional effects resulting in serotonin syndrome (SS) in humans. Zebrafish embryo-larvae were exposed to citalopram, tramadol and 1:1 binary mixture from fertilization until 144 h post-fertilization. No effects on heart rate, spontaneous tail coiling, or death/malformations were observed in any treatment at tested concentrations. Behavior (hypoactivity in dark periods) was on the other hand affected, with lowest observed effect concentrations (LOECs) of 373 μg L−1 for citalopram, 320 μg L−1 for tramadol, and 473 μg L−1 for the 1:1 mixture. Behavioral EC50 was calculated to be 471 μg L−1 for citalopram, 411 μg L−1 for tramadol, and 713 μg L−1 for the 1:1 mixture. The results of this study conclude that tramadol and citalopram produce hypoactivity in 144 hpf zebrafish larvae. Further, a 1:1 binary mixture of the two caused the same response, albeit at a higher concentration, possibly due to SS.

Highlights

Pharmaceutical drug residues are regularly detected in the surface water environment in the ng to mg LÀ1 concentration range (Fick et al, 2009; Grabicova et al, 2017)
Uncovering mixture effects of selective serotonin reuptake inhibitor (SSRI) and opioids on zebrafish models can inform about the risk of polluting the environment with human pharmaceuticals affecting the 5-HT system
This study was performed to understand whether citalopram, tramadol, and a mixture thereof would affect developing zebrafish embryo spontaneous tail coiling, heart rate, death/malformation incidence, and larval behavior

Summary

Introduction

Pharmaceutical drug residues are regularly detected in the surface water environment in the ng to mg LÀ1 concentration range (Fick et al, 2009; Grabicova et al, 2017). Pharmaceutical compounds end up in surface water mainly due to inadequate removal in sewage treatment plants (Lindberg et al, 2014; Luo et al, 2014). Bachour et al / Chemosphere 238 (2020) 124587 proposed to have about 86% orthologs to human drug targets (Gunnarsson et al, 2008). Water-dwelling organisms continuously exposed to anti-depressant and anti-anxiety drugs might be affected by e.g. increased predation pressure (Klaminder et al, 2019). There is a need for research establishing drug-drug interaction properties of pharmaceuticals mixtures in non-target species (Backhaus, 2014; Gunnarsson et al, 2019)

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