The effect of imipramine, ketamine, and zinc in the mouse model of depression.

Relationship between the chronic and excessive exposure to glucocorticoids and the development of psychiatric disorders, including depression, has been described in the literature. We decided to investigate whether a combination of agents with antidepressant activity (i.e., imipramine, ketamine, and Zn(2+)) may influence/reverse the depressogenic effect of dexamethasone therapy. The antidepressant-like effect was assessed by the forced swim test in adult mice. The inhibitory activity of dexamethasone was dose-dependent: only the highest tested dose of the glucocorticoid (i.e., 64 μg/kg) given as a single injection increased immobility time, whereas 16 μg/kg/day of dexamethasone administered repeatedly (for 14 days) induced a significant alteration in animal behavior. Both the acute or sub-chronic administration of the active doses of imipramine (10 mg/kg), Zn(2+) (30 mg/kg), and ketamine (30 mg/kg), and the combinations of their per se inactive doses reversed the inhibitory activity of dexamethasone (16 μg/kg/day) administered for 14 consecutive days. Whereas a single injection of an inhibitory dose of dexamethasone (64 μg/kg) was not able to abolish the antidepressant effect of imipramine (5 mg/kg), Zn(2+) (10 mg/kg), and imipramine-Zn(2+) combination (2.5 and 5 mg/kg, respectively) given once a day for 14 consecutive days. Our findings indicate that the chronic dexamethasone injection procedure has some potential as an animal model of depression and they further support the theory of interplay between glutamatergic neurotransmission and the chronic or excessive exposition to glucocorticoids.