Since cognitive deficits are common for mood disorders, animal models are often used to find potential targets for their pharmacotherapy. Here we test three potential nootropic compounds acting through NMDA receptors and activation of nuclear chromatin receptors (etimisol) on zebrafish behavior in the novel tank test. Behavioral testing was performed between 11.00 and 17.00 h. Prior to testing, fish were pre-exposed in a 0.5-L plastic beaker for 20 min to either drugtreated or drug-free vehicle, 0.1% solution of DMSO, devoid of own behavioral effects in zebrafish, and commonly used in zebrafish drug studies. For treatment, fish were randomly divided into 4 groups (n = 15): drug-free control, 100 mg/L, 200 mg/L and 300 mg/L for NMDA antagonist, 130 mg/L, 260 mg/L and 390 mg/L for NMDA agonist and 5 mg/L, 10 mg/L and 20 mg/L for etimisol. Doses were chosen based on our pilot studies with this drug. Fish were then exposed to the novel tank test, assessing their anxiety, habituation and locomotion. Results: Acute NMDA agonist (2-Methylimidazole-4,5-Dicarboxylic Acid) decreased adult zebrafish locomotion, as fish treated with 390 mg/L showed significantly lower rate of moving than did the control group and other groups tested (p<0.005). Fish from the 390 mg/L cohort showed higher meander and turn angle (P<0.05, T able 1) compared to normal control zebrafish. Interestingly, the rate of not moving was also higher in the 390 mg/L treated fish. Acute NMDA-antagonist treatment with (2-Propylimidazole-4,5-Dicarboxylic Acid) showed that fish from both 200 and 300 mg/L groups cover shorter distance (P<0.05) and have lower velocity compared to the control group. Meander was higher in the 300 mg/L group (P<0.05). Compared to control fish, the ‘moving’ was also significantly lower in the 300 mg/L treated zebrafish (p<0.05). The rate of not moving was also higher in the 300 mg/L treated fish. Collectively, this profile suggests hypolocomotor effects in zebrafish treated with both acute NMDA agonist and antagonist. In contrast, etimisol-treated fish showed no statistical differences vs. controls. While no per-minute habituation changes were observed in NMDA agonist and antagonist experiment for both Group and Minute factors, it is evident that both NMDA-agonist and antagonist had minute and dose effect for in zone top rate and zone transition. Conclusion: In summary, zebrafish behavioral phenotype under NMDA antagonists presented as decreased locomotor activity and, clearly, may expand beyond direct NMDA-receptor agonism/antagonism. More thorough analyses of habituation profile and other cognitive phenotypes is needed. The sensitivity of fish to both drugs tested supports the growing utility of zebrafish as powerful biological sensors and screens for glutamatergic nootropic drugs. Further experiments evaluating zebrafish memory in T–maze are needed to better understand the exact effect on these compounds on zebrafish short- and long-term memory.