Considering that intracellular signaling pathways that modulate brain BDNF are implicated in antidepressant responses, this study investigated whether signaling pathway inhibitors upstream to BDNF might influence the antidepressant-like effect of zinc, a metal that has been shown to display antidepressant properties. To this end, the influence of i.c.v. administration of H-89 (1 μg/site, PKA inhibitor), KN-62 (1 μg/site, CAMKII inhibitor), chelerythrine (1 μg/site, PKC inhibitor), PD98059 (5 μg/site, MEK1/2 inhibitor), U0126 (5 μg/site, MEK1/2 inhibitor), LY294002 (10 nmol/site, PI3K inhibitor) on the reduction of immobility time in the tail suspension test (TST) elicited by ZnCl 2 (10 mg/kg, p.o.) was investigated. Moreover, the effect of the combination of sub-effective doses of ZnCl 2 (1 mg/kg, p.o.) and AR-A014418 (0.001 μg/site, GSK-3β inhibitor) was evaluated. The occurrence of changes in CREB phosphorylation and BDNF immunocontent in the hippocampus and prefrontal cortex of mice following ZnCl 2 treatment was also investigated. The anti-immobility effect of ZnCl 2 in the TST was prevented by treatment with PKA, PKC, CAMKII, MEK1/2 or PI3K inhibitors. Furthermore, ZnCl 2 in combination with AR-A014418 caused a synergistic anti-immobility effect in the TST. None of the treatments altered locomotor activity of mice. ZnCl 2 treatment caused no alteration in CREB phosphorylation and BDNF immunocontent. The results extend literature data regarding the mechanisms underlying the antidepressant-like action of zinc by indicating that its antidepressant-like effect may be dependent on the activation of PKA, CAMKII, PKC, ERK, and PI3K/GSK-3β pathways. However, zinc is not able to acutely increase BDNF in the hippocampus and prefrontal cortex.