Objective: To identify drug combinations with serotonergic potential and help clinicians to avoid combined use of serotonin-augmenting drugs. Methodology: This experimental study was conducted on thirty Wistar albino mice, divided into 3 equal groups (I, II, III) treated with distilled water, tramadol+metoclopramide and tramadol only bid for 15 days. Animal behavior, exploratory and locomotor activity were checked using sticky label, novel object and open filed tests. Results were analyzed by two-way ANOVA followed by Scheffe test. Results: Difference in animal behavior was significant with respect to rearing (p?0.01, p?0.001), freezing (p?0.001, p?0.05) and grooming (p?0.01, p?0.001) when group II was compared with I and III, respectively. Difference was also significant (p?0.001) when group III was compared with I. In open field test, animals of II and III groups showed hyperlocomotion (p?0.001) when compared with group I. Difference between II and III was also significant (p?0.001). In novelty-based tests (novel object and sticky label test), animals showed high level of vigilance (p?0.001) in groups II and III as compared to group I. Conclusion: Identification of serotonin-enhancing drugs and combinations is important to ensure patient safety. Animals can act as useful models for such identification.