Screening for drugs to reduce aggression in zebrafish
Introduction
Aggression is an adaptive behaviour that animals use to protect offspring, access resources, establish social hierarchies and to defend themselves (Koolhaas et al., 1999). It is an important component of everyday social interactions. However, aggression is metabolically costly (Yuan et al., 2018) and fighting has the potential to lead to injury or death; the expression of this behaviour has to be tightly controlled. Aggression is also a symptom of several human psychiatric disorders. It is a core component of intermittent explosive disorder and a comorbid symptom of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, substance abuse disorder, bipolar disorder, conduct disorder and schizophrenia (Coccaro et al., 1998, Malki et al., 2016, Monuteaux et al., 2009, Nevels et al., 2010). Human aggression can be verbal or physical and may include anger as a sign of hostility. Uncontrolled aggression is a societal problem and can lead to antisocial behaviour, delinquency and crime (Gibbon et al., 2010). Human aggression is managed using a combination of behavioural, cognitive and pharmacological therapies (Vitiello and Stoff, 1997). However, the drugs that are used to treat this behaviour show limited efficacy and may have unwanted side effects (Nevels et al., 2010, Polzer et al., 2007, Scotto Rosato et al., 2012, Wernicke et al., 2003). It is clear that novel drugs with increased potency and a more selective mechanism of action are needed.
Section snippets
Animal models of aggression
There is a long and rich history of studying aggression in the laboratory. Animal models are useful tools to study behaviour because their genetic background and environment can be tightly controlled. It is possible to collect brain tissue, and the levels of neurotransmitters and hormones can be measured (Malki et al., 2016). Animals that are commonly used to study aggression include rats and mice (Takahashi and Miczek, 2014), voles (Gobrogge and Wang, 2011), fish (Freudenberg et al., 2016,
Zebrafish aggression
Zebrafish are a cyprinid schooling fish that have already been used to study aggression (Teles et al., 2013). Characteristic agonistic postures include erecting the fins, thrashing the tail, biting, splashing and directing short bouts of swimming against an opponent (Gerlai et al., 2000, Spence et al., 2008). Both male and female zebrafish express aggression (Dahlbom et al., 2012, Norton et al., 2011), although there may be sex-specific differences in the neurotransmitters that underpin this
Screening for drugs that can alter behaviour
It is challenging to identify drugs for complex behaviours such as aggression because they are influenced by multiple signalling pathways (Pangalos et al., 2007). Recent research has shown that behaviour-based screens represent one approach to circumvent this issue (MacRae and Peterson, 2015, Rihel and Schier, 2012). Compared to single target in vitro screens, whole organism paradigms maintain the complex architecture of the brain and are ideal to examine drugs that act at multiple receptors (
Investigating the effect of known drugs on aggression
Several studies have already shown that drug treatment can alter zebrafish aggression (Echevarria et al., 2011, Herculano and Maximino, 2014). Application of the selective serotonin (5-HT) reuptake inhibitor fluoxetine hydrochloride can reduce aggression (Norton et al., 2011) and alter expression of the 5-HT pathways genes 5-hydroxytryptamine (serotonin) receptor 1b, 5-hydroxytryptamine (serotonin) receptor 2b and solute carrier 6a4b (previously sertb) in the brain (Theodoridi et al., 2017).
Toxicological studies of environmental pollutants
A number of studies have pioneered the use of zebrafish in environmental toxicology. This research has the potential to provide insights into how accumulation of pollutants in the food chain might affect reproduction, social interactions and physiology in both humans and other animals. For example, an increase in zebrafish aggression might alter dominance-subordinate hierarchies, thereby disrupting the formation of social groups with implications for foraging, mating and predator avoidance (
Unbiased zebrafish aggression screens
The zebrafish is an ideal model to conduct an unbiased screen for novel drugs to reduce aggression. Aggression can be measured in juveniles that are small enough to permit several animals to be recorded in parallel; analysis of this behaviour has already been automated; and multiple studies have shown that drugs applied by immersion are behaviourally active (see above). High-throughput screens for compounds that modify sleep, photomotor response, light/dark behaviour, locomotion, freezing and
Investigating the neural circuits that control aggression
A current limitation in zebrafish research is that the neural circuits that control aggression have not been characterised fully. Pharmacological dissection of this behaviour could help address this issue. Mapping the location of drug targets can be used to define the brain areas and cell types that are important for this behaviour. In order to generate an appropriate aggressive response animals have to integrate information from both internal and external stimuli. Activation of the stress axis
Conclusion
Several lines of evidence suggest that zebrafish represent a good model to screen for drugs that can alter aggression. Robust behavioural protocols have been developed and aggressive postures are well characterised (Gerlai et al., 2000, Way et al., 2015). The recent implementation of software that can track pairs of fish simultaneously will provide an exciting opportunity to dissect how dynamic social interactions lead to dominant and subordinate behaviour (Laan et al., 2018). Further research
Conflicts of interest
The author declares no conflicts of interest.
Acknowledgements
I dedicate this review to the memory of my friend and colleague Cassiano Rambo. The ideas and research leading to this review received funding from the European Community’s seventh framework programme (FP7/2007–2013) under grant agreement no. 602805. I am grateful to members of the Norton lab for discussions and feedback.
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