Activation of mTOR dependent signaling pathway is a necessary mechanism of antidepressant-like activity of zinc.

The rapid antidepressant response to the N-methyl-D-aspartate (NMDA) receptor antagonists is mediated by activation of the mammalian target of the rapamycin (mTOR) signaling pathway, an increase in the synthesis of synaptic proteins and formation of new synapses in the prefrontal cortex (PFC) of rats. Zinc (Zn), which is a potent NMDA receptor antagonist, exerts antidepressant-like effects in screening tests and models of depression. We focused these studies in investigating whether activation of the mTOR signaling pathway is also a necessary mechanism of the antidepressant-like activity of Zn. We observed that a single injection of Zn (5 mg/kg) induced an increase in the phosphorylation of mTOR and p70S6K 30 min and 3 h after Zn treatment at time points when Zn produced also an antidepressant-like effect in the forced swim test (FST). Furthermore, Zn administered 3 h before the decapitation increased the level of brain derived neurotrophic factor (BDNF), GluA1 and synapsin I. An elevated level of GluA1 and synapsin I was still observed 24 h after the Zn treatment, although Zn did not produce any effects in the FST at that time point. We also observed that pretreatment with rapamycin (mTORC1 inhibitor), LY294002 (PI3K inhibitor), H-89 (PKA inhibitor) and GF109203X (PKC inhibitor) blocked the antidepressant-like effect of Zn in FST in rats and blocks Zn-induced activation of mTOR signaling proteins (analyzed 30 min after Zn administration). These studies indicated that the antidepressant-like activity of Zn depends on the activation of mTOR signaling and other signaling pathways related to neuroplasticity, which can indirectly modulate mTOR function.