(±) Citronellal Exerts Antidepressant and Modulatory Effects on Duloxetine Possibly Through Serotonin and Norepinephrine Reuptake Interaction Pathway: In Vivo Approach with Molecular Docking

Abstract This study aims to assess the antidepressant and modulatory activities of citronellal (CIT) on duloxetine (DUX) and its possible underlying mechanisms through in vivo and in silico studies. Hence, the forced swimming test (FST), tail suspension test (TST), and open field test (OFT) were carried out. Mice were treated with different doses of CIT (50, 100, and 200 mg/kg, p.o.), while DUX (15 mg/kg, p.o.) was used as a positive control and a vehicle served as a negative control. Additionally, molecular docking was conducted to evaluate binding interactions. Results demonstrated that CIT dose‐dependently and significantly ( p < 0.05) alleviated immobility time in both the FST and TST. At a dose of 200 mg/kg, CIT showed notable effects with immobility times of 42.17 ± 3.70 and 70.17 ± 2.56 s in the FST and TST, respectively. In combination therapy, CIT (100 mg/kg) modulated the activity of DUX. However, antidepressant activity is confirmed by the OFT test, which reduced the locomotion activity. Further, CIT exhibited a moderate binding affinity (−6.1 kcal/mol) toward both the serotonin and norepinephrine reuptake transporters (SRT and NRT) by forming several bonds. In conclusion, CIT demonstrated moderate antidepressant activity, possibly by interacting with SRT and NRT.