Article

Perspectives on zebrafish neurobehavioral pharmacology

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  • ZENEREI Institute
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... For example, it has a typical vertebrate brain that shares its basic neuroanatomical layout with that of other vertebrate species (Tropepe and Sive, 2003), and its neurotransmitter systems are also similar to those of mammals (Chatterjee and Gerlai, 2009). For the latter reason, and not surprisingly, drugs developed for human clinical applications, or for other mammalian species, have often been found efficacious in zebrafish acting through similar if not identical receptors and biochemical mechanisms compared to those of mammals Levin et al., 2015). For these reasons, the zebrafish has been suggested as an appropriate laboratory tool for the screening of not only mutations but also drugs and compounds. ...
... Why should any experimenter use it then? There are numerous specific reasons, some of which we have discussed in this review, others have been emphasized elsewhere in the literature (Chen and Ekker, 2004;Conant and Wolfe, 2008;Gerlai, 2010Gerlai, , 2012Gerlai, , 2015Kalueff et al., 2014;Levin et al., 2015;Morris, 2009;Patton and Zon, 2001;Pickart and Klee, 2014;Rihel and Schier, 2012;Sison et al., 2006;Stewart et al., 2015aStewart et al., , 2014. From its practical advantages, low cost and simplicity, through the ease with which it may be manipulated using a variety of tools, to its translational relevance, many of the features of the zebrafish suggest that this small fish will continue to make waves in research. ...
Article
The zebrafish represents an excellent compromise between system complexity and practical simplicity, features that make it useful for modeling and mechanistic analysis of complex brain disorders. Also promising are screens for psychoactive drugs with effects on larval and adult zebrafish behavior. This review, based upon a recent symposium held at the 2016 IBNS Congress, provides different perspectives on how the zebrafish may be utilized to advance research into human central nervous system disorders. It starts with a discussion on an important bottleneck in zebrafish research, measuring the behavior of this species (specifically shoaling), and continues with examples on research on autism spectrum disorder in larval zebrafish, on screening natural products for compounds with psychoactive properties in adult zebrafish, and on the development of a zebrafish model of fetal alcohol spectrum disorders. By providing information on a broad spectrum of brain disorders, experimental methods, and scientific approaches using both larval and adult zebrafish, the review is intended to showcase this underutilized laboratory species for behavioral neuroscience and psychopharmacology research.
... In recent years, the zebrafish (Danio rerio) has emerged as a new alternative to study a wide range of complex behavioral and neuropsychiatric disorders, such as schizophrenia and depression [7][8][9] . Importantly, zebrafish have been shown to develop conditioned place preference and withdrawal symptoms after exposure to opioids and other drugs of abuse, such as cocaine and alcohol [10][11][12][13][14] . ...
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Opioid use disorder (OUD) has become a leading cause of death in the US, yet current therapeutic strategies remain highly inadequate. To identify novel potential treatments for OUD, we screened a targeted selection of over 100 drugs, using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride did not interfere with the antinociceptive effect of opioids in rat models of neuropathic pain. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish, in a fashion akin to the effects of finasteride. Our results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new option for this disorder.
... The zebrafish (Danio rerio) has become an outstanding tool for biological psychiatry (Levin et al., 2015) and neurodevelopmental studies (Roper and Tanguay, 2018), due to its fast embryonic ex-utero development and highly conserved genetic programming during early stages of life (Kalueff et al., 2013). Thus, this study aimed to evaluate the long-term effects of embryonic exposure to low concentrations of PM through behavioral endpoints across different developmental stages. ...
Article
Permethrin (PM) is one of the most used synthetic pyrethroid worldwide. Exposure to this compound during pregnancy and early childhood has been indicated as a risk factor for neurodevelopmental disorders. We evaluated the long-term effects of embryonic PM exposure in different stages of zebrafish development. Briefly, embryos (3 hpf) were exposed to sub-lethal concentrations of PM (25 and 50 μg.L-1) during 24 h and then behavioral parameters were evaluated during embryonic (28 hpf), eleutheroembryonic (3 dpf), larval (7 dpf), and adult stages (90 dpf). PM exposure decreased spontaneous movement at 28 hpf and decreased thigmotaxis in eleutheroembryos. The long-term effects of PM include changes in non-motor behaviors such as fear and anxiety in larva and adults. Adults embryonically exposed to PM also showed a significant increase in aggressiveness parameters. These results demonstrated that embryonic exposure to PM induces persistent neurotoxic effects in adulthood, which can impair the cognitive and behavioral fitness of non-target species contributing to a rise in neurodevelopmental disorders.
... The zebrafish model has been used widely in studies of developmental neurobehavioral toxicology (Bailey et al., 2013;Guo, 2009;Joseph et al., 2012;Levin et al., 2015;McCollum et al., 2011;Nishimura et al., 2015). In particular, the zebrafish model has been shown to be sensitive to the short-and long-term behavioral impacts of flame retardant chemicals and mixtures Cheng et al., 2017;Glazer et al., 2018;Jarema et al., 2015;Noyes et al., 2015;Oliveri et al., 2015;Usenko et al., 2011;Zhao et al., 2014). ...
Article
As the older class of brominated flame retardants (BFRs) are phased out of commercial use because of findings of neurotoxicity with developmental exposure, a newer class of flame retardants have been introduced, the organophosphate flame retardants (OPFRs). Presently, little is known about the potential for developmental neurotoxicity or the behavioral consequences of OPFR exposure. Our aim was to characterize the life-long neurobehavioral effects of four widely used OPFRs using the zebrafish model. Zebrafish embryos were exposed to 0.1% DMSO (vehicle control); or one of the following treatments isopropylated phenyl phosphate (IPP) (0.01, 0.03, 0.1, 0.3 µM); butylphenyl diphenyl phosphate (BPDP) (0.003, 0.03, 0.3, 3 µM); 2-ethylhexyl diphenyl phosphate (EHDP) (0.03, 0.3, 1 µM); isodecyl diphenyl phosphate (IDDP) (0.1, 0.3, 1, 10 µM) from 0-5 days post fertilization. On Day 6 the larvae were tested for motility under alternating dark and light conditions. Finally, at 5-7 months of age the exposed fish and controls were tested on a battery of behavioral tests to assess emotional function, sensorimotor response, social interaction and predator evasion. These tests showed chemical-specific short-term effects of altered motility in larvae in all of the tested compounds, and long-term impairment of anxiety-related behavior in adults following IPP, BPDP or EHDP exposures. Our results show that OPFRs may not be a safe alternative to the phased-out BFRs and may cause behavioral impacts throughout the lifespan. Further research should evaluate the risk to mammalian experimental models and humans.
... Monoamine neurotransmitters, including serotonin (5-HT), dopamine (DA) and noradrenaline (NA), are implicated in the regulation of a large number of processes, such as motor control, social behaviour, cognition, sleep, appetite, and anxiety in vertebrates [6][7][8][9]. In zebrafish, 5-HT and DA are the two most studied monoamines [10,11]. Serotonin (5-hydroxytryptamine, 5-HT) serves as both a neurotransmitter and hormone; in higher vertebrates, 5-HT acts throughout the body, including the central nervous system (CNS), peripheral nervous system, cardiovascular system, and endocrine system; it also participates in sensory perception and many behaviours [12]. ...
Article
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Background: With increased social pressure, individuals face a high risk of depression. Subsequently, depression affects cognitive behaviour and negatively impacts daily life. Fortunately, the Traditional Chinese Medicine Jia Wei Xiao Yao (JWXY) capsule is effective in reducing depression and improving cognitive behaviour. Methods: The constituents of JWXY capsule were identified by ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry analyses. We analysed behaviours of depression-like zebrafish in the novel tank with an automatic 3D video-tracking system and conducted the colour preference test, as well detected physiological changes after sertraline and JWXY capsule treatments. Results: Both sertraline and JWXY capsule rescued the decreased locomotive behaviour and depression phenotype of zebrafish caused by reserpine. JWXY capsule especially improved the inhibited exploratory behaviour caused by reserpine. In addition, with the onset of depressive behaviour, zebrafish exhibited alterations in cognitive behaviour as indicated by colour preference changes. However, compared with sertraline, JWXY capsule was more efficaciously in rescuing this change in the colour preference pattern. Moreover, an increased level of cortisol, increased expression of tyrosine hydroxylase (TH) and decreased monoamine neurotransmitters, including serotonin (5-HT) and noradrenaline, were involved in the depressive behaviours. In addition, sertraline and JWXY capsule rescued the depressive phenotype and cognitive behaviour of zebrafish by altering the levels of endogenous cortisol and monoamine neurotransmitters. Conclusions: JWXY capsule was more effectively than sertraline in rescuing reserpine-induced depression and cognitive disorder in zebrafish. Potentially, our study can provide new insights into the clinical treatment of depression and the mechanism of action of JWXY capsule.
... The excellent biological characteristics (e.g. small size, easy breeding and high fecundity; short life cycle, rapid development of embryo, transparent embryo and body; Lucas et al., 2014;Wang et al., 2016) and high conservation of gene function and many molecular pathways compared with their human orthologues (Liu et al., 2017b), have made zebrafish emerge as a prominent vertebrate model system based on phenotype for disease modelling (Schartl, 2014;Gurevich et al., 2015), drug screening (Baraban et al., 2013;Veinotte et al., 2014), pharmacology (Levin et al., 2015;Wijk et al., 2017), target identification (Schenone et al., 2013;Shen et al., 2015), and toxicology (Asharani et al., 2011;McGee et al., 2013;Dai et al., 2014;Chakraborty et al., 2016). Zebrafish larvae possess the most homologs of human including heart, intestine, liver, kidney, skin, skeletal muscles, spleen, central nervous system, siwm bladder (SB; be homologous to lung; Zhang et al., 2016), and so on. ...
... Because zebrafish display a high genetic and physiological conservation (Levin et al., 2015;Stewart et al., 2015), as well as robust aversive behavioral responses (Kalueff et al., 2013), this species is a suitable model organism in biological psychiatry and translational neuroscience research (Caramillo et al., 2015;Lima et al., 2016;Maximino et al., 2015;Stewart et al., 2014). Here, CAS exposure was associated with the most preferred side of the CPA apparatus, eliciting avoidance tendencies as well as fearful responses (freezing, risk assessment) which were not observed in the 'safe' compartment. ...
Article
Anxiety, trauma- and stressor-related disorders are severe psychiatric conditions that affect human population worldwide. Given their genetic tractability, evolutionarily conserved neurotransmitter systems, and extensive behavioral repertoire, zebrafish have become an emergent model organism in translational neuroscience. Here, we investigate whether a single exposure to conspecific alarm substance (CAS) produces fear conditioning in zebrafish using a conditioned place aversion (CPA) paradigm, as well as the persistence of aversive responses at different time intervals. While CAS elicited freezing and erratic movements at conditioning phase, zebrafish showed a robust avoidance for the CAS-paired compartment and increased risk assessment up to 7 days postconditioning. Additionally, we observed the existence of two behavioral phenotypes (high- and low-avoider fish) that present different fear-like responses at conditioning phase and evasion of the conditioning side at postconditioning trials. Collectively, we show a prolonged conditioned place aversion in zebrafish after a single CAS conditioning session, reinforcing the use of fear conditioning protocols as valuable strategies for modeling psychiatric disorders-related phenotypes in zebrafish.
... are scarcer. It has been demonstrated that the two neurotransmitters play a similar role to that observed in other vertebrates [2][3][4][5][6][7][8]. ...
Article
Full-text available
Zebrafish were exposed through diet to two environmentally relevant polycyclic aromatic hydrocarbons (PAHs) mixtures of contrasted compositions, one of pyrolytic (PY) origin and one from light crude oil (LO). Monoamine concentrations were quantified in the brains of the fish after six month of exposure. A significant decrease in noradrenaline (NA) was observed in fish exposed to both mixtures, while a decrease in serotonin (5HT) and dopamine (DA) was observed only in LO-exposed fish. A decrease in metabolites of 5HT and DA was observed in fish exposed to both mixtures. Several behavioural disruptions were observed that depended on mixtures, and parallels were made with changes in monoamine concentrations. Indeed, we observed an increase in anxiety in fish exposed to both mixtures, which could be related to the decrease in 5HT and/or NA, while disruptions of daily activity rhythms were observed in LO fish, which could be related to the decrease in DA. Taken together, these results showed that (i) chronic exposures to PAHs mixtures disrupted brain monoamine contents, which could underlie behavioural disruptions, and that (ii) the biological responses depended on mixture compositions.
Article
Opioid use disorder (OUD) has become a leading cause of death in the US, yet current therapeutic strategies remain highly inadequate. To identify novel potential treatments for OUD, we screened a targeted selection of over 100 drugs using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride reduced the physical signs associated with opioid withdrawal. In rat models of neuropathic pain, finasteride did not alter the antinociceptive effect of opioids and reduced withdrawal-induced hyperalgesia. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish in a fashion akin to the effects of finasteride. These results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new treatment option for this disorder.
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