E-CIGARETTES AS A POTENTIAL GATEWAY TO ALTERED SENSITIVITY TO DRUGS OF ABUSE: A MICE MODEL OF NICOTINE VAPOR EXPOSURE DURING ADOLESCENCE

Electronic cigarettes have become the primary source of nicotine exposure among adolescents; however, data on the long-term consequences of exposure remain limited. Here, we tested the hypothesis that adolescent electronic cigarettes exposure induces behavioral alterations in adulthood and that subsequent exposure to psychoactive substances modulates these effects, aligned with the gateway theory. Adolescent Swiss mice (both sexes) were exposed to nicotine vapor (VAPE; nicotine 48mg/ml + 40:60 (vol:vol) vegetable glycerol:propylene glycol; 4h/day, postnatal days 30–45) or ambient air. After a 15-day interval, behavioral tests were initiated. Immediately before each test, the young adult mice received saline, nicotine (0.5mg/kg/i.p.), or ketamine (10mg/kg/i.p). Adolescent VAPE exposure did not produce long-term alterations in place conditioning, locomotor activity, anxiety-like behavior, novelty seeking, or aversive memory. Contrastingly, young adulthood ketamine induced male place conditioning and hyperlocomotion, reduced anxiety-like behavior in both sexes, and enhanced female long-term aversive memory. Nicotine exposure during the same period induced place conditioning in females, with no other effects. Importantly, VAPE modulated behavioral responses to subsequent drug challenges. It prevented nicotine-induced conditioning in females and ketamine-induced conditioning in males. Conversely, it potentiated other effects. Specifically, animals previously exposed to VAPE exhibited enhanced hyperlocomotion in response to subthreshold effects of ketamine in females and nicotine in males. Aversive memory was improved in response to nicotine, whereas novelty-seeking was enhanced following ketamine exposure. Collectively, these findings suggest that adolescent VAPE alters behavioral responses to later drug exposure, supporting the concept of e-cigarettes as a gateway to altered sensitivity to drugs of abuse.