iabetes mellitus is a chronic disease that causes neuronal plasticity and increased hypothalamic pituitary adrenal (HPA) axis ofstress disorders. The change in metabolism is reportedly associated with inadequate response to antianxiety and antidepressant agents.Objective:This study aimed to determine the effect of milnacipran antidepressants on anxiety-like behavior in mice withdiabetes mellitus.Methods:Male ICR mice were divided into naive, stress, diabetes mellitus (DM), DM+stress groups to measure anxiety-like behavior. Diabetes mellitus was induced using alloxan, and electric footshock stress was used as a stressor for 14 consecutive days. Anxiety-like behavior was measured using the light-dark box (LDB) and elevated plus maze (EPM) test at days 0, 7 and 14. The antidepressant milnacipran (MIL) was given for 7 days, on days 8 to 14. On day 14, evaluation of anxiety-like behavior after administration of MIL was carried out in all groups using LDB and EPM tests.Results:The results showed that administration of milnacipran effectively ameliorated anxiety-like behavior in the non-DM, but not in the DM group, using the LDB test. A similar result was demonstrated in the EPM test showing the non-DM group's attenuation after milnacipran administration.Conclusion:The present results indicate that there is an inadequate attenuation of the anxiety-like behavior after treatment with milnacipran in diabetes conditions