Current Psychopharmacology - Volume 5, Issue 2, 2016

Background: Impulsivity is poorly planned, premature or inap- propriate behaviour, and deficits in impulse control are linked to a number of neuropsychiatric disorders. There are a number of theories relating to the neural basis of impulsivity, but the precise molecular mechanisms of im- pulse control are not clearly understood. Motor impulsivity has been ob- served in adult zebrafish, but in order to increase throughput it would be beneficial if early markers could be identified in larvae. One such method was recently shown to have some potential efficacy in zebrafish larvae, re- lating to an ADHD morphant (lphn3.1) showing increases in motor 'peaks' during free swimming behaviour. Objective: The aim of this study was to carry out a pharmacological evaluation of motor 'peaks' as a measure of motor impulsivity in larval zebrafish, as well as evaluate the behav- iour of mutant lines that might be predicted to show variation in motor impulsivity. Method: 6dpf zebrafish larvae were filmed for 90-seconds following incubation in amisul- pride (a DRD2/3 antagonist), nicotine, apomorphine (a non-specific dopamine agonist), atomoxetine (a norepinephrine reuptake inhibitor), and methylphenidate (a combined dopa- mine/norepinephrine agonist). We also filmed 6dpf larvae homozygous and heterozygous for mutations in pink1, disc1, and ache. In all larvae, we analysed distance moved and motor 'peaks', calculated as number of 3-second bins in which the larva traveled > 10mm. Results: Atomoxetine and methylphenidate, which reduce impulsivity in humans and other mammalian models, reduced motor peaks while having no effect on overall distance traveled. Apomorphine increased locomotor peaks in a bimodal manner. disc1 homozygous mutants showed lower peaks than wild-type siblings. Finally, although nicotine increased distance traveled, there were no effects on motor peaks. Conclusion: The results suggest that analysis of motor peaks may be a promising method for the early detection of impulsivity-related phenotypes.

Background: Melatonin is an evolutionarily highly conserved molecule. In humans, exogenous melatonin has been shown to entrain cir- cadian rhythms to light dark cycles and act as an antioxidant. Many com- plex brain disorders, such as autism and Alzheimer's disease, are associated with abnormal melatonin production or melatonin metabolism. Exogenous melatonin may serve as a potential treatment to improve sleeping patterns and delay neuronal deterioration. Objective: Here we review the advantages of using zebrafish to study the pharmacology of exogenous melatonin treatments to rescue endogenous melatonin abnormalities. Method: We perform a literature review to describe the human melatonin system, zebrafish melatonin system, zebrafish advantages as a model organism, and melatonin research using zebrafish. Conclusions: Zebrafish is a model organism for genetics, physiology, chronobiology, geron- tology, and pharmacology studies. Future melatonin research can incorporate all of these fields to better understand melatonin mechanisms in wildtype and mutant zebrafish to discov- er new potential treatments. A standardized treatment method for all developmental stages should be established to encourage interdisciplinary work.

Purpose: To review current findings on the neuro- and psycho- pharmacology of monoamine neurotransmitters in zebrafish, as well as its consequences for psychopharmacology and evolutionary neuroscience. Methods: A narrative review of the relevant papers known to the authors was conducted. Results: Monoamine neurotransmitters are major neuromodulatory mecha- nisms in the vertebrate brain, associated with most psychological functions. The chemical anatomy of these systems and their molecular underpinnings are assumed to be highly conserved in the brain of all vertebrates, including zebrafish. This conservation is the basis for reductionist models and the central argument for the use of zebrafish in psychopharmacology research. The development of behavioral assays in zebrafish allowed the psychopharmacological investigation of monoaminergic functions in this species. In the review, we demonstrate that behavioral functions of these systems are highly conserved, in spite of important species differences in genetics and neuroanatomy. These differences in spite of functional conservance, previously made mainly in relation to the serotonergic system, are shown to be widespread. Conclusions: The consequences for these discrepancies for reductionist strategies, for the evolution of brain and behavior, and for the use of zebrafish as a model organism are dis- cussed.

Background: Psychiatric disorders related to fear and anxiety are common throughout the world, and their neurobiological mechanisms are not fully understood. Studying animal models has been a common strategy to probe mechanisms of normal and pathological brain functioning. Experimental paradigms originally developed with mammalian models, such as predator exposure, fear learning, exposure to predator-related olfactory cues and novelty, have been aquatically tailored for a newer model in translational neuroscience, the zebrafish. Objective: Our aim was to explore the utility of zebrafish models of fear and anxiety and to describe currently employed experimental paradigms, as well as relevant behavioral endpoints and biomarkers. Conclusion: We conclude that zebrafish are a promising model to help elucidate the underlying mechanisms related to fear and anxiety. This is partly due to robust behavioral and endocrine responses, pharmacological sensitivity, ease of genetic manipulation, and amenability to high-throughput screening due to low-cost and small size. However, the zebrafish is a relatively new model and further research is needed to truly exploit the potential of this aquatic species.

Background: The inhibitory (or passive) avoidance paradigm is widely used to assess the effects of drugs on emotion, learning and memory in rodents. The zebrafish is gaining more and more popularity as an animal model in, among others, psychopharmacological research. In zebrafish, inhibitory avoidance is also used as assay to assess the effects of drugs and other treatments on fear-associated learning. The inhibitory avoidance paradigm is based on the conflict between (i) the innate response to enter a dark area to avoid a brightly lit area (scototaxis) and (ii) avoiding exposure to a shock in the dark area, i.e. contextual (shock-environment) fear-learning. Objective: This review summarises recent studies that characterised different features of the inhibitory avoidance paradigm. This knowledge is necessary to fully appreciate drug-related effects in this task. Results: These studies have revealed factors that affect performance of zebrafish in the task, e.g. test-related parameters (such as shock intensity) and subject-characteristics at the time of testing (including age, strain and rearing conditions). In addition, they allowed generating hypotheses on physiological and genetic mechanisms underlying inhibitory avoidance in zebrafish. Conclusion: The inhibitory avoidance assay is a useful research tool to study emotion, learning and memory in zebrafish. Directions for future research are indicated, which may further optimise the use of the inhibitory avoidance assay in zebrafish as research tool.

Background. The zebrafish has become a popular animal model for behavioral pharmacology. One of the greatest advantages of the zebrafish is its amenability for high throughput screens to identify anxiety altering compounds. The novel tank diving test is arguably one of the most commonly utilized behavioral tests for quantifying anxiety-like behavioral responses in zebrafish. However, a number of context-dependent anxiety-like behavioral responses have recently been reported in the literature for this task, and the validity of using a single measure, the diving response, has been questioned. Objective. In this review, we discuss multiple behavioral parameters that can be used to evaluate performance in the novel tank diving test which can serve as indicators of anxiety. In addition, we also discuss the difficulties associated with interpretation of behavioral measures of anxiety, a question complicated by context- dependent behavioral responses induced by handling the fish with a net, a known stressor. Conclusion. The zebrafish is a relative newcomer in the psychopharmacological analysis of anxiety, but the increasing number of efficient behavioural tests and the translational relevance of this species make the zebrafish a potentially useful laboratory species for screening of anxiolytic compounds.

Background: The zebrafish has been a favorite of developmental biologists and geneticists for decades, however, recently, it has gained popularity among behavior researchers too. The reason for the popularity of this species is that while it is a simple vertebrate, it possesses numerous features that make it translationally relevant. Objective: Social interaction is an essential component of human as well as zebrafish behavior; yet, the biological mechanisms underlying social behavior and its dysfunction remain poorly understood in both species. This review focuses on pharmacological manipulation of social behavior in zebrafish, studies where the ultimate goal is to understand the psychopharmacology of human behavior. Methods: We focused specifically on quantification of social interaction, specifically shoaling, in zebrafish, and compared it to rodent literature where appropriate. If no social studies exist for specific classes of compounds in zebrafish or if other behaviors may help with interpretation of social responses, we also highlighted non-social behaviors (locomotion, anxiety, etc). Results: We discussed findings on the effect of exposure of zebrafish to alcohol, psychostimulants, depressants and other drugs of abuse. Comparison of studies that have quantified and manipulated zebrafish social behavior of either single zebrafish or groups of zebrafish high-light both growth and gaps in this rapidly evolving field. Conclusion: Although new in psychopharmacology research, the zebrafish will be an important tool with which analysis and modeling of human social behavior and disorders involving social abnormalities including Fetal Alcohol Spectrum Disorders, Autism spectrum disorders, and Schizophrenia may be facilitated.

Background: Epilepsy is a chronic disorder of the brain. Globally, an estimated 2.4 million people are diagnosed with epilepsy each year. Recent studies have shown that 70% of epileptic patients can be successfully treated with anti-epileptic drugs. Unfortunately, 30% of the patients still suffer from intractable epilepsy, a problem that represents a difficult scientific challenge. Crucial genetic research and high throughput drug screening are combined together to search for treatment for refractory seizures. Goals. Development of new animal models amenable to genetic manipulation and drug screening, e.g. the zebrafish (Danio rerio), is an important goal and represents a promising step. In this review, we summarize general aspects of epilepsy and the advances through history, and emphasize the importance of the zebrafish as an animal model representing new research strategies leading to proper treatment of human epilepsy. We also describe the advances in research using both the larvae and adult zebrafish, and discuss the barriers which zebrafish must overcome to become a better animal model for a variety of neurological disorders, including epileptic seizures and epilepsy. Conclusion. Even though zebrafish larvae seem to be more attractive as a tool, adult zebrafish are also very valuable, as they can be used to study the impact of genetic manipulation and drugs on behavioral changes after seizures.

Background: In vivo studies are crucial for the identification of pathogenic cellular and molecular mechanisms. Animal models are especially relevant due to their systems' integrity and evaluation of multiple translational parameters. Objective: This review presents a general panorama of the pharmacological and genetic seizure models using this species as a platform for disease modeling and accelerated drug discovery. Method: We performed a literature review about the use of zebrafish to model seizures and epilepsy. Conclusion: The zebrafish is a prominent model organism with considerable degree of physiological and genetic conservation especially suitable for behavioral and electrophysiological investigation of seizure mechanisms. Its sensitivity to chemoconvulsant and straightforwardness in modern genetic approaches supports its competitive contribution to epilepsy research.