Cordycepin attenuates nicotine-induced behavioral sensitization through inhibition of NF-κB signaling in rats

Nicotine exposure triggers behavioral sensitization, a process closely linked to neuroinflammatory cascades and dysregulation of the mesolimbic dopaminergic system. Although cordycepin, a major bioactive component of Cordyceps militaris, possesses potent anti-inflammatory and neuroprotective properties, its therapeutic potential against nicotine-induced neuroadaptations has not been fully established. This study investigated the protective effects of cordycepin on nicotine-induced behavioral and neurochemical alterations, focusing on the NF-κB signaling pathway in a rat model. Male Sprague-Dawley rats were administered nicotine (0.4 mg/kg, s.c.) for seven consecutive days, followed by a three-day withdrawal and a nicotine challenge on day 11. Cordycepin (1, 2.5, or 5 mg/kg, i.p.) was co-administered during the sensitization phase. Behavioral sensitization was quantified via locomotor activity, while molecular changes in the ventral tegmental area (VTA) and nucleus accumbens (NAc) were analyzed using Enzyme-Linked Immunosorbent Assay (ELISA) and immunohistochemistry. Repeated nicotine administration significantly increased locomotor activity and stimulated dopaminergic activation, evidenced by elevated expression of tyrosine hydroxylase (TH) and increased dopamine levels in the VTA and NAc. These changes were accompanied by increased oxidative stress markers and pro-inflammatory cytokines (IL-1β, TNF-α), alongside a reduction in neurotrophic factors. Systemic administration of cordycepin suppressed nicotine-induced locomotor sensitization. Mechanistically, cordycepin inhibited the nuclear translocation of NF-κB, thereby reducing neuroinflammation and oxidative damage within the mesolimbic circuit. In conclusion, these results demonstrate that cordycepin mitigates nicotine-induced behavioral sensitization by modulating NF-κB-mediated neuroinflammatory pathways. Our findings suggest that cordycepin may serve as a novel pharmacological intervention for treating nicotine-related neuroadaptations and addiction.