Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation

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, he influence of i.c.v. administralion of H-89 (1 mu g/sire, PKA inhibitor), KN-62 (1 mu g/sile, CAMKII inhibitor), chelerythrine (1 mu g/site, PKC inhibitor), PD98059 (5 mu g/sile, MEK1/2 inhibitor), U0126 (5 mu g/site, MEK1/2 inhibitor), LY294002 (10 nmolisile, PI31K inhibitor) on the reduction of immobilily Lime in Lhe Lail suspension Lest. (TST) elicited by ZnCl2 (10 mg kg, p.o.) was invesligalecl. Moreover, he effecl of Lhe combination of sub effective doses of ZnCl2 (1 mg/kg, p.o.) and AR -A014418 (0.001 Lig/sile, GSK-3 beta inhibilor) was evalualed. The occurrence of changes in CREB phosphorylalion and BDNF immunoconlenl in he hippocampus and prefroffial corlex of mice following ZnCl2 lrealment was also invesligaled. The anLi-immobilily effecl of ZnCl2 in the TST was preveffied by lrealmenl wiLh PIO\ PKC, CAMKII, MEK1/2 or PI31K inhibitors. Furthermore, ZnCl2 in combination with AR-A014418 caused a synergistic anti-immobility effect in the TST. None of the treatments altered locomotor activity of mice. ZnCl2 treatment caused no alteration in CREB phosphorylation and BDNF immunocontent. The results extend literature data regarding the mechanisms underlying the antidepressantike action of zinc by indicating that its antidepressant-like effect may be dependent on the activation of PKA, CAMKII, PKC, ERK, and P13K/GSK-30 pathways. However, zinc is not able to acutely increase BDNF in the hippocampus and prefrontal cortex. (C) 2015 Elsevier Inc. All rights reserved,