Synergistic antidepressant-like effect of xylopic acid co-administered with selected antidepressants

Xylopic acid (XA), a kaurene diterpene from the dried fruits of Xylopia aethiopica, has anxiolytic- and antidepressant-like activity in mice and zebrafish. We aimed to assess the potential synergistic antidepressant-like effects of XA when combined with selected antidepressants in the mouse forced-swim test.

The antidepressant-like effect of xylopic acid (XA) (10, 30, 100 mgkg^-1), fluoxetine (Flx) (3, 10, 30 mgkg^-1), sertraline (Sert) (3, 10, 30 mgkg^-1), imipramine (Imi) (10, 30, 100 mgkg-1) and ketamine (Ket) (0.1, 0.3, 1.0 mgkg^-1), was evaluated in forced swim test. The dose (ED₅₀) that achieved a 50% reduction in immobility time was determined from the respective log-dose response curves. XA and the selected antidepressants were co-administered in fixed-dose ratio combinations (1/2:1/2, 1/4:1/4, 1/8:1/8) of the ED₅₀ to identify the experimental ED₅₀ (ED_50mix). The theoretical ED₅₀(ED_50add), of all combinations was determined using isobolograms and compared with the ED_50mix to identify the nature of the interaction. The effect of dose combinations on general locomotor activity was assessed in the open-field test.

The interaction index (γ) for the following XA combinations, XA/Flx, XA/Sert, XA/Imi and XA/Ket were 0.42, 0.41, 0.31 and 0.34. An independent sample t-test revealed that the experimental ED₅₀ (ED_50mix) was significantly lower than the theoretical ED₅₀ (ED_50add) in all combinations of XA, indicative of a synergistic antidepressant-like effect. However, combinations of XA with ketamine significantly reduced general locomotor activity at all dose combinations.

The co-administration of xylopic acid and fluoxetine, imipramine, sertraline and ketamine produces a synergistic antidepressant-like effect in mice.