Time-, dose- and transgenerational effects of fluoxetine on the behavioural responses of zebrafish to a conspecific alarm substance

Shuraiqi, Asma Al; Al-Habsi, Aziz A.; Barry, Michael J.

doi:10.1016/j.envpol.2020.116164

Cited by 31 publications

(30 citation statements)

References 64 publications

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“…Although fluoxetine has been commonly used as an anxiolytic drug in neuropsychiatric studies using zebrafish, time-dose–response studies looking at the effects of fluoxetine using water exposure as the administration route in this species is lacking. A recent study has explored the long-term effects of fluoxetine in zebrafish behavior up to 28 days after acute exposure to different concentrations, where the authors found that the fluoxetine effects vary depending on time of behavioral testing (Al Shuraiqi et al 2021 ). However, fluoxetine short time-dose–response in anxiety-related paradigms is still unknown being an important step for the understanding of data variability across labs and the mechanisms underlying fluoxetine inducing anxiolytic and anxiogenic phenotypes.…”

Section: Discussionmentioning

confidence: 99%

The zebrafish (Danio rerio) anxiety test battery: comparison of behavioral responses in the novel tank diving and light–dark tasks following exposure to anxiogenic and anxiolytic compounds

2021

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Rationale Triangulation of approaches (i.e., using several tests of the same construct) can be extremely useful for increasing the robustness of the findings being widely used when working with behavioral testing, especially when using rodents as a translational model. Although zebrafish are widely used in neuropharmacology research due to their high-throughput screening potential for new therapeutic drugs, behavioral test battery effects following pharmacological manipulations are still unknown. Methods Here, we tested the effects of an anxiety test battery and test time following pharmacological manipulations in zebrafish by using two behavioral tasks: the novel tank diving task (NTT) and the light–dark test (LDT). Fluoxetine and conspecific alarm substance (CAS) were chosen to induce anxiolytic and anxiogenic-like behavior, respectively. Results For non-drug-treated animals, no differences were observed for testing order (NTT → LDT or LDT → NTT) and there was a strong correlation between performances on the two behavioral tasks. However, we found that during drug treatment, NTT/LDT responses are affected by the tested order depending on the test time being fluoxetine effects higher at the second behavioral task (6 min later) and CAS effects lower across time. Conclusions Overall, our data supports the use of baseline behavior assessment using this anxiety test battery. However, when working with drug exposure, data analysis must carefully consider time-drug-response and data variability across behavioral tasks.

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Section: Discussionmentioning

confidence: 99%

The zebrafish (Danio rerio) anxiety test battery: comparison of behavioral responses in the novel tank diving and light–dark tasks following exposure to anxiogenic and anxiolytic compounds

2021

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“…This is considered to underlie the persistent developmental neurotoxicity of VNX. Nevertheless, for both VNX and FLX, additional sex-specific transgenerational effects on neurobehaviour have also been demonstrated, rooted in the disruption of the cortisol stress axis [ 34 , 35 , 36 ]. The lack of locomotor recovery observed in 5-dpf zebrafish exposure to VNX, indeed, supports a DNT involvement for this compound.…”

Section: Discussionmentioning

confidence: 99%

“…For VNX, recent studies have shown that VNX exposure starting at early stages can alter neurobehaviour at 5 dpf [ 32 , 33 ]. In addition, for FLX and VNX transgenerational changes in neurobehaviour have also been reported [ 34 , 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test

Atzei

Jense

Zwart

et al. 2021

IJERPH

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Humans are exposed daily to complex mixtures of chemical substances via food intake, inhalation, and dermal contact. Developmental neurotoxicity is an understudied area and entails one of the most complex areas in toxicology. Animal studies for developmental neurotoxicity (DNT) are hardly performed in the context of regular hazard studies, as they are costly and time consuming and provide only limited information as to human relevance. There is a need for a combination of in vitro and in silico tests for the assessment of chemically induced DNT in humans. The zebrafish (Danio rerio) embryo (ZFE) provides a powerful model to study DNT because it shows fast neurodevelopment with a large resemblance to the higher vertebrate, including the human system. One of the suitable readouts for DNT testing in the zebrafish is neurobehaviour (stimulus-provoked locomotion) since this provides integrated information on the functionality and status of the entire nervous system of the embryo. In the current study, environmentally relevant pharmaceuticals and their mixtures were investigated using the zebrafish light-dark transition test. Zebrafish embryos were exposed to three neuroactive compounds of concern, carbamazepine (CBZ), fluoxetine (FLX), and venlafaxine (VNX), as well as their main metabolites, carbamazepine 10,11-epoxide (CBZ 10,11E), norfluoxetine (norFLX), and desvenlafaxine (desVNX). All the studied compounds, except CBZ 10,11E, dose-dependently inhibited zebrafish locomotor activity, providing a distinct behavioural phenotype. Mixture experiments with these pharmaceuticals identified that dose addition was confirmed for all the studied binary mixtures (CBZ-FLX, CBZ-VNX, and VNX-FLX), thereby supporting the zebrafish embryo as a model for studying the cumulative effect of chemical mixtures in DNT. This study shows that pharmaceuticals and a mixture thereof affect locomotor activity in zebrafish. The test is directly applicable in environmental risk assessment; however, further studies are required to assess the relevance of these findings for developmental neurotoxicity in humans.

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“…Thus, an increase in the consumption of antidepressants is expected and will consequently lead to increased environmental levels and potential effects to biota present in an aquatic environment, the final destination of environmental pollutants. Fluoxetine, known to be a selective serotonin reuptake inhibitor (SSRI), is generally prescribed for the treatment of human depression, anxiety, compulsive behavior, and eating disorders [2][3][4][5][6][7]. This drug is known to act at the central nervous system, blocking the serotonin transport, leading to its accumulation in the synaptic cleft [4,5,[8][9][10][11][12][13], allowing an attenuation of anxiety and depressive symptoms (anxiolytic effect) [12,14].…”

Section: Introductionmentioning

confidence: 99%

“…Serotonin (5-HT) is a neurotransmitter that has a fundamental role in regulating the development of the brain and spinal cord and, during this development, acts as an important neurotrophic factor in neuronal proliferation, differentiation, axonal growth, migration, and synaptogenesis [15,16]. Additionally, it has the ability to modulate parameters related to behavior such as locomotion, stress, appetite, reproduction, aggressiveness, and social interactions [2,7,13,[16][17][18][19]. In the freshwater environment, concentrations of fluoxetine have been detected at levels ranging from 0.0004 to 3.645 µg/L in wastewater treatment plants (WWTP) [20][21][22][23][24][25][26][27][28][29][30][31], 0.0005 to 0.056 µg/L in surface waters and groundwaters [29,[31][32][33][34][35][36][37] and, for drinking water, the levels vary between 0.0005 and 0.0008 µg/L [38,39].…”

Section: Introductionmentioning

confidence: 99%

Chronic Effects of Fluoxetine on Danio rerio: A Biochemical and Behavioral Perspective

et al. 2022

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Fluoxetine is an antidepressant widely used to treat depressive and anxiety states. Due to its mode of action in the central nervous system (selective serotonin reuptake inhibitor (SSRI)), it becomes toxic to non-target organisms, leading to changes that are harmful to their survival. In this work, the effects of fluoxetine on juvenile zebrafish (Danio rerio) were evaluated, assessing biochemical (phase II biotransformation—glutathione S-transferase (GST), neurotransmission—acetylcholinesterase (ChE), energy metabolism—lactate dehydrogenase (LDH), and oxidative stress—glutathione peroxidase (GPx)) and behavior endpoints (swimming behavior, social behavior, and thigmotaxis) after 21 days exposure to 0 (control), 0.1, 1 and 10 µg/L. Biochemically, although chronic exposure did not induce significant effects on neurotransmission and energy metabolism, GPx activity was decreased after exposure to 10 µg/L of fluoxetine. At a behavioral level, exploratory and social behavior was not affected. However, changes in the swimming pattern of exposed fish were observed in light and dark periods (decreased locomotor activity). Overall, the data show that juvenile fish chronically exposed to fluoxetine may exhibit behavioral changes, affecting their ability to respond to environmental stressors and the interaction with other fish.

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Time-, dose- and transgenerational effects of fluoxetine on the behavioural responses of zebrafish to a conspecific alarm substance

Cited by 31 publications

References 64 publications

The zebrafish (Danio rerio) anxiety test battery: comparison of behavioral responses in the novel tank diving and light–dark tasks following exposure to anxiogenic and anxiolytic compounds

The zebrafish (Danio rerio) anxiety test battery: comparison of behavioral responses in the novel tank diving and light–dark tasks following exposure to anxiogenic and anxiolytic compounds

Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test

Chronic Effects of Fluoxetine on Danio rerio: A Biochemical and Behavioral Perspective

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