This study compared the rewarding and aversive effects of nicotine in adolescent, adult, and adult rats pre-exposed to nicotine during adolescence. Prior to conditioning, the rats were tested for their initial preference for either of 2 distinct compartments. Adolescent and adult rats then received various nicotine doses in their initially non-preferred side on one day and saline in the other side on alternate days. This 2-day procedure was repeated over 8 consecutive days. Following conditioning, rats were re-tested for their preference. Another cohort of adolescent and adult rats were conditioned with various doses of d-amphetamine. Nicotine produced CPP in an inverted U-shaped manner in both age groups. However, adolescents displayed a larger upward shift in CPP that was significant across a wider dose range relative to adults. There were no developmental differences to CPP produced by d-amphetamine. In a final study, adolescents were prepared with pumps that delivered nicotine for 14 days. These rats were conditioned later as adults using the same procedures used previously. Pre-exposure to nicotine during adolescence diminished the aversive effects produced by the highest nicotine dose in naïve adults. Taken together, these studies provide a basis for enhanced vulnerability to nicotine during adolescence.

Introduction-The objective of this study was to examine age-, hormone-, and sex-dependent differences to the behavioral effects of nicotine using place-conditioning procedures in female rats.

Tobacco use is a major economic and health problem. It is particularly concerning that women consume more tobacco products, have a more difficult time quitting smoking and are less likely to benefit from smoking cessation therapy than men. As a result, women are at higher risk of developing tobacco-related diseases. Clinical evidence suggests that women are more susceptible to anxiety disorders, and are more likely to smoke in order to cope with stress than men. During smoking abstinence, women experience more intense anxiety than men and report that the anxiety-reducing effects of smoking are the main reason for their continued tobacco use and relapse. Consistent with this, pre-clinical studies using rodent models suggest that females display more intense stress during nicotine withdrawal than males. This review posits that in women, stress is a principal factor that promotes the initiation of tobacco use and relapse behavior during abstinence. Studies are reviewed at both the clinical and pre-clinical levels to provide support for our hypothesis that stress plays a central role in promoting tobacco use vulnerability in females. The clinical implications of this work are also considered with regard to treatment approaches and the need for more research to help reduce health disparities produced by tobacco use in women.

Vulnerability to nicotine addiction is significantly increased in individuals who begin smoking during adolescence; however, the underlying mechanisms of this phenomenon remain unclear. This study examined the motivational effects of nicotine withdrawal in adolescent and adult (PND 60-75) rats using the conditioned place aversion paradigm. Male Wistar rats were tested for their initial preference for either of two distinct compartments of our conditioning apparatus. Rats were then implanted with subcutaneous (sc) pumps that produce equivalent blood plasma levels of nicotine for 14 days. Conditioning was conducted over the last 8 days of nicotine exposure. Rats received the nicotinic antagonist mecamylamine (1.5 or 3.0 mg/kg, sc) to precipitate withdrawal in their initially preferred compartment, and on alternate days they received saline in their non-preferred compartment. Following conditioning, rats were re-tested for their preference for each compartment. A subsequent study was conducted to examine potential developmental differences in learning place aversion produced by another aversive stimulus, lithium chloride (LiCl). Rats received LiCl (0, 10, 30, or 100 mg/kg, sc) in their initially preferred side using similar conditioning procedures. Adults displayed robust place aversion produced by nicotine withdrawal. This effect was lower in adolescent rats even in a group of young rats that received 7 additional days of nicotine exposure prior to conditioning. This developmental difference was specific to nicotine withdrawal since there were no differences between adolescents and adults in learning place aversion with LiCl. Our findings demonstrating reduced effects of nicotine withdrawal constitute a powerful basis for the increased vulnerability to nicotine dependence during adolescence.