The zebrafish tail immobilization (ZTI) test as a new tool to assess stress-related behavior and a potential screen for drugs affecting despair-like states.

BACKGROUND: Affective disorders, especially depression and anxiety, are highly prevalent, debilitating mental illnesses. Animal experimental models are a valuable tool in translational affective neuroscience research. A hallmark phenotype of clinical and experimental depression, the learned helplessness, has become a key target for 'behavioral despair'-based animal models of depression. The zebrafish (Danio rerio) has recently emerged as a promising novel organism for affective disease modeling and CNS drug screening. Despite being widely used to assess stress and anxiety-like behaviors, there are presently no clear-cut despair-like models in zebrafish. NEW METHOD: Here, we introduce a novel behavioral paradigm, the zebrafish tail immobilization (ZTI) test, as a potential tool to assess zebrafish despair-like behavior. Conceptually similar to rodent 'despair' models, the ZTI protocol involves immobilizing the caudal half of the fish body for 5 min, leaving the cranial part to move freely, suspended vertically in a small beaker with water. RESULTS: To validate this model, we used exposure to low-voltage electric shock, alarm pheromone, selected antidepressants (sertraline and amitriptyline) and an anxiolytic drug benzodiazepine (phenazepam), assessing the number of mobility episodes, time spent 'moving', total distance moved and other activity measures of the cranial part of the body, using video-tracking. Both electric shock and alarm pheromone decreased zebrafish activity in this test, antidepressants increased it, and phenazepam was inactive. Furthermore, a 5-min ZTI exposure increased serotonin turnover, elevating the 5-hydroxyindoleacetic acid/serotonin ratio in zebrafish brain, while electric shock prior to ZTI elevated both this and the 3,4-dihydroxyphenylacetic acid/dopamine ratios. In contrast, preexposure to antidepressants sertraline and amitriptyline lowered both ratios, compared to the ZTI test-exposed fish. COMPARISON WITH EXISTINGMETHOD(S): The ZTI test is the first despair-like experimental model in zebrafish. CONCLUSIONS: Collectively, this study suggests the ZTI test as a potentially useful protocol to assess stress-/despair-related behaviors, potentially relevant to CNS drug screening and behavioral phenotyping of zebrafish.

Animal models of major depressive disorder and the implications for drug discovery and development.

INTRODUCTION: Depression is a highly debilitating psychiatric disorder that affects the global population and causes severe disabilities and suicide. Depression pathogenesis remains poorly understood, and the disorder is often treatment-resistant and recurrent, necessitating the development of novel therapies, models and concepts in this field. Areas covered: Animal models are indispensable for translational biological psychiatry, and markedly advance the study of depression. Novel approaches continuously emerge that may help untangle the disorder heterogeneity and unclear categories of disease classification systems. Some of these approaches include widening the spectrum of model species used for translational research, using a broader range of test paradigms, exploring new pathogenic pathways and biomarkers, and focusing more closely on processes beyond neural cells (e.g. glial, inflammatory and metabolic deficits). Expert opinion: Dividing the core symptoms into easily translatable, evolutionarily conserved phenotypes is an effective way to reevaluate current depression modeling. Conceptually novel approaches based on the endophenotype paradigm, cross-species trait genetics and 'domain interplay concept', as well as using a wider spectrum of model organisms and target systems will enhance experimental modeling of depression and antidepressant drug discovery.