In human populations, cigarettes and alcohol generally serve as gateway drugs, which people use first before progressing to marijuana, cocaine or other illicit substances. To understand the biological basis of the gateway sequence of drug use, we developed an animal model in mice and focused on the effects of nicotine on subsequent responses to cocaine. We found that pretreatment of mice with nicotine increased the response to cocaine as assessed by both addiction-related behaviors and synaptic plasticity in the striatum, a brain region critical for addiction-related reward. Locomotor sensitization was increased by 98%, conditioned place preference was increased by 78%, and cocaine-induced reduction in long-term potentiation (LTP) was enhanced by 24%. The responses to cocaine were altered only when nicotine was administered first, and nicotine and cocaine were then administered concurrently. Reversing the order of drug administration was ineffective. Cocaine had no effect on nicotine induced behaviors and synaptic plasticity. Nicotine primed the response to cocaine by enhancing its ability to induce transcriptional activation of the FosB gene through inhibiting histone deacetylase, causing global histone acetylation in the striatum. We tested this conclusion further with a histone deacetylase inhibitor and found that it similarly simulated the actions of nicotine on cocaine by priming the response to cocaine, and enhancing FosB gene expression and LTP depression in the nucleus accumbens. Conversely, in a genetic mouse model of Rubinstein Taybi’s syndrome, characterized by reduced histone acetylation, the effects of cocaine on LTP were diminished. We achieved a similar effect pharmacologically by infusing a low-dose of theophylline, an activator of histone deacetylase, into the nucleus accumbens. These data from mice prompted an analysis of epidemiological data, which indicated that most cocaine users initiate cocaine use after the onset of smoking while actively smoking and that initiating cocaine use after smoking increases the risk of becoming dependent on cocaine, consistent with our data in mice. If our findings in mice apply to humans, a decrease in smoking rates in young people could also lead to a decrease in cocaine addiction.

Little is known about the natural history of drug dependence. This article describes the development and predictors of DSM-IV nicotine dependence in adolescence when tobacco use is initiated. In a two-stage design, a survey was administered to 6th-10th graders in the Chicago Public Schools to select a cohort of adolescents. Household interviews were conducted with adolescents five times and with one parent (predominantly mothers) three times over two years. The analytical sample includes 353 youths, who started using tobacco within 12 months preceding Wave 1 or between Waves 1-5. Survival analysis estimated latency to individual DSM-IV nicotine dependence criteria and the full dependence syndrome. Twenty-five percent of youths experienced the syndrome within 23 months of tobacco use onset. Tolerance, impaired control and withdrawal were experienced most frequently. Youths who experienced full dependence experienced their first symptom faster after tobacco use onset than those who experienced only one criterion through the end of the observation period. Cox proportional hazards models estimated the importance of time-constant and time-varying sociodemographic, tobacco and other drug use, parental and peer smoking, social psychological and biological risk factors for experiencing the first criterion and the full syndrome. Pleasant initial sensitivity to tobacco and number of cigarettes smoked the prior month predicted both outcomes. Parental dependence predicted the full syndrome. Significant covariates were generally the same across gender and racial/ethnic subgroups. The predictive significance of the initial smoking experience and parental dependence highlight the potential importance of genetic factors in the etiology of nicotine dependence.

The few identified racial/ethnic differences in predictors of smoking behavior suggest that universal prevention and intervention efforts could reach most adolescents regardless of race/ethnicity. With 2 exceptions, important contextual factors remain to be identified.

Nicotine metabolism has been hypothesized to affect patterns of smoking. The recent development of a noninvasive measure of nicotine metabolism, the nicotine metabolite ratio (trans-3'-hydroxycotinine/cotinine), makes it possible to examine the association between rate of nicotine metabolism and smoking behavior in the general population. This US study examined group differences in the ratio measured in urine and the association between the ratio and multiple measures of smoking behavior and nicotine dependence in a large, national representative sample of young adults. The sample included 900 daily smokers aged 18-26 years from wave III (2001-2002) of the National Longitudinal Survey of Adolescent Health. Nicotine dependence was measured by using the Fagerström Test for Nicotine Dependence. Females had higher nicotine metabolite ratios than males; Whites and Hispanics had higher nicotine metabolite ratios than African Americans or Asians. This finding is consistent with those from laboratory studies of older smokers based on intravenous infusion of nicotine. No significant association was found between the nicotine metabolite ratio and number of cigarettes smoked per day or nicotine dependence. The availability of a noninvasive measure makes possible systematic testing of causal hypotheses generated by laboratory studies in the general population.

We examine the association between education and smoking by women in the population, including smoking during pregnancy, and identify risk factors for smoking and the consequences of smoking in pregnancy for children's smoking and behavioral problems. Secondary analyses of four national data sets were implemented: The National Survey of Drug Use and Health (2006), the National Longitudinal Survey of Youth (1979–2004); the National Longitudinal Survey of Adolescent Health (Wave III); The National Health and Nutrition Examination Survey (2005-2006). The lower the level of education, the greater the risk of being a current smoker, smoking daily, smoking heavily, being nicotine dependent, starting to smoke at an early age, having higher levels of circulating cotinine per cigarettes smoked, and continuing to smoke in pregnancy. The educational gradient is especially strong in pregnancy. Educational level and smoking in pregnancy independently increase the risk of offspring smoking and antisocial and anxious/depressed behavior problems. These effects persist with control for other covariates, except maternal age at child's birth, which accounts for the impact of education on offspring smoking and anxious/depressed behavior problems. Women with low education should be the target of public health efforts toward reducing tobacco use. These efforts need to focus as much on social conditions that affect women's lives as on individual level interventions. These interventions would have beneficial effects not only for the women themselves but also for their offspring.