Adam D. Collier

Zebrafish and conditioned place preference: A translational model of drug reward

Addiction and substance abuse are found ubiquitously throughout human society. In the United States, these disorders are responsible for amassing hundreds of billions of dollars in annual costs associated with healthcare, crime and lost productivity. Efficacious treatments remain few in number, the development of which will be facilitated by comprehension of environmental, genetic, pharmacological and neurobiological mechanisms implicated in the pathogenesis of addiction. Animal models such as the zebrafish (Danio rerio) have gained momentum within various domains of translational research, and as a model of complex brain disorders (e.g., drug abuse). Behavioral quantification within the conditioned place preference (CPP) paradigm serves as a measure of the rewarding qualities of a given substance. If the animal develops an increase in preference for the drug paired environment, it is inferred that the drug has positive-reinforcing properties. This paper discusses the utility of the zebrafish model in conjunction with the CPP paradigm and reports CPP behavior following acute exposure to 0.0%, 0.25%, 0.50%, and 1.00% alcohol, and 0 mg/L, 50 mg/L, 100 mg/L and 150 mg/L caffeine.

The utility of the zebrafish model in conditioned place preference to assess the rewarding effects of drugs.

Substance abuse is a significant public health concern both domestically and worldwide. The persistent use of substances regardless of aversive consequences forces the user to give higher priority to the drug than to normal activities and obligations. The harmful and hazardous use of psychoactive substances can lead to a dependence syndrome. In this regard, the genetic and neurobiological underpinnings of reward-seeking behavior need to be fully understood in order to develop effective pharmacotherapies and other methods of treatment. Animal models are often implemented in preclinical screening for testing the efficacy of novel treatments. Several paradigms exist that model various facets of addiction including sensitization, tolerance, withdrawal, drug seeking, extinction, and relapse. Self-administration and, most notably, conditioned place preference (CPP) are relatively simple tests that serve as indicators of the aforementioned aspects of addiction by means of behavioral quantification. CPP is a commonly used technique to evaluate the motivational effects of compounds and experiences that have been associated with a positive or negative reward, which capitalizes on the basic principles of Pavlovian conditioning. During training, the unconditioned stimulus is consistently paired with a neutral set of environmental stimuli, which obtain, during conditioning, secondary motivational properties that elicit approach behavior in the absence of the unconditioned stimulus. For over 50 years, rodents have been the primary test subjects. However, the zebrafish (Danio rerio) is gaining favor as a valuable model organism in the fields of biology, genetics, and behavioral neuroscience. This paper presents a discussion on the merits, advantages, and limitations of the zebrafish model and its utility in relation to CPP.

Anxiogenic-like effects of chronic nicotine exposure in zebrafish

Nicotine is one of the most widely used and abused legal drugs. Although its pharmacological profile has been extensively investigated in humans and rodents, nicotine CNS action remains poorly understood. The importance of finding evolutionarily conserved signaling pathways, and the need to apply high-throughput in vivo screens for CNS drug discovery, necessitate novel efficient experimental models for nicotine research. Zebrafish (Danio rerio) are rapidly emerging as an excellent organism for studying drug abuse, neuropharmacology and toxicology and have recently been applied to testing nicotine. Anxiolytic, rewarding and memory-modulating effects of acute nicotine treatment in zebrafish are consistently reported in the literature. However, while nicotine abuse is more relevant to long-term exposure models, little is known about chronic effects of nicotine on zebrafish behavior. In the present study, chronic 4-day exposure to 1-2mg/L nicotine mildly increased adult zebrafish shoaling but did not alter baseline cortisol levels. We also found that chronic exposure to nicotine evokes robust anxiogenic behavioral responses in zebrafish tested in the novel tank test paradigm. Generally paralleling clinical and rodent data on anxiogenic effects of chronic nicotine, our study supports the developing utility of zebrafish for nicotine research.

Zebrafish models in neuropsychopharmacology and CNS drug discovery

Despite the high prevalence of neuropsychiatric disorders, their aetiology and molecular mechanisms remain poorly understood. The zebrafish (Danio rerio) is increasingly utilized as a powerful animal model in neuropharmacology research and in vivo drug screening. Collectively, this makes zebrafish a useful tool for drug discovery and the identification of disordered molecular pathways. Here, we discuss zebrafish models of selected human neuropsychiatric disorders and drug‐induced phenotypes. As well as covering a broad range of brain disorders (from anxiety and psychoses to neurodegeneration), we also summarize recent developments in zebrafish genetics and small molecule screening, which markedly enhance the disease modelling and the discovery of novel drug targets.

Modeling PTSD in the zebrafish: are we there yet?

Post-traumatic stress disorder is an anxiety disorder that can develop following one or more traumatic events that threaten ones safety or make the victim feel helpless. Currently there are an increasing number of cases in the population in part due to the number of soldiers returning from combat. The disorder is characterized by symptoms that include hypervigilance, sleep disturbances, social and cognitive degradation, and memory flashbacks. Most of the research has been centered on the human and rodent as subjects but recently another viable contender has emerged - the zebrafish (Danio rerio). The zebrafish is a strong comparative model with the ability to exhibit a wide variety of behaviors, complex learning, and neurobiological changes that can be extrapolated to the human condition. The zebrafish is an ideal organism to study pharmacological treatments as well as the neurological underpinnings of the disorder. Here we review a sampling of the human and rodent model literature on post-traumatic stress disorder focusing on symptomology, current treatments, and stress paradigms. We also make the argument for the inclusion of the zebrafish model in future studies investigating the causes, symptoms, and treatments of post-traumatic stress disorder.

Zebrafish models of autism spectrum disorder

ABSTRACT Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by motor, social and cognitive deficits that develop early during childhood. The pathogenesis of ASD is not well characterized and involves a multifaceted interaction between genetic, neurobiological and environmental factors. Animal (experimental) models possess evolutionarily conserved behaviors and molecular pathways that are highly relevant for studying ASD. The zebrafish (Danio rerio) is a relatively new animal model with promise for understanding the pathogenesis of complex brain disorders and discovering novel treatments. As a highly social and genetically tractable organism, zebrafish have recently been applied to model a variety of deficits relevant to ASD. Here, we discuss the developing utility of zebrafish models of ASD, as well as current behavioral, toxicological and genetic models of ASD, and future directions of research in this field.

Modeling consequences of prolonged strong unpredictable stress in zebrafish: Complex effects on behavior and physiology

&NA; Chronic stress is the major pathogenetic factor of human anxiety and depression. Zebrafish (Danio rerio) have become a novel popular model species for neuroscience research and CNS drug discovery. The utility of zebrafish for mimicking human affective disorders is also rapidly growing. Here, we present a new zebrafish model of clinically relevant, prolonged unpredictable strong chronic stress (PUCS). The 5‐week PUCS induced overt anxiety‐like and motor retardation‐like behaviors in adult zebrafish, also elevating whole‐body cortisol and proinflammatory cytokines ‐ interleukins IL‐1&bgr; and IL‐6. PUCS also elevated whole‐body levels of the anti‐inflammatory cytokine IL‐10 and increased the density of dendritic spines in zebrafish telencephalic neurons. Chronic treatment of fish with an antidepressant fluoxetine (0.1 mg/L for 8 days) normalized their behavioral and endocrine phenotypes, as well as corrected stress‐elevated IL‐1&bgr; and IL‐6 levels, similar to clinical and rodent data. The CNS expression of the bdnf gene, the two genes of its receptors (trkB, p75), and the gfap gene of glia biomarker, the glial fibrillary acidic protein, was unaltered in all three groups. However, PUCS elevated whole‐body BDNF levels and the telencephalic dendritic spine density (which were corrected by fluoxetine), thereby somewhat differing from the effects of chronic stress in rodents. Together, these findings support zebrafish as a useful in‐vivo model of chronic stress, also calling for further cross‐species studies of both shared/overlapping and distinct neurobiological responses to chronic stress. HighlightsHere, we report a zebrafish model of prolonged unpredictable chronic stress (PUCS).The 5‐week PUCS induced overt anxiety‐like and motor retardation‐like behaviorsPUCS elevated whole‐body cortisol and proinflammatory cytokines IL‐1&bgr; and IL‐6.PUCS also elevated the anti‐inflammatory cytokine IL‐10 and increased the density of dendritic spines in telencephalic neurons.Chronic treatment with an antidepressant fluoxetine corrected these behavioral and physiological responses.

Improving treatment of neurodevelopmental disorders: recommendations based on preclinical studies

Introduction: Neurodevelopmental disorders (NDDs) are common and severely debilitating. Their chronic nature and reliance on both genetic and environmental factors makes studying NDDs and their treatment a challenging task. Areas covered: Herein, the authors discuss the neurobiological mechanisms of NDDs, and present recommendations on their translational research and therapy, outlined by the International Stress and Behavior Society. Various drugs currently prescribed to treat NDDs also represent a highly diverse group. Acting on various neurotransmitter and physiological systems, these drugs often lack specificity of action, and are commonly used to treat multiple other psychiatric conditions. There has also been relatively little progress in the development of novel medications to treat NDDs. Based on clinical, preclinical and translational models of NDDs, our recommendations cover a wide range of methodological approaches and conceptual strategies. Expert opinion: To improve pharmacotherapy and drug discovery for NDDs, we need a stronger emphasis on targeting multiple endophenotypes, a better dissection of genetic/epigenetic factors or “hidden heritability,” and a careful consideration of potential developmental/trophic roles of brain neurotransmitters. The validity of animal NDD models can be improved through discovery of novel (behavioral, physiological and neuroimaging) biomarkers, applying proper environmental enrichment, widening the spectrum of model organisms, targeting developmental trajectories of NDD-related behaviors and comorbid conditions beyond traditional NDDs. While these recommendations cannot be addressed all in once, our increased understanding of NDD pathobiology may trigger innovative cross-disciplinary research expanding beyond traditional methods and concepts.

Understanding zebrafish cognition

Zebrafish (Danio rerio) are rapidly becoming a popular model organism in translational and cognitive neuroscience research. Both larval and adult zebrafish continue to increase our understanding of cognitive mechanisms and their genetic and pharmacological modulation. Here, we discuss the developing utility of zebrafish in understanding cognitive phenotypes and their deficits, relevant to a wide range human brain disorders. We also discuss the potential of zebrafish models for high-throughput genetic mutant and small molecule screening (e.g., amnestics, cognitive enhancers, neurodevelopmental/neurodegenerative drugs), which becomes critical for identifying novel candidate genes and molecular drug targets to treat cognitive deficits. In addition to discussing the existing challenges and future strategic directions in this field, we emphasize how zebrafish models of cognitive phenotypes continue to form an interesting and rapidly emerging new field in neuroscience.

Assessing Cognitive Phenotypes in Zebrafish

Zebrafish are becoming increasingly utilized in behavioral studies as a model of human learning and memory. The existing studies indicate that this species is capable of a variety of cognitive processes, demonstrating its value as a model organism. Popular zebrafish behavioral paradigms to assess various aspects of learning and memory include the startle response, novel tank, learned spatial alternation, three-chamber tank, T-maze and plus maze. Each paradigm is sensitive to pharmacological, genetic and/or experimental manipulations, and within each test specific methodologies and apparatuses have been developed to accommodate the abilities and limitations of this aquatic model, as reviewed here.