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.