Abstract: This study aims to investigate the effects of nicotine exposure during puberty on cocaine addiction behaviors in adult rats and to investigate the underlying mechanisms. Male Wistar rats, aged 30 days, were divided into two groups: saline-exposed group and nicotine-exposed group. The nicotine-exposed group received subcutaneous injections (sc) of 0.3 mg·kg^-1 nicotine solution three times daily for 15 consecutive days, while the saline-exposed group received an equal volume of saline. On day 60 post-birth, blood was collected from the orbital sinus to separate serum. On day 62, rats underwent jugular vein catheterization surgery and self-administration (SA) training for cocaine, which lasted for 10 consecutive days. The fixed ratio (FR) schedule was gradually increased. After training, rats displayed stable nose-poke behavior for cocaine seeking. Dose-response tests (DR) and progressive ratio tests (PR) were performed to examine whether nicotine exposure during adolescence influenced cocaine addiction in adulthood. This experiment was approved by the Animal Ethics Committee of Institute of Materia Medica, Chinese Academy of Medical Sciences (approval number: 00004401). In the DR test, nicotine-exposed rats showed significantly higher numbers of effective cocaine injections at doses of 0.03, 0.1, and 0.3 mg·kg^-1 compared to the saline-exposed group. The nicotine-exposed group exhibited more pronounced craving for cocaine. In the PR test, at 0.75 mg·kg^-1 cocaine dose, nicotine-exposed rats tended to have higher breakpoints (BP) than the saline-exposed group. Cytokine antibody array and ELISA of serum revealed that CCL5 level in the nicotine-exposed group was significantly higher than that in the saline-exposed group. Moreover, in the DR test, the number of cocaine injections obtained at 0 and 0.3 mg·kg^-¹ cocaine doses correlated significantly with CCL5 levels. In conclusion, nicotine administration during puberty in rats can significantly increase their addiction to cocaine and self-administration behavior in adulthood, exhibiting distinct drug dependence characteristics. The content of CCL5 in rat serum is positively correlated with cocaine addictive behavior.