Background: Cumulative evidence shows that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is involved in the depressive disorders and natural or synthetic glucocorticoids have a direct effect on HPA activity.

Objectives: Considering the reports that show zinc deficiency is one of the causes of depressive-like behavior, the current study aimed to examine the effects of systemic injection of zinc chloride (ZnCl₂) and/or dexamethasone sodium-phosphate (DEX) on depression in adult male rats.

Materials and Methods: Different groups received ZnCl₂ (2.5, 5, 10, and 20 mg/kg) and DEX (0.5, 1, 5, 10, and 30 mg/kg) and then depression was assessed in the forced swimming test (FST).

Results: Results showed that DEX 1 significantly increased, while DEX 30 and groups treated with zinc 10 mg/kg and zinc 20 mg/kg decreased total immobility time as compared to that of saline group. Also there was a significant decrease of total immobility time when zinc administered to rats already received DEX 1, compared with that of control group.

Conclusions: The current study findings suggest that zinc has antidepressant effects dose dependently, while administration of DEX induced dual effects on depression; therefore, a low dose of DEX showed an increased level of depressive-like behavior while higher doses had antidepressant effects. Also, results showed that zinc administration could ameliorate depressive-like behavior induced via dexamethasone in FST.