Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain's initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as Npas2 Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK/MAPK-targets like gephyrin, and modulates the synaptic AMPAR/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC-NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN preexposed group, which include PACAP/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

Nonmedical Prescription Opioid Use by Parents and Adolescents in the US.

BACKGROUND: To date, intergenerational patterns of nonmedical prescription opioid (NMPO) use have not been examined. We investigate the association between parental and adolescent NMPO use in the United States. METHODS: Data are from 35 000 parent-child dyads with an adolescent aged 12 to 17 years from the 2004-2012 nationally representative National Surveys on Drug Use and Health. Using multivariable logistic regression models, we estimated the association between self-reported parental and adolescent lifetime NMPO use, controlling for parental and adolescent use of other drugs, attitudes about drug use, parental and adolescent psychosocial risk factors, and sociodemographic characteristics. RESULTS: Controlling for other factors, parental NMPO use was associated with adolescent NMPO use (adjusted odds ratio [aOR] 1.30; 95% confidence interval [CI] 1.09-1.56). Mothers' use had a stronger association with adolescent use than fathers' use (aOR 1.62 [95% CI 1.28-2.056] versus aOR 0.98 [95% CI 0.74-1.24]). Associations between parental and adolescent NMPO use did not differ by adolescent sex or race and/or ethnicity. Parental lifetime smoking, low monitoring, and parent-adolescent conflict were uniquely associated with adolescent NMPO use (aOR 1.19-1.24) as were adolescent smoking, marijuana use, depression, delinquency, and perceived schoolmates' drug use (aOR 1.25-1.71). Perceived risk of drug use and religiosity were associated with lower rates of adolescent NMPO use (aOR 0.77-0.93). Use among older adolescents was higher than among younger adolescents (aOR 1.27; 95% CI 1.21-1.34). CONCLUSIONS: Parent-based interventions targeted at adolescent NMPO use should address parental NMPO use and smoking and promote positive parenting.

Birth Cohorts Analysis of Adolescent Cigarette Smoking and Subsequent Marijuana and Cocaine Use.

OBJECTIVES: To examine whether the drug behavior of adults from different birth cohorts is shaped by adolescent drug experiences and whether adult prevalence of marijuana and cocaine use depends on adolescent cigarette or alcohol use prevalence. METHODS: We analyzed 18 birth cohorts comprising 8th, 10th, and 12th graders, sampled from 1991 to 2008, from Monitoring the Future, an annual nationally representative cross-sectional survey of high school students in the United States (n = 864 443). RESULTS: Within cohorts, lifetime rates of 8th and 10th grade cigarette use were significantly associated with subsequent lifetime rates of marijuana and cocaine use, controlling for trends in use and social norms toward drug use. Each percent increase (or decrease) in 8th and 10th grade smoking was associated with an 8% increase (or decrease) in prevalence of later marijuana use and 14% to 23% increase (or decrease) in prevalence of later cocaine use. Relationships were consistent by gender and race/ethnicity. CONCLUSIONS: Prevalences of smoking in 8th and 10th grade and of marijuana and cocaine use in 12th grade are associated. Public health campaigns should focus on early stages of adolescence, when drug use habits are forming.

Nicotine Dependence in Adolescence and Physical Health Symptoms in Early Adulthood.

INTRODUCTION: To examine the prospective associations of Diagnostic and Statistical Manual of Mental Disorders nicotine dependence (ND) and other individual and parental factors in adolescence on self-reported health symptoms in early adulthood. METHODS: Multiethnic prospective longitudinal cohort of adolescents from grades 6-10 and a parent (N = 908) from the Chicago Public Schools. Adolescents were interviewed five times at 6-month intervals (Waves 1-5) and once 4.5 years later (Wave 6). Parents were interviewed annually three times (W1, W3, W5). Multivariate regressions estimated prospective associations of Diagnostic and Statistical Manual of Mental Disorders ND, other individual and familial risk factors in adolescence (mean age 16.6) on physical health symptoms in early adulthood (mean age 21.3), controlling for health symptoms in adolescence. RESULTS: Levels of health symptoms declined from adolescence to early adulthood, except among dependent smokers. Nicotine dependent adolescents reported more health symptoms as young adults than nonsmokers and nondependent smokers, especially if depressed. ND and health symptoms in adolescence were the strongest predictors of health in early adulthood. These two adolescent factors, depression, and the familial factors of parental ND, depression and health conditions, each independently predicted health symptoms in young adulthood. Females reported more symptoms than males. CONCLUSIONS: There is continuity of health status over time. ND, depression, and parental factors in adolescence contribute to poor health in early adulthood. The findings highlight not only the role of adolescent behavior, but the importance of the family in the development of young adult health. Reducing smoking, particularly ND, and depression among adolescents and parents will decrease physical health burden.

Intergenerational Patterns of Smoking and Nicotine Dependence Among US Adolescents.

OBJECTIVES: We examined associations between parental and adolescent smoking and nicotine dependence in the United States. METHODS: We used data from the 2004 to 2012 National Survey on Drug Use and Health, which ascertained smoking behaviors of 1 parent and 1 adolescent aged 12 to 17 years in 35 000 dyads. We estimated associations between parental and adolescent smoking behaviors, adjusted for covariates. RESULTS: Parental current dependence was strongly associated with adolescents' lifetime smoking (adjusted odds ratio [AOR] = 2.96; 95% confidence interval [CI] = 2.47, 3.55), whereas parental current nondependent smoking (AOR = 2.26; 95% CI = 1.92, 2.67) and former smoking (AOR = 1.51; 95% CI = 1.31, 1.75) were less strongly associated. Only parental nicotine dependence was associated with adolescent nicotine dependence (AOR = 1.66; 95% CI = 1.00, 2.74). Associations between parental and adolescent smoking did not differ by race/ethnicity. Parents' education, marital status, and parenting and adolescents' mental health, beliefs about smoking, perception of schoolmates' smoking, and other substance use predicted adolescent smoking and dependence. CONCLUSIONS: Reducing parental smoking would reduce adolescent smoking. Prevention efforts should encourage parental smoking cessation, improve parenting, address adolescent mental health, and reinforce adolescents' negative beliefs about smoking.

Reciprocal associations between cigarette consumption and DSM-IV nicotine dependence criteria in adolescent smokers.

AIMS: To examine the inter-relationships between cigarette consumption and DSM-IV nicotine dependence (ND) criteria from smoking onset in adolescence up to 7 years later, adjusting for alcohol consumption and DSM-IV alcohol dependence (AD) criteria. DESIGN: A cohort drawn from grades 6-10 in an urban school system was interviewed five times at 6-month intervals (waves 1-5) and 4.5 years later (wave 6). A parent was interviewed three times. SETTING: Chicago, Illinois. PARTICIPANTS: Recent smokers (n = 409). MEASUREMENTS: Structured household interviews ascertained number of cigarettes smoked, DSM-IV ND symptoms, drinks consumed, DSM-IV AD symptoms, and selected covariates. Reciprocal prospective associations between number of cigarettes smoked and ND criteria, controlling for time-varying alcohol consumption and dependence criteria, were examined with cross-lagged models. FINDINGS: Reciprocal associations between number of cigarettes smoked and ND criteria were both significant. Cigarette consumption had stronger associations with later ND [ß = 0.25, 95% confidence interval (CI) = 0.17-0.32] than dependence had with later cigarette consumption (ß = 0.09, 95% CI = 0.01-0.16). Alcohol and cigarette consumption influenced each other; AD scores were associated with later ND scores but not the reverse. Reports of pleasant initial experiences from smoking were associated positively with cigarette consumption and ND the first year after smoking onset; later smoking onset was negatively associated with cigarette consumption the seventh year after onset; parental ND predicted cigarette consumption and ND throughout. CONCLUSIONS: In adolescent smokers, higher cigarette consumption predicts later severity of DSM-IV nicotine dependence more than the reverse. Smoking and drinking also influence each other mutually over time.

D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus.

The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We find that a single injection of cocaine does not alter LTP. However, pretreatment with nicotine followed by a single injection of cocaine causes a substantial enhancement of LTP. This priming effect of nicotine is unidirectional: There is no enhancement of LTP if cocaine is administrated prior to nicotine. The facilitation induced by nicotine and cocaine can be blocked by oral administration of the dopamine D1/D5 receptor antagonist (SKF 83566) and enhanced by the D1/D5 agonist (SKF 38393). Application of the histone deacetylation inhibitor suberoylanilide hydroxamic acid (SAHA) simulates the priming effect of nicotine on cocaine. By contrast, the priming effect of nicotine on cocaine is blocked in genetically modified mice that are haploinsufficient for the CREB-binding protein (CBP) and possess only one functional CBP allele and therefore exhibit a reduction in histone acetylation. These results demonstrate that the DG of the hippocampus is an important brain region contributing to the priming effect of nicotine on cocaine. Moreover, both activation of dopamine-D1 receptor/PKA signaling pathway and histone deacetylation/CBP mediated transcription are required for the nicotine priming effect in the DG.

Nicotine primes the effect of cocaine on the induction of LTP in the amygdala.

In human populations, there is a well-defined sequence of involvement in drugs of abuse, in which the use of nicotine or alcohol precedes the use of marijuana, which in turn, precedes the use of cocaine. The term "Gateway Hypothesis" describes this developmental sequence of drug involvement. In prior work, we have developed a mouse model to study the underlying metaplastic behavioral, cellular and molecular mechanisms by which exposure to one drug, namely nicotine, affects the response to another drug, namely cocaine. We found that nicotine enhances significantly the changes in synaptic plasticity in the striatum induced by cocaine (Levine et al., 2011). Here we ask: does the metaplastic effect of nicotine on cocaine also apply in the amygdala, a brain region that is involved in the orchestration of emotions and in drug addiction? We find that pretreatment with nicotine enhances long-term synaptic potentiation (LTP) in response to cocaine in the amygdala. Both short-term (1 day) and long-term (7 days) pre-exposure to nicotine facilitate the induction of LTP by cocaine. The effect of nicotine on LTP is unidirectional; exposure to nicotine following treatment with cocaine is ineffective. This metaplastic effect of nicotine on cocaine is long lasting but reversible. The facilitation of LTP can be obtained for 24 but not 40 days after cessation of nicotine. As is the case in the striatum, pretreatment with Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, simulates the priming effect of nicotine. These results provide further evidence that the priming effect of nicotine may be achieved, at least partially, by the inhibition of histone acetylation and indicate that the amygdala appears to be an important brain structure for the processing of the metaplastic effect of nicotine on cocaine. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.

Trajectories of criteria of nicotine dependence from adolescence to early adulthood.

BACKGROUND: To identify patterns and correlates of developmental trajectories of DSM-IV nicotine dependence criteria from adolescence to early adulthood. METHODS: The analytical sample of lifetime smokers (N=877) is from a longitudinal cohort of 6th-10th graders drawn from an urban school system. Subjects were interviewed 5 times at 6-month intervals and once 4.5 years later. Growth mixture models were estimated to identify trajectories of DSM-IV nicotine dependence criteria over ages 12-23. RESULTS: A four-class solution fitted the data best: No dependence criteria (class 1, 32.0%); early onset/chronic course (class 2, 26.1%); early onset/remission (class 3, 15.4%); late onset (class 4, 26.5%). There appeared to be three critical periods. At ages 12-15, symptoms increased rapidly. As of age 16, the early onset/chronic class stabilized at high levels of symptoms, the early onset/remission class started its symptomatic decline, and the late onset class experienced a sharp increase in symptoms. At age 20, there was a convergence in the prevalence of symptoms experienced at high (classes 2 and 4) and low levels (classes 1 and 3). Extensiveness of smoking and marijuana use were associated with higher baseline levels of nicotine dependence criteria. Anxiety disorders were associated with all three symptomatic trajectories. Parental smoking and nicotine dependence were associated specifically with the early/chronic class, while pleasant initial sensitivity and earlier onset ages of cigarette and marijuana use characterized the two early onset classes (2 and 3). CONCLUSIONS: Trajectories of dependence criteria constitute an advantageous phenotype for research and intervention over static summaries of smoking behaviors.

Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine.

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 used it to study 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 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 inhibition of histone deacetylase, which caused global histone acetylation in the striatum. We tested this conclusion further and found that a histone deacetylase inhibitor simulated the actions of nicotine by priming the response to cocaine and enhancing FosB gene expression and LTP depression in the nucleus accumbens. Conversely, in a genetic mouse model characterized by reduced histone acetylation, the effects of cocaine on LTP were diminished. We achieved a similar effect by infusing a low dose of theophylline, an activator of histone deacetylase, into the nucleus accumbens. These results from mice prompted an analysis of epidemiological data, which indicated that most cocaine users initiate cocaine use after the onset of smoking and while actively still smoking, and that initiating cocaine use after smoking increases the risk of becoming dependent on cocaine, consistent with our data from mice. If our findings in mice apply to humans, a decrease in smoking rates in young people would be expected to lead to a decrease in cocaine addiction.

Comorbid psychiatric disorders and nicotine dependence in adolescence.

AIMS: To examine bidirectional influences of onset of psychiatric disorders and nicotine dependence among adolescent smokers. DESIGN: A prospective longitudinal cohort of adolescents and mothers drawn from a large city school system. Adolescents were interviewed five times and mothers three times over 2 years. SETTING: Chicago, Illinois. PARTICIPANTS: Subsample of adolescent smokers (n = 814). MEASUREMENTS: Selected DSM-IV psychiatric disorders, nicotine dependence and selected risk factors were ascertained. FINDINGS: Among lifetime smokers, 53.7% experienced at least one nicotine dependence criterion; 26.1% full dependence; 14.1% experienced an anxiety disorder, 18.8% a mood disorder and 29.5% a disruptive disorder. Nicotine dependence and psychiatric disorders were comorbid: nicotine-dependent youths had higher rates of individual and multiple disorders than those not dependent. Controlling for other covariates, mood disorder and nicotine dependence did not predict each other; anxiety disorder predicted nicotine dependence. Bidirectional influences were observed for disruptive disorder and nicotine dependence. Predictors of onset of full nicotine dependence included earlier onset age of tobacco use, high initial pleasant sensitivity to tobacco, alcohol and illicit drug use, abuse and dependence and parental nicotine dependence. Predictors of psychiatric disorder onset included gender, race/ethnicity, other psychiatric disorders, illicit drug abuse or dependence and parental depression and delinquency. CONCLUSIONS: Initial pleasant experiences of smoking are predictive of later development of nicotine dependence. There may be reciprocal influences between disruptive disorder and development of nicotine dependence in adolescence, and intergenerational transmission of parental nicotine dependence and psychopathology.

Sequencing of DSM-IV criteria of nicotine dependence.

AIMS: To determine whether there is a sequence in which adolescents experience symptoms of nicotine dependence (ND) as per the DSM-IV. DESIGN: A two-stage design was implemented to select a multi-ethnic target sample of adolescents from a school survey of 6th-10th graders from the Chicago Public Schools. The cohort was interviewed at home five times with structured computerized interviews at 6-month intervals over a 2-year period. PARTICIPANTS: Subsample of new tobacco users (n = 353) who had started to use tobacco within 12 months prior to wave 1 or between waves 1 and 5. MEASUREMENTS AND STATISTICAL METHODS: Monthly histories of DSM-IV symptoms of ND were obtained. Log-linear quasi-independence models were estimated to identify the fit of different cumulative models of progression among the four most prevalent dependence criteria (tolerance, impaired control, withdrawal, unsuccessful attempts to quit), indexed by specific symptoms, by gender and race/ethnicity. FINDINGS: Pathways varied slightly across groups. The proportions who could be classified in a progression pathway not by chance ranged from 50.7% to 68.8%. Overall, tolerance and impaired control appeared first and preceded withdrawal; impaired control preceded attempts to quit. For males, tolerance was experienced first, with withdrawal a minor path of entry; for females withdrawal was experienced last, tolerance and impaired control were experienced first. For African Americans, tolerance by itself was experienced first; for other groups an alternative path began with impaired control. CONCLUSIONS: The prevalence and sequence of criteria of ND fit our understanding of the neuropharmacology of ND. The order among symptoms early in the process of dependence may differ from the severity order of symptoms among those who persist in smoking.

Educational attainment and smoking among women: risk factors and consequences for offspring.

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); 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.

ADOLESCENTS' INCONSISTENCY IN SELF-REPORTED SMOKING: A COMPARISON OF REPORTS IN SCHOOL AND IN HOUSEHOLD SETTINGS.

Extent and sources of inconsistency in self-reported cigarette smoking between self-administered school surveys and household interviews was examined in two longitudinal multiethnic adolescent samples, the urban Transition to Nicotine Dependence in Adolescence (TND) (N = 832) and the National Longitudinal Study of Adolescent Health (Add Health) (N = 4,414). Inconsistency was defined as a positive report of smoking in school followed by a negative report in the household. Smoking questions were ascertained with paper-and-pencil instruments (PAPI-SAQ) in school in both studies, and computer-assisted personal interviewing (CAPI) in TND but audio computer-assisted self-interviewing (ACASI) in Add Health in the household. In TND, 23.5 percent of youths who reported smoking lifetime and 20.4 percent of those who reported smoking the last 12 months in the school survey reported in the household never having smoked; in Add Health, the latter was 8.6 percent. Logistic regressions identified five common correlates of inconsistency across the two studies: younger age, ethnic minority status, lesser involvement in deviant activities, having nonsmoking parents and friends. In TND, interviewing of youth and parent by the same interviewer increased inconsistent reporting. Matching the definition of inconsistent reporting and the age, gender and race/ethnic distributions of TND on an urban Add Health subsample reduced the predicted rate of inconsistency in TND. The estimated bias attributable to CAPI compared with ACASI methodology did not reach significance in the aggregated matched samples suggesting that irrespective of administration mode, household interviews decrease reporting of smoking, especially among younger, minority and more conventional youths embedded in a social network of nonsmokers.

Comorbidity of psychiatric disorders and nicotine dependence among adolescents: findings from a prospective, longitudinal study.

OBJECTIVE: To examine prospectively the comorbidity of DSM-IV psychiatric disorders and nicotine dependence in adolescence. METHOD: A multiethnic sample (N = 1,039) of adolescents from grades 6 to 10 in the Chicago public schools (mean age 14.1 years) was interviewed at home five times, and mothers were interviewed three times over a 2-year period (2003-2005). Completion rates at each wave were 96% of the initial sample. Selected DSM-IV psychiatric disorders were ascertained from youths and mothers about youths at two annual waves with the NIMH Diagnostic Interview Schedule for Children, Version IV-Y and IV-P; DSM-IV symptoms of nicotine dependence were ascertained from youths at every wave using a measure developed for adolescents. RESULTS: Psychiatric disorders most often preceded the onset of the first criterion of nicotine dependence. Prospective associations between psychiatric disorders and nicotine dependence were examined through logistic regressions. After controlling for comorbid disorders, it was found that lifetime disruptive disorder significantly predicted the onset of a nicotine dependence criterion (adjusted odds ratio 2.1). Early onset of any psychiatric disorder increased this risk. Other predictors included novelty seeking and extensiveness of smoking. By contrast, nicotine dependence did not predict the onset of a psychiatric disorder; significant predictors included the youths' prior other psychiatric disorders, novelty seeking, and parental depression and antisocial behavior. CONCLUSIONS: Nicotine dependence does not seem to contribute to the onset of psychiatric disorders, whereas disruptive disorder is an important etiologic factor for nicotine dependence in adolescence.

Developmental trajectories of criteria of nicotine dependence in adolescence.

We describe the nature and predictors of developmental trajectories of symptoms of DSM-IV nicotine dependence in adolescence following smoking initiation. Data are from a longitudinal cohort of 324 new smokers from grades 6-10 in the Chicago Public Schools, interviewed 5 times at 6-month intervals. Monthly data on DSM-IV symptoms of nicotine dependence were available for 36 months. Growth mixture modeling was applied to the monthly histories to identify trajectories of DSM-IV criteria of nicotine dependence. A four-class solution best fitted the data: no DSM criterion (47.7%); early onset/chronic course (19.8%); early onset/remission (17.3%); late onset (15.2%). Blunt use prior to cigarette use was associated with the three symptomatic trajectories. Conduct disorder and prior heavy smoking were associated with Class 2 (chronic). Conduct disorder differentiated Class 2 from Class 4 (late onset), while pleasant initial sensitivity to the first tobacco experience was associated with Classes 2 and 3 (remit) and differentiated Class 2 from Class 4. Novelty seeking characterized Class 3. Parental dependence differentiated chronicity (Class 2) from remission (Class 3) among those who developed symptoms early. Being Hispanic reduced membership in Classes 3 and 4, and being male for Class 3. The data highlight the importance of parental nicotine dependence as a risk factor for early and sustained nicotine dependence by the offspring, pleasant initial sensitivity and conduct disorder for early onset of dependence, and blunt use prior to smoking for all trajectories. The factors important for onset of dependence are not necessarily the same as those for sustained course.

On the development of nicotine dependence in adolescence.

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 2 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 developed 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.

Urine nicotine metabolites and smoking behavior in a multiracial/multiethnic national sample of young adults.

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.