Exercise for the Prevention and Treatment of Adolescent-Onset Nicotine Addiction

Cigarette smoking is the leading cause of preventable death in the United States followed closely by obesity. Given that most adult smokers initiate tobacco use during adolescence and find it difficult to quit, preventative measures to curtail adolescent smoking initiation are necessary. Thus, one objective of this dissertation was to determine, using animal models, whether exercise might block the initiation of nicotine use. As the use of pharmacotherapies is controversial in teens due to ongoing neurodevelopment, another objective of this dissertation was to determine whether exercise would prevent nicotine relapse. Vulnerability to nicotine addiction is also apparent in women and adolescent females as they have been found to progress to dependence faster, have more difficulty quitting, a greater vulnerability to relapse, and to be at a higher risk for the smoking-related diseases than their male counterparts despite equal or even lower levels of use. Adolescent and adult female rodents also have a greater propensity for nicotine self-administration, suggesting that these sex differences in vulnerability to nicotine addiction are biological based. Thus, another objective of this dissertation was to determine if the efficacy of exercise as an intervention for nicotine addiction differs between males and females in an adolescent-onset model. Nicotine is known to produce long-lasting changes in the reward pathway, and changes within the nucleus accumbens in particular, are thought to underlie vulnerability to relapse. Given that the mechanisms for the efficacy of exercise are unknown, the final objective of this dissertation was to examine the possibility that its efficacy is related to its ability to modulate these nicotine-induced adaptations. To address these objectives, I examined the efficacy of voluntary wheel running, an animal model of aerobic exercise, at reducing nicotine use initiation and relapse vulnerabilities in adolescent male and female rats. I used electron microscopy to examine the effect of exercise on nicotine-induced structural plasticity of synapses within the nucleus accumbens. I found that contemporaneous exposure to brief bouts of exercise prevented acquisition of nicotine self-administration in adolescent rats. Exposure to brief bouts of exercise during an abstinence period also significantly attenuated subsequent nicotine-seeking in both male and female rats. However, in contrast to males, females displayed an enhanced sensitivity to the effects of environmental enrichment and/or non-aerobic exercise in a locked running wheel control condition and showed attenuated nicotine-seeking under both locked and unlocked wheel conditions. I also showed that exercise during abstinence normalized nicotine abstinence-induced structural plasticity of excitatory synapses in the nucleus accumbens. Together, the results from this dissertation demonstrate that exercise, by modulating plasticity within the reward pathway, may be an effective prevention and intervention for adolescent-onset nicotine addiction.