Aquatic toxicology of fluoxetine: Understanding the knowns and the unknowns

Abstract

Fluoxetine is one of the most prescribed psychotropic medications, and is an agent of increasing interest for environmental toxicology. Fish and other aquatic organisms are excellent models to study neuroactive small molecules like fluoxetine. However, prone to variance due to experimental factors, data obtained in these models need to be interpreted with caution, using proper experimental protocols, study designs, validated endpoints as well as well-established models and tests. Choosing the treatment protocol and dose range for fluoxetine and other serotonergic drugs is critical for obtaining valid test results and correct data interpretation. Here we discuss the value of aquatic models to study fluoxetine effects, based on prior high-quality research, and outline the directions of future translational studies in the field. We review fluoxetine-evoked phenotypes in acute vs. chronic protocols, discussing them in the contact of complex role of serotonin in behavioral regulation. We conclude that zebrafish and other aquatic models represent a useful in-vivo tool for fluoxetine pharmacology and (eco)toxicology research.

Introduction

Fluoxetine (Prozac) is a potent psychotropic drug, acting as a selective serotonin reuptake inhibitor (SSRI) to block the plasma membrane serotonin transporter, SERT (Fabbri et al., 2014, Kalueff et al., 2010, Murphy and Lesch, 2008, Stewart et al., 2013). SSRIs are currently the most prescribed psychotropic medications, and fluoxetine is the most commonly used SSRI. Therefore, fluoxetine has rapidly become one of the most important drugs in biomedicine. With the growing number of disorders treated by fluoxetine/SSRIs (from anxiety to depression and obsessions), both the annual intake and the number of patients taking these drugs, are rapidly rising. In addition to desired antidepressant effects, this also results in increased incidence of serotonin toxicity—a potentially lethal toxidrome associated with an overdose and/or combination of serotonergic drugs (Bertorini, 1997, Haberzettl et al., 2013, Kalueff et al., 2008). Paralleling clinical data, multiple experimental animal models, ranging from rodents (Haberzettl et al., 2013, Kalueff et al., 2008, Kalueff et al., 2010) to aquatic species (Egan et al., 2009, Stewart et al., 2013), have been developed to address various aspects of SSRI antidepressant action and toxicity.

Because of their increasing usage globally, fluoxetine and other SSRIs also represent a growing concern for environmental biology and aquatic toxicology (Brooks, 2014, Clements and Schreck, 2007, Dzieweczynski and Hebert, 2012, Fent et al., 2006, Fernandes et al., 2011, Kohlert et al., 2012, Lajeunesse et al., 2011, Mennigen et al., 2010a, Mennigen et al., 2010b, Mennigen et al., 2011, Morando et al., 2009, Ramirez et al., 2009, Schultz et al., 2010, Schultz et al., 2011, Silva et al., 2014, Sumpter et al., 2014, Sumpter and Margiotta-Casaluci, 2014, Weinberger and Klaper, 2014, Winder et al., 2012).

We have read with interest a recent thoughtful paper in this Journal by Sumpter and colleagues, evaluating the potency of fluoxetine in various aquatic species (Sumpter et al., 2014). As we welcome in-depth analyses of pharmacology and toxicology of this drug (Sumpter and Margiotta-Casaluci, 2014), the field may benefit from further critical discussion of this topic.

Our present contribution to this discussion will be limited to zebrafish (Danio rerio), an aquatic vertebrate species we have worked with extensively, testing SSRIs. This species also represents an excellent model for translational neuroscience of complex human brain disorders (Kalueff et al., 2014a, Kalueff et al., 2014b, Stewart et al., 2014), and is particularly useful for studying genetic (Griffiths et al., 2012, Ziv et al., 2012) and pharmacological mechanisms (Nguyen et al., 2014) of depression and antidepressant action. Finally, zebrafish have been suggested as a sensitive in-vivo neurotoxicological and ecotoxicological screen for various serotonergic drugs, including fluoxetine and other SSRIs (Grossman et al., 2010, Maximino et al., 2013a, Neelkantan et al., 2013, Sackerman et al., 2010, Stewart et al., 2011a, Stewart et al., 2013).