Cordycepin alleviates nicotine withdrawal-induced anxiety via AMPK/CREB/BDNF pathway activation in the hippocampus of male mice

Nicotine withdrawal-induced anxiety is a key contributor to the return to cigarette smoking. Cordycepin, an adenosine analogue, is hypothesized to counteract the withdrawal-induced decline in hippocampal AMP/ATP ratios and consequent AMP-activated protein kinase (AMPK) dephosphorylation, as its monophosphate derivative structurally mimics AMP and directly activates AMPK. In this study, a mouse model of chronic nicotine exposure followed by withdrawal was used to investigate whether cordycepin mitigates nicotine withdrawal-induced anxiety and its underlying mechanisms. Our results revealed that chronic nicotine exposure significantly elevated hippocampal AMPK phosphorylation, whereas nicotine withdrawal led to a sharp decline in p-AMPK levels (p-AMPK/t-AMPK: F = 23.11, P < 0.001), concomitant with pronounced anxiety-like behaviors in the elevated plus maze (open-arm time: F = 16.18, P < 0.01) and open field tests (center time: F = 6.63, P < 0.01). Pretreatment with cordycepin (10 mg/kg) effectively alleviated nicotine withdrawal-induced anxiety-like behaviors (open-arm time: F = 11.74, P < 0.01; center time: F = 5.79, P < 0.01), an effect that was counteracted by the AMPK inhibitor Compound C. Further mechanistic studies via Western blot and immunohistochemical analyses demonstrated that cordycepin activated the hippocampal AMPK/CREB/BDNF signaling pathway, restoring withdrawal-induced reductions in p-AMPK, p-CREB, and BDNF expression. This effect was further validated in PC12 cell experiments. In conclusion, cordycepin alleviates nicotine withdrawal-induced anxiety by activating the AMPK/CREB/BDNF pathway, offering preliminary experimental evidence for its potential as an adjunctive therapy for smoking cessation.