Nicotine alleviates chronic stress-induced anxiety and depressive-like behavior and hippocampal neuropathology via regulating autophagy signaling

Recently, we reported that chronic nicotine significantly improved chronic stress-induced impairments of cognition and the hippocampal synaptic plasticity in mice, however, the underlying mechanism still needs to be explored. In the present study, 32 male C57BL/6 mice were divided into four groups: control (CON), stress (CUS), stress with chronic nicotine administration (CUS + Nic) and chronic nicotine administration (Nic). The anxiety-like behavior and neuropathological alteration of DG neurons were examined. Moreover, PC12 cells were examined with corticosterone in the presence or absence of nicotine. Both cell viability and apoptosis were determined. When treated simultaneously with an unpredictable chronic mild stress (CUS), nicotine (0.2 mg/kg/d) attenuated behavioral deficits and neuropathological alterations of DG neurons. Moreover, Western blotting showed that chronic nicotine also elevated the level of autophagy makers including Beclin-1 and LC3 II triggered by CUS. In addition, concomitant treatment with nicotine (10 μM) significantly attenuated the loss of PC12 cell viability (p < .01) and apoptosis compared to that of corticosterone treatment alone. Besides, chronic nicotine also enhanced the protein and RNA expression levels of autophagy makers triggered by corticosterone, such as Beclin-1, LC3 II and p62/SQSTM1. However, the above improvements were significantly blocked by autophagy inhibitor 3-MA. Importantly, the activation of the PI3K/Akt/mTOR signaling was carefully tested to illuminate the effects of chronic nicotine. Consequently, chronic nicotine played a role of neuroprotection in either CUS mice or corticosterone cells associating with the enhancement of the autophagy signaling, which was involved in activating the PI3K/Akt/mTOR signaling.