No abstract

Long-term recurrent stress is a common cause of neuropsychiatric disorders. Animal models are widely used to study the pathogenesis of stress-related psychiatric disorders. The zebrafish (Danio rerio) is emerging as a powerful tool to study chronic stress and its mechanisms. Here, we developed a prolonged 11-week chronic unpredictable stress (PCUS) model in zebrafish to more fully mimic chronic stress in human populations. We also examined behavioral and neurochemical alterations in zebrafish, and attempted to modulate these states by 3-week treatment with an antidepressant fluoxetine, a neuroprotective omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA), a pro-inflammatory endotoxin lipopolysaccharide (LPS), and their combinations. Overall, PCUS induced severe anxiety and elevated norepinephrine levels, whereas fluoxetine (alone or combined with other agents) corrected most of these behavioral deficits. While EPA and LPS alone had little effects on the zebrafish PCUS-induced anxiety behavior, both fluoxetine (alone or in combination) and EPA restored norepinephrine levels, whereas LPS + EPA increased dopamine levels. As these data support the validity of PCUS as an effective tool to study stress-related pathologies in zebrafish, further research is needed into the ability of various conventional and novel treatments to modulate behavioral and neurochemical biomarkers of chronic stress in this model organism.

Hallucinogenic drugs potently affect brain and behavior and have also recently emerged as potentially promising agents in pharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful animal model organism for screening neuroactive drugs, including hallucinogens. Here, we test a battery of ten novel N-benzyl-2-phenylethylamine (NBPEA) derivatives with the 2,4-and 3,4-dimethoxy substitutions in the phenethylamine moiety and the −OCH 3 , −OCF 3 , −F, −Cl, and −Br substitutions in the ortho position of the phenyl ring of the N-benzyl moiety, assessing their acute behavioral and neurochemical effects in the adult zebrafish. Overall, substitutions in the Overall, substitutions in the N-benzyl moiety modulate locomotion, and substitutions in the phenethylamine moiety alter zebrafish anxiety-like behavior, also affecting the brain serotonin and/or dopamine turnover. The 24H−NBOMe(F) and 34H−NBOMe(F) treatment also reduced zebrafish despair-like behavior. Computational analyses of zebrafish behavioral data by artificial intelligence identified several distinct clusters for these agents, including anxiogenic/hypolocomotor (24H−NBF, 24H− NBOMe, and 34H−NBF), behaviorally inert (34H−NBBr, 34H−NBCl, and 34H−NBOMe), anxiogenic/hallucinogenic-like (24H−NBBr, 24H−NBCl, and 24H−NBOMe(F)), and anxiolytic/hallucinogenic-like (34H−NBOMe(F)) drugs. Our computational analyses also revealed phenotypic similarity of the behavioral activity of some NBPEAs to that of selected conventional serotonergic and antiglutamatergic hallucinogens. In silico functional molecular activity modeling further supported the overlap of the drug targets for NBPEAs tested here and the conventional serotonergic and antiglutamatergic hallucinogens. Overall, these findings suggest potent neuroactive properties of several novel synthetic NBPEAs, detected in a sensitive in vivo vertebrate model system, the zebrafish, raising the possibility of their potential clinical use and abuse.

Rare (orphan) diseases are an urgent unmet biomedical problem. Tremendous efforts and resources are expended for the search for cures for these diseases. Zebrafish can provide a powerful screening tool for novel orphan drugs, and may also deepen our mechanistic understanding of such rare pathological conditions. Here, we discuss various models of orphan diseases of the nervous system on zebrafish, and outline associated problems, limitations and prospects in the context of the development of personalized medicine.

Animal models are widely used to study common stress-induced affective disorders, such as anxiety and depression. Here, we examine behavioral and brain transcriptomic (RNA-seq) responses in rat prolonged chronic unpredictable stress (PCUS) model, and their modulation by 4-week treatment with fluoxetine, eicosapentaenoic acid (EPA), lipopolysaccharide (LPS) and their combinations. Overall, chronic stress produced anxiety-like phenotype, corrected by fluoxetine alone or in combination with EPA or LPS. EPA was anxiolytic in several tests, whereas LPS alone increased anxiety. PCUS evoked pronounced transcriptomic changes in rat hippocampi, differentially expressing >200 genes, while all pharmacological manipulations (except fluoxetine+EPA) affected only few genes. Gpr6, Drd2 and Adora2a were downregulated by chronic stress in a treatment-resistant manner, suggesting highly conserved nature of these pathogenetic genomic responses to chronic stress. Overall, these findings support the validity of rat PCUS paradigm as an effective tool to study stress-related pathologies, and calls for further research to probe how various conventional and novel drugs modulate behavioral and brain transcriptomic biomarkers of chronic stress in rodent models.