Modeling of stress and anxiety in adult zebrafish (Danio rerio) is increasingly utilized in neuroscience research and central nervous system (CNS) drug discovery. Representing the most commonly used zebrafish anxiety models, the novel tank test (NTT) focuses on zebrafish diving in response to potentially threatening stimuli, whereas the light-dark test (LDT) is based on fish scototaxis (innate preference for dark vs. bright areas). Here, we systematically evaluate the utility of these two tests, combining meta-analyses of published literature with comparative in vivo behavioral and whole-body endocrine (cortisol) testing. Overall, the NTT and LDT behaviors demonstrate a generally good cross-test correlation in vivo, whereas meta-analyses of published literature show that both tests have similar sensitivity to zebrafish anxiety-like states. Finally, NTT evokes higher levels of cortisol, likely representing a more stressful procedure than LDT. Collectively, our study reappraises NTT and LDT for studying anxiety-like states in zebrafish, and emphasizes their developing utility for neurobehavioral research. These findings can help optimize drug screening procedures by choosing more appropriate models for testing anxiolytic or anxiogenic drugs.

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Alarm reactions to a substance secreted by the damaged skin of conspecifics and closely-related species are increasingly being recognized as fear-like responses in fish. The neurochemical underpinnings of these effects are so far unknown; however, given the role of the serotonergic system on defensive behavior, it is possible that the alarm reaction is mediated by this monoamine. Exposure to conspecific alarm substance (CAS) increased anxiety-like behavior in the light/dark test in zebrafish and decreased nocifensive behavior. These effects were accompanied by increases in blood glucose, hemoglobin, epinephrine and norepinephrine levels, as well as extracellular levels of serotonin in the brain. Pretreatment with fluoxetine blocked the anxiogenic effects of CAS on the light/dark test as well as all physiological parameters and the increase in extracellular brain 5-HT, but not the reduction in nocifensive behavior. Conversely, pretreatment with the 5-HT1AR antagonist WAY 100635 blocked the effects on nocifensive behavior, but not the effects on anxiety-like behavior nor on physiological parameters. These results point to an important and complex role of the serotonergic system in the mediation of fear-potentiated behavior in the light/dark test and in fear-induced analgesia in zebrafish.