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Narcolepsy is a rare neurological disorder, with typical symptoms such as excessive daytime sleepiness and cataplexy (1–3). The main cause of narcolepsy is the selective loss of orexin neurons in the lateral hypothalamus (4). The current treatment options are associated with side effects and lack of efficacy, therefore, there is a high need for the discovery and development of new and improved drugs (5). In addition to current animal narcolepsy models, such as narcoleptic dogs and rodents, zebrafish could be of added value, since they are small diurnal non-mammalian vertebrates, which makes them suitable for high-throughput purposes, and they possess comparable basic mechanisms of sleep regulation as humans (6–8). This research project aimed to develop and pharmacologically characterize zebrafish narcolepsy models. Both novel chemically-induced models, using orexin receptor (OXR) antagonists (i.e., suvorexant, TCS-1102, and SB-674042), and a state-of-the-art transgenic narcolepsy model (i.e., Tg(hcrt:nfsB-EGFP)), which allows selective ablation of orexin neurons, were phenotypically characterized in zebrafish larvae (9). In addition, OXR agonists were used for further pharmacological characterization and as possible tools to rescue the disease phenotype. Since sleep in zebrafish is mainly characterized by behavioral criteria (7), two behavioral assays were developed to assess the objectives of the study: (1) the dark-light assay that consists of a 2h period with 30min alternating dark-light phases and is recorded during the day, and (2) the night assay, with a light period from 6 - 9 p.m., a dark period from 9 p.m. - 7 a.m., and again a light period from 7 - 8 a.m.. Both the chemically-induced and transgenic Tg(hcrt:nfsB-EGFP) zebrafish narcolepsy models showed an altered behavioral response to dark-light transitions in the two behavioral assays, which is indicative of narcolepsy. The observed differences in altered behavioral response between the two models, could be indicative of additional factors influencing the narcoleptic phenotypes, i.e., the ablation of the entire orexin neurons in contrast to only blocking the OXR. Two OXR agonists (i.e., C15454-2 and C19069) had a strong wake-promoting effect during the night assay. C15454-2 was selected for rescue experiments and was observed to rescue the narcoleptic phenotype of transgenic Tg(hcrt:nfsB-EGFP) zebrafish, which can be considered as a pharmacological validation of the model. However, this should be investigated more thoroughly, in addition to the further investigation of the rescue of the chemically-induced narcolepsy models. Taken together, this study shows the promise of chemically-induced narcolepsy models and contributes to the behavioral characterization and pharmacological validation of the transgenic Tg(hcrt:nfsB-EGFP) narcolepsy model, and therefore confirms the possible value of zebrafish narcolepsy models in future drug discovery and development, as well as in the investigation of the underlying pathophysiology of narcolepsy.