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Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million single nucleotide polymorphisms (SNPs) was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31 960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with P-values less than 10(-4) (minimum P-value 1.53 x 10(-6)). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the beta3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.

Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

Initial sensitivity to the pharmacological effects of a drug may affect patterns of future use and dependence for a wide variety of drugs. Retrospective reports of sensations experienced upon early experimentation, however, may be limited by recall bias based on time elapsed and subsequent experiences. To validate reports of early experiences with nicotine, we studied 34 smokers who had contributed retrospective data on early experiences with smoking. Half had reported experiencing a buzz from smoking their first cigarette (the "yes" group), the other half had not (the "no" group). To simulate initial sensitivity to nicotine, we asked participants to remain abstinent from smoking for 5 days to allow for the dissipation of tolerance. They then participated in a laboratory session in which they were reexposed to nicotine in an unfamiliar form (nicotine nasal spray) and asked to indicate pleasurable responses by depressing a foot pedal if and when they experienced a "pleasurable buzz." Smokers in the "yes" group were marginally more likely to be male. The two groups did not differ significantly on age or race. The "yes" group smoked significantly more cigarettes/day than the "no" group. When the two groups were compared for response to nasal spray following 5 days' abstinence, smokers in the "yes" group were marginally more likely to have signaled experiencing at least one pleasurable buzz and rated "pleasurable sensation from spray" on a 100-mm visual analogue scale administered 10 min after nicotine dosing significantly higher than were those in the "no" group. To the extent that several days' abstinence can serve as a model for initial sensitivity to nicotine, our findings validate retrospective reports of pleasurable sensations upon early smoking experimentation.

This article is a brief history of the Society for Research on Nicotine and Tobacco, now in its 10th year. During its first decade, the Society grew from around 100 to over 900 members, sponsored well-attended annual meetings and highly influential satellite conferences to promote research, provided timely electronic and print services to increase the flow of information, and founded a new journal to facilitate communication of scientific advances. These accomplishments highlight the progress that has been made in meeting the objective of the Society to stimulate new knowledge about nicotine in all its manifestations.

The rate of nicotine metabolism is hypothesized to be a determinant of how much a person smokes. That is, rapid metabolizers would be expected to need more nicotine and, therefore, smoke more than slow metabolizers. Nicotine is metabolized extensively by the liver enzyme CYP2A6, primarily to cotinine. Cotinine is itself metabolized by CYP2A6 to 3'-hydroxycotinine (3-HC). The ratio of metabolite to parent (i.e., 3-HC:cotinine) would be expected to reflect CYP2A6 activity. We measured the ratio of 3-HC:cotinine in the urine of 72 smokers. This ratio was significantly correlated with the number of cigarettes smoked per day (r=.33, p=.005), though not with the Fagerström Test for Nicotine Dependence. This finding supports the hypothesis that the rate of nicotine metabolism is a determinant of the level of cigarette consumption and supports the use of the 3-HC:cotinine ratio as a noninvasive marker of nicotine metabolism.

Positive- and negative-reinforcement consequences of smoking were assessed using a self-report inventory. Data from 429 current smokers (348 women, 81 men) were subjected to an exploratory factor analysis, with concurrent validation of resulting scales in 288 current smokers (235 women, 53 men), controlling for sex and age. The solution with three factors--positive reinforcement, negative reinforcement, and smoking patterns--provided the clearest and most interpretable factor solution. The Michigan Nicotine Reinforcement Questionnaire (M-NRQ), which yields positive- and negative-reinforcement scales, was developed based on these results. Positive-reinforcement smoking was associated with higher scores on novelty seeking, reward dependence, alcohol dependence, and pleasurable sensations upon early smoking experimentation, and with lower scores on displeasurable sensations and nausea upon early smoking experimentation. Negative-reinforcement smoking was associated with higher scores for nicotine dependence, depression, anxiety, and harm avoidance. The M-NRQ has potential as a diagnostic tool for individualizing behavioral intervention and pharmacotherapy and also may be useful in identifying new phenotypes for genetic research on smoking.

Cigarette smokers are known to be overrepresented among adults with Attention Deficit Hyperactivity Disorder (ADHD). To date, however, no attempt has been made to determine the extent to which a lifetime diagnosis of ADHD may be associated with smoking even in the absence of current symptomatology. We hypothesized that nicotine dependence and abstinence effects-especially effects relevant to ADHD symptomatology-would be more pronounced in adult ADHD smokers in comparison with those who reported childhood ADHD symptoms only. Results indicated that, in contrast to controls without ADHD symptomatology, both adult and childhood ADHD groups were significantly more likely to experience a number of nicotine withdrawal symptoms, including irritability and difficulty concentrating; in no instance did the ADHD groups differ from one another in this regard. Thus, studying people with childhood symptoms of ADHD, even in the absence of an adult diagnosis, may shed light on the known association between smoking and ADHD.

The present study used logistic regression techniques to examine the extent to which depression, anxiety, disordered eating, and nicotine dependence increased risk of experiencing craving and the eight DSM-IV withdrawal symptoms (depressed mood, insomnia, irritability, anxiety, difficulty concentrating, restlessness, decreased heart rate, increased appetite) during smoking abstinence, assessed retrospectively. Data were provided by a racially diverse sample of 365 male and female smokers recruited to participate in laboratory studies. Results indicate that variables known to be associated with smoking are risk factors for distinct and only somewhat overlapping patterns of symptomatology. Smokers scoring high on measures of anxiety, depression, or disordered eating were at increased risk primarily of experiencing withdrawal symptomatology pathognomonic to their particular disorder, whereas smokers scoring high on nicotine dependence appeared to be at increased risk of experiencing a syndromal pattern of withdrawal, encompassing craving and insomnia as well as cognitive/affective symptoms. Our results support the possibility that some individuals use smoking as a form of self-medication and suggest that elucidation of patterns of withdrawal symptomatology may contribute to improved specification of smoking phenotypes as well as facilitate treatment-matching.

Although considerable progress has been made towards understanding the role of menstrual cycle phase in smoking, little is known about the possible effects of menstrual phase upon nicotine intake, withdrawal symptomatology, and craving in women with psychiatric cofactors. Fourteen women with and without a history of Major Depressive Disorder (MDD) were studied during five biologically-confirmed phases over the course of one menstrual cycle: smoking logs, salivary cotinine, and ratings of craving and withdrawal were collected daily. During a second cycle, subjects remained abstinent for 3 consecutive days during the postmenses and premenstrual phases. Although a significant omnibus F-test emerged for cigarettes per day across phases during ad libitum smoking, only trends were observed post hoc and supported midcycle rather than premenstrual elevations. There were no significant phase differences for cotinine. Withdrawal symptomatology was markedly elevated during smoking abstinence and in women with a history of depression. but showed no evidence of phase effects. Thus, the hypothesis that depressed individuals would be differentially affected by phase and abstinence was not strongly supported by our results, though overall elevations emphasize the need for special attention to withdrawal severity in this population. Craving was significantly elevated during smoking abstinence and was significantly higher during postmenses, consistent with the midcycle elevation in smoking rate, but showed no group differences. Our findings overall lend little support for the need to control for menstrual phase under conditions of ad libitum smoking. The strong association of self-reported menstrually related dysphoria during abstinence with both craving and withdrawal symptoms, however, is consistent with an exacerbation of smoking abstinence effects in women with severe menstrual symptomatology.

The purpose of the present study was to investigate smoking abstinence effects and the dissipation of tolerance (reactivity to nicotine) under controlled laboratory conditions. Seventeen male and female regular smokers were tested first in a session following ad libitum smoking and then in an additional five sessions over the course of 11 days during which they abstained from smoking. A metered dose of nicotine was administered via intranasal spray to ensure standard exposure, and pre- and post-dosing measures of heart rate, blood pressure, cortisol, galvanic skin response (GSR), craving, and several DSM-IV withdrawal symptoms (anxiety, irritability, restlessness, difficulty concentrating, and appetite) were collected. Prior to the nicotine test dose during deprivation sessions, heart rate and systolic blood pressure evinced elements of both an 'offset abstinence pattern' (deflection in a direction opposite to that produced by smoking) and a 'transient abstinence pattern' (deflection followed by a subsequent return); for cortisol, an offset pattern was observed, whereas for GSR and craving, a transient pattern was found. With respect to loss of tolerance, heart rate reactivity was found to increase significantly after 2 days' abstinence from nicotine, and the increase was sustained in subsequent sessions. Cortisol reactivity revealed more gradual dissipation, with significant differences evident only after 9 days of abstinence. These findings extend research on nicotine abstinence effects and on the dissipation of tolerance to nicotine deprivation intervals of nearly 2 weeks and confirm prior observations of variability across different response systems.

The prevalence of smoking is markedly elevated in schizophrenia. Low smoking cessation rates and reports that some smokers with schizophrenia experience an acute increase in symptoms during attempts to quit smoking, suggest a self-medication model. Alternatively, smoking may modulate medication side effects. The effects of treated and untreated smoking abstinence on psychotic symptoms and medication side effects were examined in this study. Nineteen outpatients with schizophrenia or schizoaffective disorder participated in a randomized, double-blind, balanced crossover study: 1 day of ad libitum smoking followed by 3 days of acute smoking abstinence while wearing 22 mg/day active or placebo transdermal nicotine patches, with a return to 3 days of smoking between patch conditions. Daily symptom and side-effect ratings, nicotine and cotinine blood levels were collected. Twelve subjects completed the study. Neither positive symptoms nor mood symptoms changed. An increase in negative symptoms during the first abstinent day occurred in both placebo and active patch conditions, but was not sustained over subsequent abstinent days. Despite physiological signs of withdrawal, completers did not endorse increased nicotine withdrawal symptoms. Dropouts reported higher withdrawal symptoms, but also had no increase in psychiatric symptoms in either phase of the study. Of note, dyskinesias decreased during abstinence and placebo patch treatment, but increased during abstinence and the active patch conditions. Acute exacerbation of psychiatric symptoms is an unlikely explanation for any difficulty smokers with schizophrenia have in early abstinence.

The possible impact of menstrual phase upon reactivity to nicotine was investigated in 12 healthy women smokers. Controlled doses of nicotine were administered via an intranasal aerosol delivery device to overnight-deprived women smokers in four hormonally verified menstrual phases. Physiological, biochemical, and subjective measures were collected. Cycle-related symptomatology differed significantly across phase, with lowest values during the mid-follicular phase. No significant differences were found for baseline variables, including withdrawal measures. Nicotine increment was stable across phase, confirming reliability of the dosing method. No significant menstrual phase differences were found for physiological, subjective, or biochemical responses to nicotine. Pending investigations conducted over longer intervals, in a wider variety of subjects, findings suggest that for this type of study, complex strategies to control for menstrual-cycle phase effects may be unnecessary.

Recent evidence suggests that cigarette smoking has a heritability index around 53%. While related research on underlying mechanisms also supports the idea that genetic factors contribute to nicotine dependence--as well as to cofactors such as substance use and mood disorders--the nature of the behavioral traits and biological capacity for reinforcement that constitutes vulnerability to nicotine dependence is not well understood. The present review explores the problem of why some people become highly nicotine dependent, others develop a pattern of occasional use, and still others avoid the drug entirely despite extensive exposure and widespread experimentation with tobacco in the population. Recent research--both infrahuman and human--suggests that vulnerability to nicotine dependence is related to high initial sensitivity to nicotine and that the development of tolerance is more rapid and self-administration more extensive in such individuals. Relevant findings from neuroscience and biobehavioral research are reviewed in order to identify variables and methodologies that might improve the reliability and validity of behavioral and molecular genetic studies on cigarette smoking. The integration of research in these areas may lead to new insights in the understanding of nicotine dependence as well as to improved techniques for prevention and treatment.

Hypothesizing the existence of a subgroup of female smokers for whom nicotine masks, and abstinence unmasks, a tendency toward hyperphagia and perhaps even subthreshold disordered eating, we compared female “weight-control smokers” (WC; n = 46) and “non-weight-control smokers” (NWC; n = 52) on smoking- and eating-related variables. We also examined the relationship between weight-control smoking and withdrawal symptomatology during 48hours of nicotine abstinence (n = 23). Although WC were not more depressed, anxious, or nicotine-dependent than NWC, they were significantly more likely to report weight gain and increased hunger during abstinence; they also scored higher on Cognitive Restraint and Disinhibition (Three-Factor Eating Questionnaire). The expected correlation of cotinine with weight emerged for NWC but not for WC. Weight-control smoking correlated with increased eating during abstinence. Our findings suggest that WC use dietary restraint as well as smoking to manage weight, and that abstinence may precipitate episodes of disinhibited or binge eating. If WC overinclude women vulnerable to excess or unpredictable eating and consequently to substantial weight gain that can be managed by nicotine, highly focused’treatment strategies may be helpful. The peculiar and fascinating combination of pharmacological and sociocultural factors involved in weight-control smoking has generated considerable research over the past few years. Despite these efforts, however, attempts to determine the net impact of weight-control smoking on treatment efficacy, both in terms of attracting such smokers to treatment and achieving sustained abstinence, have produced a somewhat confusing picture. In the current climate of interest in treatment matching, a question no less appropriate than that of whether weightcontrol smoking is likely to deter cessation efforts or promote relapse is that of whether treatment success rates for people motivated to smoke by nicotine’s anorectic properties can be improved upon; an answer to that question will

Nicotine intake, menstrual and smoking withdrawal symptomatology, and baseline cortisol and MHPG were assessed in nine women smokers under conditions of ad lib smoking and overnight abstinence in three menstrual phases (early follicular, mid-to-late follicular, and late luteal). A trend towards higher nicotine intake (p < 0.10) was observed in the mid-to-late follicular phase. Although menstrual symptomatology was not significantly elevated during the smoking abstinence condition overall, abstinence appeared to prevent the normal reduction in symptomatology during the mid-to-late follicular phase that occurred under conditions of ad lib smoking. Menstrual and withdrawal symptoms were highly correlated, and both were most pronounced during the late luteal/abstinence condition. The smoking-specific item "craving" reflected this pattern, though in attenuated form, suggesting that the observed exacerbation of withdrawal symptomatology was not simply due to generalized dysphoria, as queried in both instruments. MHPG was significantly elevated in the late luteal phase, whereas cortisol was significantly higher during ad lib smoking than during abstinence and tended to be highest in the mid-to-late follicular phase. Further investigation will be needed to determine the functional significance of these findings for understanding and treating smoking in women.

Two studies were conducted to replicate and extend previous demonstrations of smoking-induced, dose-related reports of euphoria, and to confirm this relationship using measures of plasma nicotine. In experiment 1, overnight-deprived subjects, in three different sessions, smoked ultralow-, high-nicotine, and usual-brand cigarettes. In experiment 2, ultralow-, medium-, and high-nicotine cigarettes were used, and plasma nicotine was measured. In both studies, subjects were asked to depress a button during euphoric sensations. Number of sensations for the ultralow-nicotine cigarette was significantly lower than for the high-nicotine cigarette in the first study, and than for both the medium- and high-nicotine conditions in the second; a significant linear trend was observed for number of sensations as a function of plasma nicotine level in the second study. For the high-nicotine cigarette, 19 of 22 subjects experienced at least one sensation (mean around three), starting around 2.5 min after lighting up. Together, these studies support the existence of a dose-response relationship for nicotine-induced euphoric sensations; suggest that they are more pronounced following overnight abstinence than following minimal deprivation, and in more dependent smokers; and characterize in detail the temporal features of these sensations.

The effects of nicotine, like those of other drugs with potential for abuse and dependence, are centrally mediated. The impact of nicotine on the central nervous system is neuroregulatory in nature, affecting biochemical and physiological functions in a manner that reinforces drug-taking behavior. Dose-dependent neurotransmitter and neuroendocrine effects occur as plasma nicotine levels rise when a cigarette is smoked. Circulating levels of norepinephrine and epinephrine increase, and the bioavailability of dopamine is altered as well. Among the neuroendocrine effects are release of arginine vasopressin, beta-endorphin, adrenocorticotropic hormone, and cortisol. Notably, several of these neurochemicals are psychoactive and/or known to modulate behavior. Thus, affective states or cognitive demands may be favorably modified (at least temporarily) by nicotine intake. When nicotine is inhaled, the neuroregulatory effects just described are immediately available and the reinforcing effects of the drug are maximized. On the other hand, nicotine gum and most other nicotine replacement vehicles in current use have a slower onset of action, resulting in less reinforcement value. Recent data suggest that smoking cessation rates may be optimized by tailoring the dose of nicotine replacement (for example, 2 or 5 mg of nicotine gum) to the individual degree of nicotine dependence. In view of the dynamic interactions between the neuroregulatory effects of nicotine and a host of environmental conditions, nicotine replacement therapy is best carried out in combination with behavior modification techniques.

INTRODUCTION Male and female never-smokers stratified on parental history of smoking were tested for possible differences in susceptibility to the hedonic effects of nicotine. METHODS We recruited nicotine-exposed never-smokers with two never-smoking biological parents (PH-) or two ever-smoking biological parents (PH+). After completing a baseline assessment battery focusing on conditions or behaviors associated with smoking, participants were tested for subjective and hedonic effects in response to administration of three different nicotine doses (0.0, 0.5, and 1.0 mg) via nasal spray. Physiological and biochemical reactivity also was monitored. RESULTS PH+ were significantly more likely to report having experienced a "buzz" upon early smoking experimentation and to have histories of alcohol abuse and alcoholism; they also scored higher on disordered eating. In response to nicotine dosing, PH+ reported an increase in depressed mood, compared with a minimal response in PH-, in keeping with our expectation that nicotine would have more pronounced effects in PH+. Regardless of parental history, women reported experiencing greater anxiety in response to the highest nicotine dose, compared with men. DISCUSSION Further exploration in larger samples, using more stringent selection criteria, a wider range of measures, and a less aversive dosing method, may provide a full test of the possible utility of the parental history model for illuminating biobehavioral mechanisms underlying response to nicotine. Also important would be broadening the scope of inquiry to include comparisons with ever-smokers to determine what protected PH+ from becoming smokers, despite the presence of factors that might be expected to decrease resilience and increase susceptibility.

INTRODUCTION The present study expands previous research on early experiences with tobacco by using a Multiple Indicator Multiple Causes (MIMIC) model, which permits combining indicators tapping into pleasant experiences into one latent construct and those indicators of unpleasant experiences into another latent construct. METHODS A sample of 458 participants was recruited via newspaper advertisements. Response to early experimentation with cigarettes was assessed using the Early Smoking Experiences questionnaire, in which participants were asked the following question: "The first time you tried cigarettes, did you experience any of the following? (pleasurable and displeasurable sensations [overall], pleasurable rush or buzz, dizziness, relaxation, nausea, cough, difficulty inhaling)." These experiences were rated on a scale ranging from 1 = none to 4 = intense. RESULTS The MIMIC model revealed that current smoking status and age of initial experimentation with cigarettes were significantly associated with both early pleasant and unpleasant experiences (p < .05). African Americans were less likely than Whites to have early unpleasant experiences (p < .05). No association was found between race and early pleasant experiences. DISCUSSION Our findings are consistent with the inferences that pleasant experiences in response to early experimentation with smoking lead to regular smoking and that positive experiences play a stronger role than negative experiences in the transition to regular smoking. Our study also demonstrates that the MIMIC model is pertinent and practicable in nicotine and smoking research. We recommend it as a useful tool for identifying endophenotypes related to nicotine dependence and tobacco use latent constructs.

Despite evidence that smoking behaviour increases in the context of stress, there has yet to be a clear-cut demonstration that nicotine intake is similarly enhanced. Although nicotine intake has been shown to reduce reported anxiety in the context of stress, the controlling conditions (type of stressor, intensity, temporal relationships, etc.) need further exploration. Recent findings involving nicotine's effects on the hypophyseal-adrenal axis provide a new perspective on these issues, in that increased nicotine intake during exposure to a stressor may represent, at least in part, behavioral compensation for diminished sensitivity to nicotine brought about by nicotine-stimulated corticosteroid release. Corticosteroids may decrease central nervous system excitability in a way that could account for anxiety reduction; on the other hand, anxiety reduction may be an epiphenomenon with respect to the reinforcement of smoking behaviour. The integration of behavioural, physiological, and biochemical research exemplified by the above approach should lead to a better understanding of stress and smoking.

Both smoking and psychological stress produce marked effects upon cardiovascular function, and several studies have demonstrated that in combination they produce additive or potentiating effects. More recently, it has been reported that individuals strongly reactive to psychological stress are also strongly reactive to nicotine. In an attempt to replicate and extend those findings, we examined reactivity to smoking and competitive mental arithmetic across several physiological and biochemical variables. Despite stable responding across mental arithmetic trials, we were unable to demonstrate significant correlations between reactivity to smoking and to a psychological stressor. We further observed that anxiety level, when low, was a poor predictor of desire to smoke and of withdrawal, whereas higher anxiety levels were more tightly linked to these measures. These findings have implications for the identification of individuals at risk of cardiovascular disease as well as for the design of smoking treatment and relapse prevention programs.

What does research on nicotine and tobacco use have to offer that is relevant and possibly useful to an alcohol researcher? First and foremost, nicotine and tobacco research may provide some helpful insights into addiction processes and substance use treatment in general. Smoking can be seen as a model disorder, not only because of its prevalence and its importance as a public health problem, but because the consistency of smoking behavior and the frequency of dosing (nicotine has a short addictive cycle) allow human experimentation in the laboratory without compromising relevance.' Recent technological developments in the topographical analysis of smoking behavior and in the assay of nicotine in biological substrates have facilitated both laboratory and field research, and comprehensive biobehavioral explanations of smoking/nicotine dependence have been proposed.^ Increasingly sophisticated public health campaigns have produced a dramatic decrease in smoking, with the level of smoking in the United States down from over 60% of the adult population in the early 196O's to fewer than 30% in the late 198O's. Over the same time period, therapeutic innovations have resulted in improved treatment strategies, with sustained abstinence rates of up to 50% reported for pharmacological interventions such as nicotine replacement in combination with behavior-change procedures.' The twentieth

Numerous observers have reported that smokers smoke more under stressful conditions. The most frequent explanation is that nicotine reduces anxiety, an intervening variable identified as a negative reinforcer for smoking behaviour. The conditions under which anxiety reduction occurs in response to smoking, however, have not been well defined, nor are underlying mechanisms well understood. There are several possible explanations, including Schachter's theory based on stress-induced changes in urinary pH and the hypothesis of endogenous opioid involvement. The work of Collins and his associates in animals has shown that genetic variations in corticosteroid responsiveness to nicotine are associated with differences in sensitivity to nicotine. Research in our laboratory has extended to humans Collins' findings that sensitivity to nicotine is inversely related to corticosteroid activity. We also found that the combination of a psychological stressor and smoking produced additive effects on cortisol release in humans. These findings suggest a novel way of explaining the interaction between smoking and stress, in that increased nicotine intake in the context of stress may in part reflect behavioural compensation for diminished sensitivity to nicotine when corticosteroid activity is enhanced by the stressor.

Smoking is often viewed as a comprehensive phenotype rather than a complex set of traits involving intermediate phenotypes. To explore this issue in a laboratory setting, we tested 69 smokers stratified on depression, nicotine dependence, and gender. On the third day of an initial withdrawal period, we tested for differences among participants in uncued and cued craving and withdrawal; on the fourth day, we exposed them to a controlled dose of smoke and assessed them for physiological and hedonic effects and reduction of craving and withdrawal. Following resumption of smoking for at least a week, we then tested participants on their ability to abstain for an 11-day interval. During the withdrawal test, high-depressed smokers and men exhibited elevated craving and withdrawal scores overall, whereas no differences emerged for dependence. Cue exposure produced significant increases in craving but not withdrawal. During the smoke-exposure test, men were significantly more likely than women, and high-depressed smokers more likely than low-depressed smokers, to show evidence of experiencing pleasurable "buzzes." High-dependent smokers showed significant increases in diastolic blood pressure, possibly suggestive of greater sensitivity to nicotine. During the quit test, high-dependent smokers had more difficulty abstaining than low-dependent smokers, and women more than men; no differences emerged based on depression. Independently of group membership, inability to abstain was predicted by increased anxiety, depression, and difficulty concentrating in response to cue exposure. These findings provide support for the existence of phenotypes that can be distinguished by withdrawal symptomatology (primarily driven by depression) and ability to remain abstinent (primarily driven by dependence).

Initial sensitivity to substances may affect patterns of future use and dependence. Because smoking and alcohol use are strongly linked, because animal studies indicate cross-sensitivity, and because genetic determinants of nicotine and alcohol dependence overlap, we studied the relationships between retrospectively reported responses to both substances in current smokers (n = 111) and never-smokers (n = 86). Early smoking experiences were correlated with comparable responses to alcohol in smokers, and to a lesser extent, in never-smokers. Both pleasurable early experiences with nicotine and pleasurable experiences with alcohol predicted current alcohol intake; pleasurable early experiences with alcohol also predicted alcohol dependence. Neither pleasurable nor displeasurable experiences with either substance predicted current amount smoked or degree of nicotine dependence. These preliminary findings may have implications for understanding the mechanisms underlying the smoking-alcohol link.

Two elderly patients with Parkinson's disease were treated with nicotine gum and patch. Reliable changes in symptomatology were noted, using a single-subject, placebo-control reversal design. Improvement was associated with active nicotine dosing and involved diminished tremor and disorganized thinking in one patient and diminished bradykinesia and increased energy in the other.

The emergence of depression early in a quit attempt and its relationship to ability to maintain abstinence were studied in 99 depressed and non-depressed women smokers. Participants rated withdrawal symptomatology during a baseline week and the first two weeks of a quit attempt, during which they used a 21-mg nicotine patch and received behavioral counseling. Depressed women experienced greater difficulty maintaining early abstinence than non-depressed women. They were significantly more likely to smoke on the first day of abstinence and smoked marginally more days during the first week. Among participants who relapsed during the first two weeks, latency to relapse was significantly shorter for depressed women. Although craving and all withdrawal symptoms except insomnia showed significant increases over baseline, only depression showed significant group differences, with trend analyses suggesting that depression asymptotes in non-depressed women after the first week but continues increasing in depressed women. Larger increases in depression on the first day of abstinence were associated with earlier lapse. Because depression is relatively infrequent as a withdrawal symptom, it may not be a "true" withdrawal symptom except in depressed people. Identification of depressed smokers and anticipation of their increased need for support during this period may help to counteract the "first-day effect" and difficulties during early abstinence.

Recent research suggests that people who become smokers may be more sensitive to the positive effects of nicotine upon initial exposure than those who do not take up smoking. The present study was designed to extend these findings to a sample of college-age women never-smokers and light smokers. Subjects were asked to rate pleasurable and displeasurable sensations upon first smoking and to indicate the presence or absence of pleasurable rush or buzz, relaxation, dizziness, nausea, and cough. Pleasurable sensations were marginally greater in smokers; pleasurable rush or buzz and dizziness were significantly more likely to be reported by smokers. Relaxation, displeasurable sensations, nausea, and cough did not differ significantly between groups. Fagerstrom Test for Nicotine Dependence scores significantly predicted pleasurable but not displeasurable sensations; Center for Epidemiological Studies-Depression scores predicted neither. These findings lend further support to the following conclusions: (1) people who become cigarette smokers experience more pleasurable sensations upon initial exposure to tobacco than their never-smoking counterparts; and (2) unpleasant reactions to the first cigarette do not protect against subsequent smoking.

The effect of corticosteroids upon the cortisol response to nicotine from smoking was investigated in five heavy smokers. Corticosteroid activity was manipulated by administering dexamethasone, a synthetic glucocorticoid (1 mg orally, 14 h before), in a double-blind, placebo-controlled procedure. Testing took place in the middle of the day and involved the smoking of two high-nicotine (2.87 mg) research cigarettes over a 15-min period. The dexamethasone condition was characterized by a pronounced suppression of baseline plasma cortisol, as expected, and by a significant dampening of the cortisol response to nicotine, indicating diminished sensitivity to nicotine under conditions of enhanced corticosteroid activity.

Aims. Recent research suggests that people who become smokers may be more sensitive to the positive effects of nicotine than those who do not take up smoking . Design and setting. The present study was designed to investigate this hypothesis by querying initial experiences with cigarette smoking in smokers, ex-smokers and never-smokers recruited from the local community . Participants. Subjects were 80 women (23 highly dependent smokers (Fagerstrom Tolerance Questionnaire score 7), 30 less-dependent smokers (FTQ6), 12 ex-smokers and 15 never-smokers) . Measurements. Subjects were asked to rate pleasurable sensations and displeasurable sensations on a scale of 1=none to 4=intense, and to indicate the presence or absence of pleasurable rush or buzz, relaxation, dizziness, nausea and cough; social context was also queried. Pleasurable rush or buzz, relaxation, dizziness, nausea and cough were related to ratings of pleasurable and unpleasant sensations to establish their affective valence . Findings. Pleasurable sensations, pleasurable rush or buzz and relaxation (pleasant effects) were significantly more likely to occur in the smoker categories than in never-smokers. The ratio of pleasurable to unpleasant sensations, computed as an index of overall hedonic impact of initial exposure, also significantly favored the smoker categories. By contrast, unpleasant sensations, nausea and cough (unpleasant effects) did not differ significantly among groups. Dizziness, which did not definitely emerge as either pleasurable or unpleasant, was significantly more likely to be reported among the smoker groups than among never-smokers . Conclusions. People who become highly dependent cigarette smokers appear to have more pleasurable sensations at their initial exposure to tobacco; unpleasant reactions to the first cigarette do not seem to protect against subsequent smoking.

The present report examines efforts to elucidate the role of opioid mechanisms in the reinforcement of smoking. A number of approaches have been used to evaluate nicotine-opioid interactions. Opiate agonists such as heroin or methadone have been found to increase cigarette smoking reliably in humans, and morphine has been shown to increase the potency and efficacy of nicotine in rats. There is also an extensive literature documenting the nicotine-stimulated release of endogenous opioids in various brain regions involved in the mediation of opiate reinforcement. Blockade studies using opioid antagonists have not been as conclusive. Although animal models have demonstrated commonalities between nicotine withdrawal and the opiate abstinence syndrome, including reversibility by morphine, and although the impact of nicotine on certain response systems such as respiratory reflexes has clearly been shown to involve opioid mediation, attempts to demonstrate opioid modulation for the key indicators of smoking reinforcement—cigarette consumption and nicotine self-administration—have been fraught with difficulty. Resolution of the apparent contradictions will require taking into account: (a) the biphasic properties of nicotine-opioid effects at higher doses and anti-opioid effects at lower doses; (b) the contributions of the opioid receptor populations — mu, kappa, sigma — stimulated at various dose levels; (c) the possibility that endogenous-opioid activity is entrained primarily during the acquisition or re-acquisition of nicotine self-administration; (d) the possibility that the endogenous opioid response does contribute to nicotine reinforcement but only as a delimited component of the neuroregulatory cascade of nicotine; and (e) the possibility that opioids contribute primarily to nicotine reinforcement under special conditions such as stress. Taking these considerations into account should allow studies on endogenous opioid effects to begin to do justice to the complexity of both smoking behavior and the actions of nicotine.

Both menstrual phase and nicotine have been shown to affect task performance. Though conflicting results have been reported, at least one well-controlled study has demonstrated that women at midluteal phase show superior performance on speech articulation and speeded motor coordination tests, but poorer performance on perceptual-spatial tests, than during menses. Smokers have demonstrated superior performance on numerous tasks following nicotine than following placebo. To explore the separate and combined influence of these factors, we studied 13 regularly-menstruating smokers using a two (smoking vs. 12 hours' abstinence) by two (menstrual vs. midluteal phase) factorial design. During each session, subjects completed a test battery including two speeded motor coordination tasks, a computerized reaction time test, and the Stroop (1935) color/word test. Subjects completed the Stroop color and color-word tasks significantly faster after ad lib smoking than after overnight abstinence. No other significant differences emerged. Our findings replicate, in an all-female sample, previous reports that speed of cognitive processing is reduced by nicotine abstinence (or enhanced by nicotine administration). Our failure to observe menstrual cycle effects raises the possibility that the anti-estrogenic effects of smoking may attenuate phase differences in performance.

To determine whether cigarette smoking and other drug use are affected by menstrual phase, daily diaries rating menstrual symptomatology, smoking, and alcohol and caffeine intake in female smokers were examined. Women with premenstrual symptomatology were excluded. Menstrual symptomatology peaked during menses and was accounted for primarily by symptoms indicative of physical discomfort. Smoking did not differ as a function of menstrual phase, nor did there emerge any systematic intrasubject correlation between symptomatology and smoking. Alcohol and caffeine intake also failed to show phase-related differences. It was concluded that substance intake is highly stable across the menstrual cycle in female smokers.

The present within-subjects, crossover study was designed to assess the short-term effects of several nicotine replacement strategies. After completing a 2 day smoking baseline, 18 (7 M, 11 F) smokers(≥ 20 cpd) went through the following conditions, each for two full days, in randomized order: a)nicotine chewing gum; b) 24 hour nicotine patch; c) 16 hour nicotine patch; d) two 24 hour nicotine patches; e) 24 hour nicotine patch plus nicotine gum; f) no medication. Only conditions b, c, d, and f will be compared here. Subjects provided self-report and objective data on 5 occasions during each 2 day period (7–8 AM &5–6 PM), and smoked ad lib for the 5 days between conditions. Between group comparisons of abnormal dreams found (at AM visit): 24 hour patch double & 24 hour patch > baseline. Between group comparisons of interrupted sleep found (at AM visit): double 24 hour patch > baseline. Between group comparisons of difficulty getting to sleep found (at AM visit): double 24 hour patch > baseline & 16 hour patch. Saliva nicotine and cotinine values will be presented. These results suggest that use of a double strength nicotine patch can have significant effects on sleep. While some subjects on 24 hour patch reported sleep disturbances, there was no significant difference between 16 & 24 patch use on self-reported sleep disturbances.

Investigations of gender differences in the frequency and/or intensity of smoking withdrawal symptomatology have yielded conflicting findings. Several studies using measures collected both before abstinence and at the peak of symptomatology have failed to find gender differences. Yet, when asked to rate symptomatology experienced during past quit attempts, women have repeatedly been shown to endorse significantly more symptomatology than men. A possible explanation is that, although men and women show no differences when rating symptoms prospectively, women remember their past withdrawal symptoms as being more severe than do men, either because women exaggerate the difficulties they experience or because men downplay them. To test this hypothesis, and to determine whether men or women were more accurate in their recollections, we combined data from two studies in which subjects were asked to assess symptoms prospectively following 2 days of abstinence, and also to rate withdrawal during past quit attempts. As predicted, we found the effects of abstinence to be similar when assessed prospectively but different when assessed retrospectively, with women reporting more symptomatology than men. Men whose retrospective and prospective responses were discordant consistently underestimated the likelihood of experiencing symptomatology; women showed no consistent trends. The total number of symptoms reported retrospectively by women was similar to the total number reported prospectively, whereas men significantly underestimated the number of symptoms that they actually experienced. These findings may suggest ways in which treatment strategies can be tailored to the differences between male and female styles in recalling past experiences with abstinence from smoking.

Alexithymia is associated with substance abuse and may interfere with successful psychotherapy. Alexithymia's relation to smoking, nicotine dependence, and smoking cessation therapy is unknown, and potentially overlaps with negative affect. Three studies addressed the relations between alexithymia, negative affect, and smoking. In Study 1, 67 young adult smokers were more depressed than 370 past or never smokers, but no different on the Toronto Alexithymia Scale total or subscale scores. In Study 2, negative affect--but not alexithymia--was related to greater nicotine dependence among 99 chronic smokers. In Study 3, alexithymia tended to predict increased patient participation in cognitive-behavioral therapy for smoking; low nicotine dependence--but neither alexithymia nor negative affect--predicted abstinence from smoking at treatment end. Alexithymia appears to be independent of negative affect and unrelated to cigarette smoking or nicotine dependence, suggesting that the affect regulation deficits in alexithymia play a negligible role in nicotine addiction.

The purpose of this study was to assess the test-retest stability of the Fagerstrom Tolerance Questionnaire (FTQ) in two samples: (a) paid subjects in an American laboratory; data were collected via telephone screen and subsequently via questions embedded in a written history; and (b) smokers hospitalized for depression in Paris; data were collected via a written questionnaire upon admission and again after 3 weeks of treatment for depression. Reliability data are also presented for a recently revised version of the FTQ, the Fagerstrom Test for Nicotine Dependence (FTND), and compared with FTQ data collected in a subsample of subjects in the American database who received both versions of the questionnaire. Both the FTQ (in both samples) and the FTND proved to be highly reliable. The validity of the scales, using cotinine, number of years smoked, and the "addictive" factor on the Classification of Smoking by Motives questionnaire as criterion variables, was also supported. No relationship between FTQ score and severity of depression was detected in either sample. Internal consistency was somewhat higher for the FTND than for the FTQ, replicating previous findings in the literature.

Sensitivity to nicotine was explored using test doses administered via intra-nasal aerosol in 10 smokers and 10 never-smokers. Smokers received 1.50 mg nicotine (in 2 sprays, < 5 seconds apart, one spray per nostril); never-smokers received either 0.50 mg (n = 3) or 0.25 mg (n = 7) nicotine. Accumulation of nicotine in plasma, per unit dose administered, was nearly four times greater in never-smokers than in smokers, indicating differences in pharmacokinetic tolerance. To examine sensitivity to nicotine without this confound, peak physiological reactivity (heart rate and blood pressure changes) was divided by peak plasma nicotine increment and the ratio was expressed as a function of cotinine level prior to dosing, thereby relating sensitivity to nicotine to history of exposure. In smokers, functional sensitivity to nicotine was inversely related to customary nicotine intake, replicating previous findings for light and heavy smokers. The observation that never-smokers were not much more sensitive to nicotine than light smokers is notable given the disparity in previous history of exposure.

This study tested the temporal stability and within-subject consistency of the Diagnostic and Statistical Manual-III-R (DSM-III-R) nicotine withdrawal symptoms in 39 (21 female, 18 male) regular smokers. Subjects provided withdrawal symptom ratings while smoking ad libitum and during two 48-hour abstinence periods that were separated by 1 week. All but two symptoms, increased eating and hunger, demonstrated adequate temporal stability (i.e., stability coefficients > or = .70). Within-subject consistency was found for impatience, anxiety, difficulty concentrating, and irritability. The total (average) score emerged as the most stable and consistent indicator of withdrawal. Results of a cluster analysis suggest the presence of two groups of smokers based on the withdrawal experience. Possible reasons for variability in nicotine withdrawal symptom reports are discussed.

The present report describes an Intranasal Nicotine Aerosol Delivery Device (INADD) employing an artist's airbrush as aerosolizer and precise, electromechanical control of spray duration. It was designed for the administration of controlled doses of nicotine in a laboratory setting and has been used successfully in over 30 smokers and nonsmokers of both genders. In the present study, nicotine was administered to 12 male smokers at three different doses (0.05 mg, 1.00 mg, and 2.00 mg), and at the same dose (1 mg) on three different occasions. The low dose produced a minimal change in plasma nicotine, while the high dose produced a peak increment of around 16 ng/ml. The medium dose reliably produced a peak increment of around 8-9 ng/ml on all three occasions. Nicotine in plasma showed a sharp rise followed by a slower decline, mimicking the pattern associated with cigarette smoking. Physiological and biochemical responses showed significant dose-response relationships. Subjective reports suggested that aerosol dosing was somewhat aversive, but it is unclear whether this effect is intrinsic to the method or due to other factors. The device described in this report answers the need for a safe and easy means of controlling nicotine dose. Moreover, since nicotine administration via aerosol is novel for both smokers and non-smokers, minimizing the contributions of behavioral tolerance and habituation to the dosing vehicle, it lends itself to the comparison of the pharmacological effects of nicotine between experienced and naive subjects.

Cigarette smokers weigh less than comparably aged nonsmokers, and many gain weight following cessation. Though some evidence suggests that nicotine reduces food intake, with a selective effect on sweet-tasting foods, the issue remains unresolved. In the current study, 64 women (20 smokers, 26 never-smokers, and 18 ex-smokers) were tested for sweet taste preference; 9 of these smokers were studied under conditions of both ad lib smoking and overnight abstinence, in three hormonally verified menstrual phases. 1) Although no overall differences were detected in taste preference among the three groups, significantly more smokers than nonsmokers preferred the higher sucrose concentrations. 2) No significant differences due to menstrual phase were observed. 3) Although preference ratings did not differ significantly between overnight abstinence and ad lib smoking, a subset of smokers who preferred higher sucrose concentrations rated their preference for the solutions significantly higher during the ad lib smoking sessions. Our findings suggest that smoking and nonsmoking women differ with respect to taste preference and that, at least in a subset of female smokers, preference is affected by nicotine abstinence/acute dosing.

More American women are taking up smoking than men and fewer are quitting; if current trends continue, rates for women will surpass those for men by the mid-1990's. But ironically, much of what is known about the biobehavioural aspects of smoking is based on research using male subjects. The present paper reviews evidence suggesting that: (1) women may differ from men with regard to nicotine intake and/or effects; (2) nicotine intake and effects may be influenced by menstrual cycle phase; (3) oral contraceptive use and estrogen replacement therapy may affect intake and effects of nicotine; (4) the effects of chronic nicotine use on female reproductive endocrinology may have implications for the reinforcement of smoking; and (5) pharmacological agents used to treat smoking may have different effects in women than in men. Guidelines and suggestions are presented by future biobehavioural research in women, including standardization of assessment procedures, attention to the use of appropriate controls, and use of pharmacological probes.

The effect of fluoxetine hydrochloride, a 5-HT uptake inhibitor (60 mg/day PO), in preventing weight gain associated with nicotine reduction was investigated in participants in a double-blind, placebo-controlled smoking-cessation trial. A lunch of cheese pizza and chocolate bars was offered, and caloric intake was monitored. The analysis focused on subjects (placebo: n = 11; fluoxetine: n = 10) who succeeded in reaching cotinine levels of less than 50% of their starting cotinine levels (signifying a stringent reduction in nicotine intake) and who participated in pre- and post-nicotine reduction lunch sessions 70 days apart. Subjects on placebo gained significantly more weight (mean +/- SEM = +3.3 +/- 0.7 kg) than subjects on fluoxetine (-0.6 +/- 1.2 kg). In fluoxetine-treated subjects, weight gain/loss was strongly correlated with initial body mass index, with higher BMI being associated with greater decreases in weight. A trend towards decreased caloric intake in the fluoxetine group was observed; the change in total calories at lunch was significantly correlated with weight change, an association accounted for principally by change in pizza intake. We conclude that fluoxetine treatment effectively prevents the weight gain that accompanies nicotine reduction and that this phenomenon is mediated, at least in part, by diminished caloric intake.

The effects of a psychological stressor and nicotine upon corticosteroid release were investigated using a full factorial, repeated-measures design in eight moderate smokers. Sessions involved the presentation of either competitive mental arithmetic or reading aloud and either smoking a usual cigarette or sham smoking. Self-reported anxiety increased after exposure to competitive mental arithmetic, confirming the stressfulness of the procedure. Cortisol levels increased significantly in response to psychological stress and showed a trend towards a significant elevation over time in response to nicotine self-administration. The two manipulations in combination produced additive effects upon plasma cortisol. These findings underscore the usefulness of the corticosteroid response as a marker of the impact of different procedures and suggest that it may provide an indicator for exploring the mechanisms by which nicotine-stress interactions are mediated. Systematic research that varies temporal and other parameters involving nicotine and various stressors will be needed to resolve inconsistencies in the literature on smoking and anxiety in the context of stress.

The Fagerstrom Tolerance Questionnaire (TQ) is often used in both research and treatment contexts to evaluate nicotine tolerance and physiological dependence in cigarette smokers. Recently, however, questions about its validity and its usefulness in comparison to other easily collected measures have been raised. In the present study, 100 male subjects reporting for experimental sessions (Sample I) and 50 male and female subjects entering a smoking cessation clinic program (Sample II) were administered the TQ and determinations of plasma cotinine during ad libitum smoking were made. TQ scores were found to be correlated with cotinine levels in both samples, and several of the individual items proved to have statistically significant discriminatory value. Other schemes for determining degree of dependence were considered and found not to be superior to the TQ. Suggestions for further refining the TQ are reviewed.

A cigarette-smoke delivery system is described in which nicotine dosage was delimited by having the subject inhale a measured amount of smoke to a predetermined depth and duration of inhalation. A plastic syringe was used to “inject” a specified amount of cigarette smoke into the subject’s mouth, and an airbag containing 1 liter of air was used to provide a “chaser” with a fixed volume of inhalation for the smoke. Using plasma nicotine boost as an indicator, dose control was found to be nearly linear for the three dose levels employed; in the high-dose condition, plasma nicotine levels were moderately consistent within subjects over three successive administrations. Between-subject variability was considerably greater than within-subject variability, however, suggesting that each smoker obtained a characteristic nicotine boost that reflected individual differences in nicotine pharmacokinetics in addition to nicotine intake per se.

Smokers' ability to regulate nicotine intake by varying topographical parameters such as depth of inhalation and number of puffs makes it difficult to administer standardized doses of nicotine as delivered from smoking. A number of studies have claimed to control these parameters without confirming the effectiveness of such procedures by measures of plasma nicotine. The purpose of the present study was to determine whether specifying onset and duration of each puff would result in accurate dosing. Plasma nicotine boosts for five “paced puffers” were compared across two sessions and with similar data for five “free smokers.” Neither between-subject consistency nor within-subject reproducibility was improved by this paced puffing procedure, despite apparent topographical control.