Development of Dependence in Smokers and Rodents With Voluntary Nicotine Intake: Similarities and Differences

Introduction Smoking and vaping throughout adolescence and early adulthood lead to nicotine dependence. Nicotine withdrawal is associated with somatic and affective withdrawal symptoms that contribute to smoking and relapse. Affective nicotine withdrawal symptoms in humans include craving for cigarettes, depression, anxiety, trouble sleeping, and cognitive deficits. Methods Herein, we review clinical studies that investigated nicotine dependence in people who smoke or vape. We also discuss studies that investigated the development of dependence in animals with oral nicotine intake, nicotine aerosol self-administration, and intravenous nicotine self-administration. Results Clinical studies report that adolescents who smoke daily develop nicotine dependence before those who smoke infrequently, but ultimately all smokers become dependent in adulthood. Preclinical studies indicate that rats that self-administer nicotine also become dependent. Rats that self-administer nicotine display somatic withdrawal signs and affective withdrawal signs, including increased anxiety and depressive-like behavior, cognitive deficits, and allodynia. Most nicotine withdrawal signs were observed in rodents with daily (7 days/week) or intermittent long access (23-hour) to nicotine. Clinical smoking studies report symptoms of nicotine dependence in adolescents of both sexes, but virtually all preclinical nicotine self-administration studies have been done with adult male rats. Conclusions The role of sex and age in the development of dependence in nicotine self-administration studies remains under-investigated. However, the role of sex and age in nicotine withdrawal has been thoroughly evaluated in studies in which nicotine was administered noncontingently. We discuss the need for volitional nicotine self-administration studies that explore the gradual development of dependence during adolescence and adulthood in rodents of both sexes. Implications The reviewed clinical studies investigated the development of nicotine dependence in male and female adolescent and young adult smokers and vapers. These studies indicate that most adolescent smokers and vapers gradually become nicotine dependent. Preclinical studies with rodents show that nicotine intake in widely used self-administration models also leads to dependence. However, almost all animal studies that investigated the development of nicotine dependence have been conducted with adult male rats. To better model smoking and vaping, it is important that nicotine intake in rats or mice starts during adolescence and that both sexes are included.

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Summary: Adolescents and young adults who smoke or vape can develop nicotine dependence, leading to withdrawal symptoms such as cravings, depression, anxiety, sleep problems, and cognitive deficits. Clinical studies show that daily smokers have a higher risk of developing dependence compared to occasional smokers, and this dependence develops in adulthood. Preclinical studies with animals indicate that rats self-administering nicotine also show signs of dependence, including anxiety, depressive behavior, cognitive deficits, and changes in sensitivity to pain. It is important to include both sexes and start nicotine intake during adolescence in animal studies to better model smoking and vaping.