Serving Substance Abuse Professionals Since 1993

Last Update: 06.03.12

C O R K O N L I N E

powerpoint presentations
CORK database search
resource materials
bibliographies
clinical tools
user services
newsletters
about cork
home

CORK Bibliography: Nicotine, Acute Effects

62 citations. January 2009 to present

Prepared: March 2012

Adamopoulos D; Argacha JF; Gujic M; Preumont N; Degaute JP; van de Borne P. Acute effects of nicotine on arterial stiffness and wave reflection in health young non-smokers. Clinical and Experimental Pharmacology & Physiology 36(8): 784-789, 2009. (32 refs.)

Recently, we have demonstrated that cigarette smoke exposure proportionally increases plasma nicotine levels and arterial wave reflection to the aorta. However, the exact contribution of nicotine to the smoke-induced enhancement of wave reflection and the potential underlying mechanisms have not been fully investigated. The present study was a prospective study in 15 healthy male non-smokers. All received a placebo and a 2 mg nicotine tablet, according to a randomized double-blind cross-over study design. Each subject underwent repeated measurements at baseline and for 1 h after nicotine or placebo intake, using carotid-femoral pulse wave velocity (PWV) to assess arterial compliance. Concurrently, aortic pressures and the augmentation index were evaluated using applanation tonometry. Plasma nicotine concentrations achieved 1 h after intake of the nicotine tablet reached comparable levels to those achieved after 1 h exposure to passive smoke (3.6 +/- 0.4 vs 3.2 +/- 0.4 ng/mL, respectively; P = 0.4). Nicotine enhanced arterial wave reflection to the aorta, as assessed by the augmentation index corrected for heart rate (4.2 +/- 1.3 vs -0.7 +/- 0.8% with placebo; P = 0.001). In addition, a progressive increase in carotid-femoral PWV was noted after nicotine administration (0.3 +/- 0.1 vs -0.02 +/- 0.1 m/s with placebo; P = 0.04). This remained significant even after adjustment for changes in mean blood pressure and heart rate (P = 0.01). Plasma nicotine concentrations comparable to those achieved after exposure to passive smoke enhance arterial wave reflection to the aorta. This is accompanied by an increase in carotid-femoral PWV, denoting a deterioration of arterial compliance by nicotine.

Ashare RL; Baschnagel JS; Hawk LW. Subjective effects of transdermal nicotine among nonsmokers. Experimental and Clinical Psychopharmacology 18(2): 167-174, 2010. (51 refs.)

The subjective experience of nicotine, which may be influenced by personality traits as well as environmental factors, may be important for understanding the factors associated with the initiation and maintenance of nicotine dependence. The present study examined the effects of 7 mg transdermal nicotine among a relatively large sample (n = 91; 44 women) of college-aged nonsmokers. Using a placebo controlled, double-blind, within-subjects design, nicotine's effects were examined at rest and again after participants completed a sustained attention task. Sex and personality factors (Behavioral Inhibition and Behavioral Approach; BIS/BAS Scales; Carver & White, 1994) were examined as potential moderators. Overall, the effects of nicotine were generally modest and unpleasant. In the context of the cognitive task, nicotine increased nausea and negative affect but reduced fatigue, relative to placebo. In contrast, effects of nicotine during the initial 4 hr of patch administration, in which participants were in their natural environments, were moderated by individual differences in behavioral approach. Neither behavioral inhibition nor gender reliably moderated any subjective effects of nicotine. The present work suggests transdermal nicotine exerts only modest, mostly negative effects among nonsmokers. Future work should examine both contextual and personality moderators in large samples of participants who are exposed to nicotine through multiple routes of administration.

Bates ML; Brenza TM; Ben-Jebria A; Bascom R; Ultman JS. Longitudinal distribution of ozone absorption in the lung: Comparison of cigarette smokers and nonsmokers. Toxicology and Applied Pharmacology 236(3): 270-275, 2009. (37 refs.)

In nonsmokers, ozone (O-3) is removed primarily by the epithelial lining fluid (ELF) of the conducting airways. We hypothesized that cigarette smokers, whose ELF antioxidant capacity may be limited by smoking, would remove less O-3 from their conducting airways than nonsmokers. We recruited 29 nonsmokers (17M, 12F) and 30 smokers (19M, 11F, 4 +/- 4 pack-years) with similar anthropometric characteristics and measured the longitudinal distribution Of O-3 using the bolus inhalation method. We also assessed the physiological effect of this transient exposure regimen using forced spirometry and capnography. Contrary to our hypothesis, the penetration volume at which 50% of a bolus was absorbed was not different between smokers and nonsmokers (97.1 +/- 5.4 mL versus 97.9 +/- 5.8 mL. p = 0.92). However, smokers did experience an increase in the slope of the alveolar plateau of the capnogram (S-N) (8.1 +/- 3.2%, p = 0.02) and a small decrease in FEV1 (-1.3 +/- 0.6%, p = 0.03), whereas nonsmokers did not (Delta FEV1 -0.1 +/- 0.5% and Delta S-N -0.2 +/- 2.5%, p >0.10). Thus, smokers are more sensitive to inhaled O-3 boluses than nonsmokers, despite a similar internal dose distribution.

Benjamin RM. Exposure to tobacco smoke causes immediate damage: A report of the Surgeon General. (editorial). Public Health Reports 126(2): 158-159, 2011. (4 refs.)

Blank MD; Cobb CO; Kilgalen B; Austin J; Weaver MF; Shihadeh A; Eissenberg T et al. Acute effects of waterpipe tobacco smoking: A double-blind, placebo-control study. Drug and Alcohol Dependence 116(1-3): 102-109, 2011. (47 refs.)

Background: Waterpipe tobacco smoking usually involves heating flavored tobacco with charcoal and inhaling the resulting smoke after it has passed through water. Waterpipe tobacco smoking increases heart rate and produces subjective effects similar to those reported by cigarette smokers. These responses are thought to be nicotine-mediated, though no placebo-control studies exist. Accordingly, this double-blind, placebo-control study compared the acute physiological and subjective effects of waterpipe tobacco smoking to those produced when participants used a waterpipe to smoke a flavor-matched, tobacco-free preparation. Methods: Occasional waterpipe tobacco smokers (n = 37; 2-5 monthly smoking episodes for >= 6 months) completed two double-blind, counterbalanced sessions that differed by product: preferred brand/flavor of waterpipe tobacco or flavor-matched, tobacco-free preparation. For each 45-min, ad lib smoking episode blood and expired air CO were sampled, cardiovascular and respiratory response were measured, and subjective response was assessed. Results: Waterpipe tobacco smoking significantly increased mean (+/-SEM) plasma nicotine concentration (3.6 +/- 0.7 ng/ml) and heart rate (8.6 +/- 1.4 bpm) while placebo did not (0.1 +/- 0.0 ng/ml; 1.3 +/- 0.9 bpm). For carboxyhemoglobin (COHb) and expired air CO, significant increases were observed for tobacco (3.8 +/- 0.4%; 27.9 +/- 2.6 ppm) and for placebo (3.9 +/- 0.4%; 27.7 +/- 3.3 ppm) with no differences across condition. Independent of condition, symptoms of nicotine/tobacco abstinence (e.g., "urges to smoke", "anxious") were reduced and direct effects (e.g., "dizzy", "satisfy") increased. Discussion: These results from the first placebo-control study of waterpipe tobacco smoking demonstrate that waterpipe-induced heart rate increases are almost certainly mediated by nicotine though the subjective effects observed in these occasional smokers were not.

Boissoneault J; Gilbertson R; Prather R; Nixon SJ. Contrasting behavioral effects of acute nicotine and chronic smoking in detoxified alcoholics. Addictive Behaviors 36(12): 1344-1348, 2011. (35 refs.)

Background: Current literature suggests that acute nicotine administration provides a compensatory mechanism by which alcoholics might alleviate attentional deficits. In contrast, chronic smoking is increasingly recognized as negatively affecting neurobehavioral integrity. These opposing effects have not been simultaneously examined. Thus, we sought to a) extend previous work by exploring the effects of acute nicotine effects on vigilance components of attention and replicate previous findings suggesting that treatment-seeking alcoholics experience benefit to a greater extent than do other groups; and b) to examine the impact of chronic smoking on these tasks and across subgroups. Methods: Substance abusing participants (N = 86) were recruited and subgrouped on the basis of dependency criteria as either alcoholics, alcoholics with co-morbid stimulant dependence, or stimulant dependent individuals. Groups of cigarette-smoking (N = 17) and non-smoking (N = 22) community controls were recruited as comparison groups. Smoking subjects were assigned a placebo, low, or high dose nicotine patch in a double-blind placebo controlled fashion. Non-smoking controls were administered either a placebo or low dose. Testing occurred after dose stabilization. Results: General linear models indicated greater sensitivity to acute nicotine administration among alcoholics than other groups when controlling for the effect of intensity of smoking history, as reflected by pack-years. Pack-years correlated negatively with performance measures in alcoholics but not stimulant abusing subgroups or smoking controls. Finally, regression analyses demonstrated that pack-years predicted poorer performance only for the alcoholic subgroup. Conclusions: These results support previous work finding a compensatory effect of acute nicotine administration on attentional performance in alcoholics and reinforce the consideration of recent nicotine use as a confound in neurocognitive studies of alcoholics. Of particular interest is the finding that smoking history as reflected in pack-years predicted poorer performance, but only among alcoholics. Further systematic study of these opposing effects among alcoholics and other groups using a broader array of tasks is needed.

Brody AL; Olmstead RE; Abrams AL; Costello MR; Khan A; Kozman D et al. Effect of a history of major depressive disorder on smoking-induced dopamine release. Biological Psychiatry 66(9): 898-901, 2009. (20 refs.)

Background: Dopamine (DA) system dysfunction is implicated in the pathophysiology of major depressive disorder (MDD). We sought to determine if cigarette smokers with a history of MDD and current mild depressive symptoms have abnormal smoking-induced DA release (measured indirectly as change in C-11-raclopride binding potential [BPND]). Methods: Fifty-six cigarette smokers either with (n = 10) or without (n = 46) a history of MDD (MDD+ and MDD-, respectively) underwent bolus-plus-continuous-infusion C-11-raclopride positron emission tomography, during which they smoked a regular cigarette. Presmoking to postsmoking changes in C-11-raclopride BPND were compared between groups. Also, correlations were determined between change in BPND and depression, anxiety, and withdrawal rating scale scores for the MDD+ group. Results: The MDD+ group had a significantly greater reduction in C-11-raclopride BPND (-16.3%) than the MDD- group (-8.4%) (analysis of covariance [ANCOVA], p = .03). Significant negative correlations were found between depression/anxiety and change in C-11-raclopride BPND (r = -.77, p < .01 and r = -.74, p = .01, respectively). Conclusions: MDD+ smokers have greater smoking-induced DA release than MDD- smokers, and higher depression/anxiety levels are associated with greater smoking-induced DA release. These findings support the theory that MDD+ smokers have DA system dysfunction, including heightened smoking-induced DA release.

Ciftci O; Caliskan M; Guilu H; Erdogan D; Topcu S; Guler O et al. Acute effects of smoking light cigarettes on coronary microvascular functions. Clinical Cardiology 32(4): 210-214, 2009. (21 refs.)

Background: To date, there has been no study comparing the possible acute effects on coronary microvascular functions of smoking light cigarettes (those with low tar and nicotine yield) and regular cigarettes. Methods: Twenty healthy volunteers (8 women and 12 men; mean age, 25.8 +/- 5.8 years) were included in a single-blind, open-label, cross-over study to compare the effects of smoking light cigarettes (containing 0.6 mg nicotine, 8 mg tar, 9 mg carbon monoxide) and smoking regular cigarettes (containing 0.9 mg nicotine, 12 mg tar, 12 Mg carbon monoxide) on coronary flow reserve (CFR). For each participant, CFR values were measured at baseline, after smoking 2 regular or light cigarettes, and 15 days later after smoking 2 cigarettes of the other kind. Results: After smoking 2 cigarettes, CFR values declined from 2.8 +/- 0.56 (baseline) to 2.31 +/- 0.51 after smoking tight cigarettes (P = .003), and from 2.8 +/- 0.56 (baseline) to 2.21 +/- 0.45 after smoking regular cigarettes (P < .001). After smoking light and regular cigarettes, CFR values were similar (P = .678). Conclusions: Light cigarette smoking has similar acute detrimental effects on coronary microvascular function and CFR as does regular cigarette smoking.

Dierker LC; Rose JS; Donny E; Tiffany S. Alcohol use as a signal for sensitivity to nicotine dependence among recent onset smokers. Addictive Behaviors 36(4): 421-426, 2011. (21 refs.)

Objective: This study evaluated the association between alcohol use, abuse and dependence and cigarette smoking to determine whether alcohol may signal greater sensitivity to nicotine dependence at very low levels of smoking. Method: Data were drawn from five annual National Surveys on Drug Use and Health and included individuals age 12 to 21 who reported first exposure to smoking within the past two years and smoking at least once in the past month. Results: Both alcohol abuse and alcohol dependence were associated with increased likelihood of symptoms that seem to tap tolerance for nicotine. These included items such as "the amount you smoke has increased"; "needing to smoke a lot more now in order to be satisfied"; and "smoking much more before starting to feel anything". Alcohol dependence, but not abuse was associated with the remaining symptoms, "after not smoking for a while, needing to smoke to feel less restless and irritable"; "craving cigarettes after not smoking for a while"; and "worrying about running out of cigarettes". All associations were not better accounted for by either alcohol use or amount smoked. Conclusion: If causally associated, treatment of alcohol-use disorders may prevent or reduce the early emergence of nicotine dependence symptoms among new smokers, very early in the smoking uptake process. If instead alcohol disorders are a signal of sensitivity for nicotine dependence best accounted for by a third variable, then adolescents with alcohol dependence and/or abuse during early exposures to smoking represents an important subgroup that may benefit from interventions directly targeting this association.

Donny EC; Caggiula AR; Weaver MT; Levin ME; Sved AF. The reinforcement-enhancing effects of nicotine: Implications for the relationship between smoking, eating and weight. Physiology & Behavior 104(1, special issue): 143-148, 2011. (104 refs.)

Concerns about body weight represent an important barrier to public health efforts aimed at reducing smoking. Epidemiological studies have found that current smokers weigh less than non-smokers, smoking cessation results in weight gain, and weight restriction is commonly cited as a reason for smoking. The mechanisms underlying the relationship between smoking and weight are complex and may involve a number of factors including changes in caloric intake, physical activity, metabolic rate, and lipogenesis. Amongst these possible mechanisms, nicotine-induced enhancement of food reinforcement may be particularly important. In this paper, we first review data from our laboratory that highlight two distinct ways in which nicotine impacts reinforced behavior: 1) by acting as a primary reinforcer: and 2) by directly (non-associatively) enhancing the reinforcing effects of other stimuli. We then elaborate on the reinforcement-enhancing effects of nicotine as they pertain to behaviors and stimuli related to food. Data from both laboratory animals and humans support the assertion that nicotine enhances the reinforcing efficacy of food and suggest that the influence of these effects on eating may be most important after nicotine cessation when nicotine's effects on satiety subside. Finally, we discuss the theoretical and clinical implications of this perspective for understanding and addressing the apparent tradeoff between smoking and weight gain. Better understanding of the mechanisms underlying the reinforcement-enhancing effects of nicotine broadly, and the effects on food reinforcement per se, may aid in the development of new treatments with better long term outcomes.

Dulude L; Labelle A; Knott VJ. Acute nicotine alteration of sensory memory impairment in smokers with schizophrenia. Journal of Clinical Psychopharmacology 30(5): 541-548, 2010 , 2010. (80 refs.)

Context: Patients with schizophrenia have a high rate of cigarette smoking and also exhibit profound deficits in sensory processing, which may in part be ameliorated by the acute actions of smoke-inhaled nicotine. The mismatch negativity (MMN), a preattentive event-related potential index of auditory sensory memory, is diminished in schizophrenia. The MMN is increased in healthy controls with acute nicotine. Objective: To utilize the MMN to compare auditory sensory memory in minimally tobacco-deprived (3 hours) patients and matched tobacco-deprived smoking controls and to assess the effects of acute nicotine on MMN-indexed sensory memory processing in the patients. Design: Event-related potentials were recorded in 2 auditory oddball paradigms, one involving tone frequency changes (frequency MMN) and one involving tone duration changes (duration MMN). Controls were assessed once under nontreatment conditions, and patients were assessed twice under randomized double-blind treatment conditions involving placebo and nicotine (8 mg) gum. Setting: Outpatient mental health center. Patients: Twelve smokers with schizophrenia and twelve control smokers. Results: Compared with the controls, the patients showed reduced frequency-MMN (P < 0.001) and duration-MMN (P < 0.04) amplitudes. In addition to prolonging peak latency in duration MMN (P < 0.01), nicotine, relative to placebo, increased the amplitude of the patients' duration MMN (P G 0.01), but not their frequency MMN, to a level comparable with that seen in the controls. Conclusions: These preliminary findings demonstrate for the first time that acute nicotine can normalize temporal aspects of sensory memory processing in patients with schizophrenia, an effect that may be mediated by activation of alpha 7 nicotinic acetylcholine receptors, the function of which is diminished in schizophrenia. These ameliorating actions of nicotine may have implications for understanding the close relationship between tobacco smoking and schizophrenia and for developing nicotinic pharmacotherapies to alleviate sensory memory impairments in schizophrenia.

Ettinger U; Williams SCR; Patel D; Michel TM; Nwaigwe A; Caceres A et al. Effects of acute nicotine on brain function in healthy smokers and non-smokers: Estimation of inter-individual response heterogeneity. Neuroimage 45(2): 549-561, 2009. (66 refs.)

The present study used functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms of nicotine effects on antisaccades (an oculomotor measure of the conflict between a reflexive response and a spatially complex volitional response) and prosaccades (involving reflexive overt attentional shifts). Given the known inter-individual variability in drug response we aimed to identify oculomotor variables and brain areas in which significant inter-individual heterogeneity in response to nicotine is observed. To do so we calculated within-session intraclass correlation (ICC) coefficients over measurements obtained before and after nicotine/placebo administration and reasoned that a significant reduction in ICC with nicotine compared to placebo would reflect the operation of significant inter-individual response heterogeneity. Thirteen light-to-moderate smokers and 11 non-smokers completed fMRI during antisaccades before and after subcutaneous injection of 12 mu g/kg nicotine or saline placebo in a double-blind, randomised, cross-over design. All participants were healthy, right-handed males. Nicotine and placebo were given on separate occasions approximately 1 week apart with time of injection kept constant. Nicotine significantly reduced antisaccade latencies in both groups. At the level of brain function, during antisaccades the blood oxygen level dependent (BOLD) response in the left frontal eye field was non-significantly reduced by nicotine while it significantly increased following placebo in non-smokers, but there was no discernible effect in smokers. During prosaccades, it was found that deactivation areas (posterior cingulate gyrus and precuneus; right superior temporal gyrus) showed enhanced deactivations following nicotine administration in both groups. ICC analysis identified significant inter-individual response heterogeneity in antisaccade reflexive errors in smokers, and in a number of brain regions, particularly in non-smokers. These findings suggest that nicotine has beneficial effects at the cognitive level and leads to reductions in task-related activations and further decreases of BOLD in deactivation areas. The comparison of within-session ICCs across drug conditions suggests that the effects of nicotine are subject to inter-individual variability at behavioural and neural levels.

Evans DE; Drobes DJ. Nicotine self-medication of cognitive-attentional processing. (review). Addiction Biology 14(1): 32-42, 2009. (125 refs.)

This article selectively reviews research concerning nicotine's effects on cognition, including the neurobiological mechanism for these effects, task and experimental features that may be important for elucidating these effects, and why these effects may have amplified motivational significance among smokers with cognitive deficit. Nicotine has effects on various cognitive processes, though most studies in humans have focused on the amelioration of cognitive deficits experienced during drug withdrawal. The direct cognitive-enhancing effect of nicotine remains a controversial topic. The relationship between attentional and non-attentional cognitive effects of nicotine is discussed in the context of cognitive self-medication. Further research should include theory-driven examination of cognitive effects of nicotine, and develop targeted smoking cessation programs based on an improved understanding of the role of cognitive self-medication in high-risk individuals.

Gonzalez A; Vujanovic AA; Johnson KA; Leyro TM; Zvolensky MJ. The role of mindful attention in regard to the relation between negative affect reduction outcome expectancies and emotional vulnerability among adult cigarette smokers. Cognitive Therapy and Research 33(6): 645-656, 2009. (81 refs.)

The present investigation examined the role of mindful attention in regard to the relation between negative affect reduction smoking outcome expectancies and anxious arousal and anhedonic depression symptoms and difficulties with emotion regulation among 174 (46% women; M (age) = 25.32 years, SD = 10.51) daily cigarette smokers. As predicted, there was a significant interaction for negative affect reduction smoking outcome expectancies and mindful attention in relation to anxious arousal symptoms and emotion regulation difficulties. Individuals endorsing both higher levels of negative affect reduction outcome expectancies and lower levels of mindful attention reported the greatest anxious arousal symptoms and difficulties with emotion regulation, while those reporting both lower levels of negative affect reduction expectancies and higher levels of mindful attention were associated with lesser anxious arousal symptoms and the least difficulties with emotion regulation. There was no interactive effect for anhedonic depression symptoms. Findings are discussed in relation to better understanding the clinically meaningful interplay between mindful attention and negative affect reduction outcome expectancies among cigarette smokers in terms of affective vulnerability.

Gorzalka BB; Hill MN; Chang SCH. Male-female differences in the effects of cannabinoids on sexual behavior and gonadal hormone function. (review). Hormones and Behavior 58(1): 91-99, 2010. (126 refs.)

The putative role of the endocannabinoid system and the effects of cannabis use in male and female sexual functioning are summarized. The influence of cannabis intake on sexual behavior and arousability appear to be dose-dependent in both men and women, although women are far more consistent in reporting facilitatory effects. Furthermore, evidence from nonhuman species indicate somewhat more beneficial than debilitating effects of cannabinoids on female sexual proceptivity and receptivity while suggesting predominantly detrimental effects on male sexual motivation and erectile functioning. Data from human and nonhuman species converge on the ephemeral nature of THC-induced testosterone decline. However, it is clear that cannabinoid-induced inhibition of male sexual behavior is independent of concurrent declines in testosterone levels. Investigations also reveal a suppression of gonadotropin release by cannabinoids across various species. Historical milestones and promising future directions in the area of cannabinoid and sexuality research are also outlined in this review.

Greenstein JE; Kassel JD; Wardle MC; Veilleux JC; Evatt DP; Heinz AJ et al. The separate and combined effects of nicotine and alcohol on working memory capacity in nonabstinent smokers. Experimental and Clinical Psychopharmacology 18(2): 120-128, 2010. (63 refs.)

Research indicates that nicotine and alcohol are often used on the same occasion. However, the reasons for their concurrent use are not well understood. We hypothesized that one reason smokers use tobacco when they drink alcohol is to compensate for alcohol's negative effects on processing capacity with nicotine's enhancement of processing capacity. As such, the present study tested this theory by using an independent groups design to examine the separate and combined acute effects of alcohol and nicotine on working memory (WM) capacity. Nonabstinent daily smokers (n = 127) performed the counting span task (CSPAN) after consuming either an alcohol (men: 0.8 g/kg; women: 0.7 g/kg) or placebo beverage and smoking either nicotinized (1.14 mg nicotine, 15.9 mg tar) or denicotinized (.06 mg nicotine, 17.9 mg tar) cigarettes. Analyses revealed that smokers who smoked the nicotinized cigarettes performed significantly worse on the CSPAN task than smokers who smoked the denicotinized cigarettes. Although there was no main effect of alcohol on WM performance, women exhibited better WM performance than men after consuming alcohol whereas men performed better than women on the WM task after consuming the placebo beverage. Findings also revealed no interaction between the two substances on WM performance. Taken together, results suggest that nicotine impairs nonabstinent smokers' verbal WM capacity and that gender moderates the effects of alcohol on WM. Furthermore, the present findings failed to support the notion that nicotine compensates for alcohol-related decrements in working memory capacity.

Haberstick BC; Ehringer MA; Lessem JM; Hopfer CJ; Hewitt JK. Dizziness and the genetic influences on subjective experiences to initial cigarette use. Addiction 106(2): 391-399, 2011. (59 refs.)

Aim: To examine individual differences in positive and negative subjective experiences to initial cigarette use. Design: Retrospective self-reports of initial subjective experiences were examined to estimate the genetic and environmental influences and the extent of their covariation across different effects. Participants: Data was drawn from 2482 young adult same-and opposite sex twins- and siblings participating in the National Longitudinal Study of Adolescent Health. Measurement: Subjective experiences were retrospectively collected using the Early Smoking Experience (ESE) questionnaire. Findings: Positive experiences evidenced moderate heritable contributions (40%, 95% CI: 0.22 to 0.56), as did an overall hedonic measure (34%, 95% CI: 0.22 to 0.46) and dizziness (34%, 95% CI: 0.15 to 0.52). Negative experiences evidenced small heritable contributions (13%, 95% CI: 0.00 to 0.36). Individual specific environmental influences were strong and accounted for the remaining proportion of observed variation in these experiences. Multivariate genetic modeling identified a moderately heritable underlying factor (37%, 95% CI: 0.22 to 0.52) that influenced the covariation of diverse subjective experiences and loaded most heavily on dizziness. Positive experiences also evidence residual genetic influences that were uncorrelated with other subjective experiences. Conclusions: How a person experiences their initial few cigarettes is due to both heritable contributions and environmental experiences unique to the person. The covariation of diverse subjective experiences appears to be due to a heritable latent sensitivity to the chemicals contained in an average cigarette and is best indexed by dizziness.

Hagiya K; Mizutani T; Yasuda S; Kawano S. Nicotine poisoning due to intravenous injection of cigarette soakage. Human & Experimental Toxicology 29(5): 427-429, 2010. (6 refs.)

A 27-year-old female nurse intravenously injected 5 mL of cigarette soakage solution that contained approximately 5.7 mg nicotine, in a suicidal attempt. Clinical manifestations consisted of nausea, palpitation, abdominal pain, repeated vomiting, and diarrhea. She remained fully conscious during this episode. About 7 hours later, she visited emergency department on foot and received fluid infusion for dehydration. She fully recovered at night of the day. This is the first documented report of acute nicotine poisoning due to intravenous injection of cigarette soakage in humans. Signs and symptoms appeared immediately after the injection, but this case seemed to be relatively mild in terms of clinical manifestation. The elimination half-life of nicotine seems to be short, that is, less than 1 hour. Therefore, if initial treatment is appropriate and the patient can survive acute phase of nicotine poisoning, prognosis is good.

Hahn B; Ross TJ; Wolkenberg FA; Shakleya DM; Huestis MA; Stein EA. Performance effects of nicotine during selective attention, divided attention, and simple stimulus detection: An fmri study. Cerebral Cortex 19(9): 1990-2000, 2009. (73 refs.)

Attention-enhancing effects of nicotine appear to depend on the nature of the attentional function. Underlying neuroanatomical mechanisms, too, may vary depending on the function modulated. This functional magnetic resonance imaging study recorded blood oxygen level-dependent (BOLD) activity in minimally deprived smokers during tasks of simple stimulus detection, selective attention, or divided attention after single-blind application of a transdermal nicotine (21 mg) or placebo patch. Smokers' performance in the placebo condition was unimpaired as compared with matched nonsmokers. Nicotine reduced reaction time (RT) in the stimulus detection and selective attention but not divided attention condition. Across all task conditions, nicotine reduced activation in frontal, temporal, thalamic, and visual regions and enhanced deactivation in so-called "default" regions. Thalamic effects correlated with RT reduction selectively during stimulus detection. An interaction with task condition was observed in middle and superior frontal gyri, where nicotine reduced activation only during stimulus detection. A visuomotor control experiment provided evidence against nonspecific effects of nicotine. In conclusion, although prefrontal activity partly displayed differential modulation by nicotine, most BOLD effects were identical across tasks, despite differential performance effects, suggesting that common neuronal mechanisms can selectively benefit different attentional functions. Overall, the effects of nicotine may be explained by increased functional efficiency and downregulated task-independent "default" functions.

Hedeker D; Mermelstein RJ; Berbaum ML; Campbell RT. Modeling mood variation associated with smoking: An application of a heterogeneous mixed-effects model for analysis of ecological momentary assessment (EMA) data. Addiction 104(2): 297-307, 2009. (37 refs.)

Mixed models are used increasingly for analysis of ecological momentary assessment (EMA) data. The variance parameters of the random effects, which indicate the degree of heterogeneity in the population of subjects, are considered usually to be homogeneous across subjects. Modeling these variances can shed light on interesting hypotheses in substance abuse research. We describe how these variances can be modeled in terms of covariates to examine the covariate effects on between-subjects variation, focusing on positive and negative mood and the degree to which these moods change as a function of smoking. The data are drawn from an EMA study of adolescent smoking. Participants were 234 adolescents, either in 9th or 10th grades, who provided EMA mood reports from both random prompts and following smoking events. We focused on two mood outcomes: measures of the subject's negative and positive affect and several covariates: gender, grade, negative mood regulation and smoking level. Following smoking, adolescents experienced higher positive affect and lower negative affect than they did at random, non-smoking times. Our analyses also indicated an increased consistency of subjective mood responses as smoking experience increased and a diminishing of mood change.

Hong LE; Gu H; Yang Y; Ross TJ; Salmeron BJ; Buchholz B et al. Association of nicotine addiction and nicotine's actions with separate cingulate cortex functional circuits. Archives of General Psychiatry 66(4): 431-441, 2009. (62 refs.)

Context: Understanding the mechanisms underlying nicotine addiction to develop more effective treatment is a public health priority. Research consistently shows that nicotine transiently improves multiple cognitive functions. However, using nicotine replacement to treat nicotine addiction yields generally inconsistent results. Although this dichotomy is well known, the reasons are unclear. Imaging studies showed that nicotine challenges almost always involve the cingulate cortex, suggesting that this locus may be a key region associated with nicotine addiction and its treatment. Objective: To identify cingulate functional circuits that are associated with the severity of nicotine addiction and study how nicotine affects them by means of region-specific resting-state functional magnetic resonance imaging. Design: Double-blind, placebo-controlled study. Setting: Outpatient clinics. Participants: Nineteen healthy smokers. Intervention: Single-dose (21- or 35-mg) nicotine patch. Main Outcome Measures: Correlation of nicotine addiction severity and cingulate resting-state functional connectivity, and effects of short-term nicotine administration on connectivity strength. Results: Clearly separated pathways that correlated with nicotine addiction vs nicotine's action were found. The severity of nicotine addiction was associated with the strength of dorsal anterior cingulate cortex (dACC) striatal circuits, which were not modified by nicotine patch administration. In contrast, short-term nicotine administration enhanced cingulate-neocortical functional connectivity patterns, which may play a role in nicotine's cognition-enhancing properties. Conclusions: Resting-state dACC-striatum functional connectivity may serve as a circuit-level biomarker for nicotine addiction, and the development of new therapeutic agents aiming to enhance the dACC-striatum functional pathways may be effective for nicotine addiction treatment.

Jacob P; Abu Raddaha AH; Dempsey D; Havel C; Peng M; Yu L et al. Nicotine, carbon monoxide, and carcinogen exposure after a single use of a water pipe. Cancer Epidemiology, Biomarkers & Prevention 20(11): 2345-2353, 2011. (23 refs.)

Background: Smoking tobacco preparations in a water pipe (hookah) is widespread in many places of the world, including the United States, where it is especially popular among young people. Many perceive water pipe smoking to be less hazardous than cigarette smoking. We studied systemic absorption of nicotine, carbon monoxide, and carcinogens from one water pipe smoking session. Methods: Sixteen subjects smoked a water pipe on a clinical research ward. Expired carbon monoxide and carboxyhemoglobin were measured, plasma samples were analyzed for nicotine concentrations, and urine samples were analyzed for the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and polycyclic aromatic hydrocarbon (PAH) metabolite biomarker concentrations. Results: We found substantial increases in plasma nicotine concentrations, comparable to cigarette smoking, and increases in carbon monoxide levels that are much higher than those typically observed from cigarette smoking, as previously published. Urinary excretion of NNAL and PAH biomarkers increased significantly following water pipe smoking. Conclusions: Absorption of nicotine in amounts comparable to cigarette smoking indicates a potential for addiction, and absorption of significant amounts of carcinogens raise concerns of cancer risk in people who smoke tobacco products in water pipes. Impact: Our data contribute to an understanding of the health impact of water pipe use.

Jaworska N; McIntosh J; Villeneuve C; Thompson A; Fisher D; Milin R et al. Effects of nicotine on electroencephalography and affect in adolescent females with major depressive disorder: A pilot study. Journal of Addiction Medicine 5(2): 123- 133, 2011. (124 refs.)

Background: Given that smoking is typically initiated during adolescence, and that this period in brain development seems to be uniquely sensitive to nicotine, depressed youth may be most susceptible to the neuromodulatory and mood-altering effects of nicotine. Electroencephalographic (EEG) studies suggest that individuals with major depressive disorder (MDD) exhibit left frontal lobe hypoactivation (indexed by increased EEG alpha), a region implicated in positive affect regulation, as well as right parietal hypoactivation. Smoking/nicotine abstinence has been associated with increased left frontal and right parietal alpha activity (reduced activation), which has been correlated with increased depression ratings; nicotine administration seems to normalize this depression-associated asymmetry. Objectives: This pilot study investigated whether acute nicotine administration in adolescent female smokers with MDD would alter resting EEG activity and affect. Methods: Subjective mood ratings and EEG recordings were acquired before and 2 hours after administering a transdermal placebo or nicotine (21 mg) patch to 8 adolescent female smokers with MDD. Results: Nicotine induced a modest increase in alpha 1 amplitude in the right hemisphere and simultaneously decreased left-favoring alpha(1) amplitude asymmetry. It also attenuated left alpha(1) and alpha(2) amplitude in the central region. Consistent with nicotine's stimulatory action, nicotine decreased theta amplitude in the right parietal region. No accompanying mood alterations were found, although smoking withdrawal and craving as well as physical symptom scores were reduced with nicotine. Conclusions: The results of this pilot study, the first to examine the electrocortical effects of nicotine in depressed adolescents, indicate that nicotine modulates EEG asymmetry measures, laying the stage for further research regarding the role of nicotine on affective neurocircuitry in this population.

Jenks RA; Higgs S. Effects of dieting status and cigarette deprivation on progressive ratio responding for cigarette puffs by young women smokers. Journal of Psychopharmacology 25(4): 530-537, 2011. (47 refs.)

There is evidence from self-report measures which suggests that young women dieters find cigarette smoking less rewarding than non-dieters. We aimed to further elucidate differences between dieters and non-dieters in their evaluation of smoking using a behavioural measure of drug reward. Thirty female undergraduates attended two sessions (cigarette deprived and non-deprived). A computer-based progressive ratio operant procedure was employed to assess the amount of effort that participants were willing to expend to gain a puff on a cigarette. The point at which responding ceased was taken as a measure of drug reward (breakpoint). Self-report measures of sensory/hedonic aspects of smoking were also completed. The breakpoints of both dieters and non-dieters were greater under deprived than non-deprived conditions but the breakpoints of dieters were significantly lower than those of the non-dieting smokers under both conditions. Self-reported enjoyment of smoking was lower for dieters than non-dieters and reports for non-dieters but not dieters were affected by deprivation level. Both behavioural and self-report measures of rewarding aspects of smoking suggest that young women dieters find smoking less rewarding than non-dieters, but self-report measures are more resistant to deprivation effects for dieters. This is consistent with the suggestion that subjective and behavioural measures assess different dimensions of the rewarding effects of smoking.

Jenks RA; Higgs S. Reactivity to smoking- and food-related cues in currently dieting and non-dieting young women smokers. Journal of Psychopharmacology 25(4): 520-529, 2011. (58 refs.)

There is some evidence to suggest that young women dieters who smoke experience greater cigarette cravings in the presence of food-related related cues. The aim of this experiment was to examine reactivity to both smoking-related and water cues by dieting and non-dieting women smokers in the presence or absence of food cues. Eighteen female undergraduates attended two sessions (food present and food absent). At each session, participants were presented with a cigarette and water cue in a counterbalanced order. Pre- and post-cue measures included the brief version of the Questionnaire for Smoking Urges, heart rate and self-reported mood. All smokers showed enhanced reactivity (increased craving and heart rate) to smoking versus water cues. For dieters there was a larger increase in cigarette craving and heart rate in response to the smoking-related cues in the presence of food compared with the absence of food, whereas for non-dieters there was a smaller increase in cigarette craving and heart rate in response to the smoking-related cues in the presence of food compared with the absence of food. Mood and appetite ratings were not significantly affected by either cue type or session. The results suggest that cue reactivity to smoking-related cues is modulated by the presence of incentive stimuli relevant to the individual.

Knott VJ; Bolton K; Heenan A; Shah D; Fisher DJ; Villeneuve C. Effects of acute nicotine on event-related potential and performance indices of auditory distraction in nonsmokers. Nicotine & Tobacco Research 11(5): 519-530, 2009. (91 refs.)

Introduction: Although nicotine has been purported to enhance attentional processes, this has been evidenced mostly in tasks of sustained attention, and its effects on selective attention and attentional control under conditions of distraction are less convincing. Methods: This study investigated the effects of nicotine on distractibility in 21 (11 males) nonsmokers with event-related potentials (ERPs) and behavioral performance measures extracted from an auditory discrimination task requiring a choice reaction time response to short-and long-duration tones, with and without imbedded deviants. Administered in a randomized, double-blind, placebo-controlled crossover design, nicotine gum (6 mg) failed to counter deviant-elicited behavioral distraction characterized by longer reaction times and increased response errors. Results: Of the deviant-elicited ERP components, nicotine did not alter the P3a-indexed attentional switching to the deviant, but in females, it tended to diminish the automatic processing of the deviant as shown by a smaller mismatch negativity component, and it attenuated attentional reorienting following deviant-elicited distraction, as reflected by a reduced reorienting negativity ERP component. Discussion: Results are discussed in relation to attentional models of nicotine and with respect to future research directions.

Koczulla AR; Noeske S; Herr C; Jorres RA; Rommelt H; Vogelmeier C et al. Acute and chronic effects of smoking on inflammation markers in exhaled breath condensate in current smokers. Respiration 79(1): 61-67, 2010. (32 refs.)

Background: Long-term cigarette smoking is associated with pulmonary inflammation, but the acute effects of smoking have been less well studied. Analysis of the exhaled breath condensate (EBC) can provide noninvasive markers that might be indicative of inflammation. Objectives: The aim of the study was to determine whether the pH, electrical conductivity and the levels of ammonium and interleukin 8 (IL-8) of EBC were altered in smokers and whether they changed after smoking a single cigarette. Methods: We included 19 healthy nonsmokers (controls), 29 asymptomatic smokers, 10 patients with stable chronic obstructive pulmonary disease (COPD) [Global Initiative for Chronic Obstructive Lung Disease stages (GOLD) stages II-III], and 10 patients with exacerbated COPD. In 13 smokers, EBC was also analyzed before and after smoking. EBC was obtained during 10 min tidal breathing with a cooled RTube (TM). pH was determined after deaeration with argon. Results: Acute smoking did not alter the pH or ammonium and IL-8 levels, but raised conductivity. As in COPD patients, the pH was significantly decreased in chronic smokers with a history of at least 10 pack-years compared to controls. Conclusions: EBC can be used to detect the acute and chronic effects of smoking. The increased conductivity of EBC after smoking suggests acute inflammatory effects. The reduced pH in chronic smokers shows cigarette-induced inflammation.

Lee DC; Perkins KA; Zimmerman E; Robbins G; Kelly TH. Effects of 24 hours of tobacco withdrawal and subsequent tobacco smoking among low and high sensation seekers. Nicotine & Tobacco Research 13(10): 943-954, 2011. (49 refs.)

Introduction: Previous studies have indicated that high sensation seekers are more sensitive to the reinforcing effects of nicotine, initiate smoking at an earlier age, and smoke greater amounts of cigarettes. This study examined the influence of sensation-seeking status on tobacco smoking following deprivation in regular tobacco users. Methods: Twenty healthy tobacco-smoking volunteers with low or high impulsive sensation-seeking subscale scores completed 2 consecutive test days per week for 3 consecutive weeks. Each week, a range of self-report, performance, and cardiovascular assessments were completed during ad libitum smoking on Day 1 and before and after the paced smoking of a tobacco cigarette containing 0.05, 0.6, or 0.9 mg of nicotine following 24 hr of tobacco deprivation on Day 2. In addition, self-administration behavior was analyzed during a 2-hr free access period after the initial tobacco administration. Results: In high sensation seekers, tobacco smoking independent of nicotine yield ameliorated deprivation effects, whereas amelioration of deprivation effects was dependent on nicotine yield among low sensation seekers. However, this effect was limited to a small subset of measures. Subsequent cigarette self-administration increased in a nicotine-dependent manner for high sensation seekers only. Conclusions: Compared with low sensation seekers, high sensation seekers were more sensitive to the withdrawal relieving effects of non-nicotine components of smoking following 24 hr of deprivation on selective measures and more sensitive to nicotine yield during subsequent tobacco self-administration. These results are consistent with studies suggesting that factors driving tobacco dependence may vary as a function of sensation-seeking status.

Li LH; Liu Y; Zhang YH; Beveridge TJR; Zhou WH. Temporal changes of smoking status and motivation among Chinese heroin-dependent, methadone-maintained smokers. Addictive Behaviors 35(10): 861-865, 2010 , 2010. (36 refs.)

Introduction: The rates of cigarette smoking remain extremely high in active heroin users and methadone-maintained patients. It remains undetermined whether smoking status and motivation would be differentially affected by heroin and methadone administration. Methods: Heroin-dependent, methadone-maintained patients were recruited in the present studies. A battery of self-report questionnaires was used in the current study, in order to assess smoking status and motivations before first heroin use, during active heroin use and after Methadone Maintenance Treatment (MMT) admission. Results: An extremely high portion of participants started smoking before first heroin use. The highest level of cigarette smoking was found during the period of active heroin use, and cigarette consumption was reported to decrease after MMT admission. A wide range of smoking motivations were found before first heroin use. Moreover, "maintaining heroin pleasure" was the primary motivation for the increase in cigarette consumption during the period of active heroin use and 1 h after heroin administration, while "habitual smoking" was the primary smoking motivation before first heroin use and after MMT admission respectively. Conclusions: The present study first demonstrated that the prolonged rewarding effect of heroin following cigarette smoking may account for the increase of nicotine consumption found in the heroin-dependent patients. It appears that heroin and methadone differentially influenced smoking status and motivation among heroin-dependent, methadone-maintained patients.

Luo S; Ainslie G; Giragosian L; Monterosso JR. Striatal hyposensitivity to delayed rewards among cigarette smokers. Drug and Alcohol Dependence 116(1-3): 18-23, 2011. (43 refs.)

Background: Brain regions that track value (including the ventral striatum) respond more during the anticipation of immediate than delayed rewards, even when the delayed rewards are larger and equally preferred to the immediate. The anticipatory response to immediate vs. delayed rewards has not previously been examined in association with cigarette smoking. Methods: Smokers (n = 35) and nonsmokers (n = 36) performed a modified monetary incentive functional Magnetic Resonance Imaging (fMRI) task (Knutson et al., 2000) that included opportunities to win either immediate or delayed rewards. The delayed rewards were larger and equally preferred to the immediate rewards. Results: Across groups, greater activation was observed in regions previously shown to track value including bilateral ventral/dorsal striatum during the anticipation of immediate relative to delayed rewards. This effect was significantly greater among smokers than nonsmokers within the right ventral striatum. This group difference was driven particularly by low striatal activation among smokers during delayed reward trials. Conclusions: The general tendency for striatal reward anticipatory activity to be attenuated when rewards are delayed is exaggerated among smokers relative to comparison participants. Among possible explanations of this relationship are that (1) low anticipatory response to delayed rewards is a phenotypic risk factor for smoking and (2) smoking-related neuroadaptations result in reduced recruitment during the anticipation of delayed rewards.

MacKillop J; Tidey JW. Cigarette demand and delayed reward discounting in nicotine-dependent individuals with schizophrenia and controls: an initial study. Psychopharmacology 216(1): 91-99, 2011. (55 refs.)

Rationale. The high prevalence of smoking and low cessation rates among individuals with schizophrenia and similar conditions are not well understood. Behavioral economics has been extensively applied to studying addictive behavior and may contribute to understanding smoking in this subpopulation. Objectives. This study compared smokers with schizophrenia or schizoaffective disorder (SS) and control smokers (CS) on indices of cigarette demand and delayed reward discounting, a behavioral economic index of impulsivity. Materials and methods. The SS (n=25) and CS (n=24) groups participated in two sessions approximately 1 week apart. During the first session, delay discounting was assessed using the Monetary Choice Questionnaire. During the second session, participants smoked their usual brand ad libitum through a smoking topography assessment device, after which cigarette demand was assessed using a cigarette purchase task. Primary comparisons were of the hyperbolic discounting function, k, and indices of cigarette demand. Results: Compared to the CS group, the SS group exhibited significantly higher intensity of demand, and significantly greater consumption and expenditure across the inelastic portion of the demand curve, but no differences were evident on the other demand indices. No differences were evident for delay discounting. The SS group also exhibited heavier smoking topography and two indices of smoking topography were significantly correlated with demand. Conclusions. These results provide further evidence of higher incentive value of cigarettes among SS individuals, but not greater impulsivity, as measured by discounting. Considerations include potentially important methodological factors and the role of satiation/withdrawal.

Maraj S; Figueredo VM; Morris DL. Cocaine and the heart. (review). Clinical Cardiology 33(5): 264-269, 2010. (39 refs.)

The use of cocaine may be associated with either acute or chronic toxicity, and approximately 5% to 10% of emergency department visits in the United States are believed to be secondary to cocaine usage. Chest pain is the most common cocaine-related medical problem, leading to the evaluation of approximately 64000 patients annually for possible myocardial infarction, of which approximately 57% are admitted to the hospital, resulting in an annual cost greater than $83 million. There is a plethora of cocaine-related cardiovascular complications, including acute myocardial ischemia and infarction, arrhythmias, sudden death, myocarditis, cardiomyopathy, hypertension, aortic ruptures, and endocarditis. There is no evidence to suggest that preexisting vascular disease is a prerequisite for the development of a cocaine-related cardiovascular event, although it may be a potentiating factor, as may be nicotine and alcohol.

Marmorstein NR; White H; Chung T; Hipwell A; Stouthamer-Loeber M; Loeber R. associations between first use of substances and change in internalizing symptoms among girls: Differences by symptom trajectory and substance use type. Journal of Clinical Child and Adolescent Psychology 39(4): 545-558, 2010. (44 refs.)

This study examined how girls' initial use of alcohol, cigarettes, and marijuana related to changes in depressive, generalized anxiety, and social anxiety symptoms, and whether these changes varied based on which internalizing symptom trajectories the girls were on. Data came from the Pittsburgh Girls Study, a community-based study of girls assessed at ages 5 to 8 and followed for 6 years. Growth mixture modeling was used to identify trajectory groups. The results indicated that for girls on a high depressive symptom trajectory, initial use of marijuana was related to further increases in depressive symptoms. Initial uses of alcohol and cigarettes were associated with overall increases in depressive symptoms, and the initial use of cigarettes was associated with an overall increase in generalized anxiety symptoms. Initial use of all substances was related to change in social anxiety, but the direction of change varied by trajectory group and substance. Links between initial use and internalizing symptoms depended on the type of substance, type of internalizing symptom, and trajectory group.

Martin LF; Davalos DB; Kisley MA. Nicotine enhances automatic temporal processing as measured by the mismatch negativity waveform. Nicotine & Tobacco Research 11(6): 698-706, 2009. (60 refs.)

Cholinergic agonists and, more specifically, nicotine, have been found to enhance a number of cognitive processes. The effect of nicotine on temporal processing is not known. The use of behavioral measures of temporal processing to measure its effect could be confounded by the general effects of nicotine on attention. Mismatch negativity (MMN) has been used as a physiological measure of automatic temporal processing to avoid this potential confound. A total of 20 subjects (11 nonsmokers and 9 smokers following 2 hr of abstinence) participated in a two-visit single-blind, placebo-controlled crossover study of the effect of nicotine on MMN indices in response to an interstimulus interval deviant. Nicotine-enhanced MMN amplitudes from baseline recording to postdrug recording greater than did the placebo condition. This enhancement was seen in both nonsmokers and smokers. Nicotine had no significant effect on MMN latency or N100 amplitude or latency. This is the first study to demonstrate a nicotine-related enhancement of MMN amplitude to an interstimulus interval duration deviant and confirms our hypothesis that nicotine enhances preattentive temporal processing. Nicotinic agonists may represent a potential therapeutic option for individuals with abnormalities in early sensory or temporal processing related to cholinergic system abnormalities. Methodologically, our paradigm of nicotine administration in abstinent smokers is important because it resulted in both minimal withdrawal symptoms and meaningful data that are not attributable solely to relief of withdrawal.

Mayhan WG; Arrick DM; Sharpe GM; Sun H. Nitric oxide synthase-dependent responses of the basilar artery during acute infusion of nicotine. Nicotine & Tobacco Research 11(3): 270-277, 2009. (70 refs.)

Our goals were to determine whether acute exposure to nicotine alters nitric oxide synthase (NOS)-dependent responses of the basilar artery and to identify a potential role for activation of NAD(P)H oxidase in nicotine-induced impairment in NOS-dependent responses of the basilar artery. We measured in vivo diameter of the basilar artery in response to NOS-dependent (acetylcholine) and NOS-independent (nitroglycerin) agonists before and during an acute infusion of nicotine (2 mu g/kg/min intravenously for 30 min followed by a maintenance dose of 0.35 mu g/kg/min). In addition, we measured superoxide anion production (lucigenin chemiluminescence) by the basilar artery in response to nicotine in the absence or presence of apocynin. We found that NOS-dependent, but not NOS-independent, vasodilation was impaired during infusion of nicotine. In addition, treatment of the basilar artery with apocynin (100 mu M, 30 min prior to infusion of nicotine) prevented nicotine-induced impairment in NOS-dependent vasodilation. Further, the production of superoxide anion was increased in the basilar artery by nicotine, and this increase could be inhibited by apocynin. Our findings suggest that acute exposure to nicotine impairs NOS-dependent dilation of the basilar artery by a mechanism that appears to be related to the release of superoxide anion. A possible source of superoxide may be via the activation of NAD(P)H oxidase.

Mello NK. Hormones, nicotine, and cocaine: Clinical studies. (review). Hormones and Behavior 58(1): 57-71, 2010. (163 refs.)

Nicotine and cocaine each stimulate hypothalamic-pituitary-adrenal and -gonadal axis hormones, and there is increasing evidence that the hormonal milieu may modulate the abuse-related effects of these drugs. This review summarizes some clinical studies of the acute effects of cigarette smoking or IV cocaine on plasma drug and hormone levels and subjective effects ratings. The temporal covariance between these dependent measures was assessed with a rapid (2 min) sampling procedure in nicotine-dependent volunteers or current cocaine users. Cigarette smoking and IV cocaine each stimulated a rapid increase in LH and ACTH, followed by gradual increases in cortisol and DHEA. Positive subjective effects ratings increased immediately after initiation of cigarette smoking or IV cocaine administration. However, in contrast to cocaine's sustained positive effects (<20 min), ratings of "high" and "rush" began to decrease within one or two puffs of a high-nicotine cigarette while nicotine levels were increasing. Peak nicotine levels increased progressively after each of three successive cigarettes smoked at 60 min intervals, but the magnitude of the subjective effects ratings and peak ACTH and cortisol levels diminished. Only DHEA increased consistently after successive cigarettes. The possible influence of neuroactive hormones on nicotine dependence and cocaine abuse and the implications for treatment of these addictive disorders are discussed.

Mullings EL; Donaldson LF; Melichar JK; Munafo MR. Effects of acute abstinence and nicotine administration on taste perception in cigarette smokers. Journal of Psychopharmacology 24(11): 1709-1715, 2010 , 2010. (44 refs.)

We investigated the effects of short-term abstinence from smoking and acute nicotine administration on taste perception in smokers. We assessed sensitivity for salt and sucrose solutions and the self-reported intensity and pleasantness of these tastes, using a previously validated model of taste perception. This was in order to investigate mechanisms by which cigarette smoking and smoking cessation may modulate dietary behaviour. Male and female daily smokers attended a single testing session. Participants were randomised to either abstain for smoking for 12 h or smoke as usual on the morning of testing. At the testing session, participants completed subjective ratings of mood and ratings of intensity and pleasantness of salt and sucrose solutions, followed by measurement of the threshold at which these solutions could be detected on the tongue. Participants were then randomised to smoking either a nicotine-containing or denicotinised cigarette, after which they completed the same measures as previously. Our data suggest that following cigarette smoking, lower taste thresholds are obtained after smoking a denicotinised cigarette compared with a nicotinised cigarette, but among females only. This effect was not observed among males and did not differ as a function of abstinence condition. In addition, among non-abstinent smokers, females demonstrated higher taste thresholds (i.e. reduced sensitivity) for salt than males, but this sex difference was not observed among abstinent smokers.

Munafo MR; Araya R. Cigarette smoking and depression: A question of causation. (editorial). British Journal of Psychiatry 196(6): 425-426, 2010. (9 refs.)

Cigarette smokers frequently describe the anxiolytic and antidepressant effects of smoking, but evidence suggests that cigarette smoking may itself increase negative affect, so that the causal direction of this association remains unclear. Although increasingly sophisticated analyses of epidemiological data may help to answer this question, observational data can never unequivocally provide evidence of causation. Here we discuss the potential utility of genetic information in determining the causal basis of the relationship of cigarette smoking and depression.

Murphy JG; MacKillop J; Tidey JW; Brazil LA; Colby SM. Validity of a demand curve measure of nicotine reinforcement with adolescent smokers. Drug and Alcohol Dependence 113(2-3): 207-214, 2011. (46 refs.)

High or inelastic demand for drugs is central to many laboratory and theoretical models of drug abuse, but it has not been widely measured with human substance abusers. The authors used a simulated cigarette purchase task to generate a demand curve measure of nicotine reinforcement in a sample of 138 adolescent smokers. Participants reported the number of cigarettes they would purchase and smoke in a hypothetical day across a range of prices, and their responses were well-described by a regression equation that has been used to construct demand curves in drug self-administration studies. Several demand curve measures were generated, including breakpoint, intensity, elasticity. P-max, and O-max. Although simulated cigarette smoking was price sensitive, smoking levels were high (8+ cigarettes/day) at prices up to 50(sic) per cigarette, and the majority of the sample reported that they would purchase at least 1 cigarette at prices as high as $2.50 per cigarette. Higher scores on the demand indices O-max, (maximum cigarette purchase expenditure), intensity (reported smoking level when cigarettes were free), and breakpoint (the first price to completely suppress consumption), and lower elasticity (sensitivity of cigarette consumption to increases in cost), were associated with greater levels of naturalistic smoking and nicotine dependence. Greater demand intensity was associated with lower motivation to change smoking. These results provide initial support for the validity of a self-report cigarette purchase task as a measure of economic demand for nicotine with adolescent smokers.

Ortells MO; Arias HR. Neuronal networks of nicotine addiction. International Journal of Biochemistry & Cell Biology 42(12): 1931-1935, 2010. (30 refs.)

Nicotine is the main psychoactive substance present in tobacco, targeting neuronal nicotinic acetylcholine receptors. The main effects of nicotine associated with smoking are nicotinic receptor activation, desensitization, and upregulation, with the subsequent modulation of the mesocorticolimbic dopaminergic system. However, there is a lack of a comprehensive explanation of their roles that effectively makes clear how nicotine dependence might be established on those grounds. Receptor upregulation is an unusual effect for a drug of abuse, because theoretically this implies less need for drug consumption. Receptor upregulation and receptor desensitization are commonly viewed as opposite, homeostatic mechanisms. We here review the available information on smoking addiction, especially under a recently presented model of nicotine dependence. In this model both receptor upregulation and receptor desensitization are responsible for establishing a biochemical mechanism of nicotine dependence, which have an important role in starting and maintaining tobacco addiction.

Penetar DM; Kouri EM; McCarthy EM; Lilly MM; Peters EN; Juliano TM et al. Nicotine pretreatment increases dysphoric effects of alcohol in luteal-phase female volunteers. International Journal of Environmental Research and Public Health 6(2): 526-546, 2009. (51 refs.)

The present report shows that nicotine enhances some of alcohol's positive and negative effects in women and that these effects are most pronounced during the luteal phase of the menstrual cycle. Ten low progesterone and 10 high progesterone/luteal-phase women received nicotine patch pretreatments (placebo or 21 mg) 3 hours before an alcohol challenge (0.4 g/kg). Subjective effects were recorded on mood adjective scales and the Addiction Research Center Inventory (ARCI). Heart rate and skin temperature were recorded. Luteal-phase women reported peak positive (e.g. "stimulated") and peak negative effects (e.g. "clumsy", "dizzy") almost twice as great as low progesterone women.

Perkins KA. Sex differences in nicotine reinforcement and reward: Influences on the persistence of tobacco smoking. Nebraska Symposium on Motivation. Motivational Impact of Nicotine and its Role in Tobacco Use 55: 143-169, 2009. (64 refs.)

This article addresses sex difference in response to nicotine. Seemingly, the smoking behavior of women is dictated less by the nicotine and more by non-nicotine factors, which may explain the greater difficulty of women in quitting. This author reviews the clinical implications of sex differences in promoting smoking persistence, the possible sources of sex differences, including pharmacokinetic, pharmacodynamic, non-pharmacological factors, and gender as a social construct. It also examines the reduced sensitivity to nicotine reinforcement and reward in women versus men. The clinical implications are discussed.

Perkins KA; Coddington SB; Karelitz JL; Jetton C; Scott JA; Wilson AS et al. Variability in initial nicotine sensitivity due to sex, history of other drug use, and parental smoking. Drug and Alcohol Dependence 99(1-3): 47-57, 2009. (62 refs.)

Initial sensitivity to nicotine's effects during early exposure to tobacco may relate to dependence vulnerability. We examined the association of initial nicotine sensitivity with individual difference factors of sex, other drug use history (i.e. cross-tolerance or cross-sensitization), and parental smoking status in young adult nonsmokers (N=131). Participants engaged in 4 sessions, the first 3 to assess the dose-response effects of nasal spray nicotine (0, 5, 10 mu g/kg) on rewarding, mood, physiological, sensory processing, and performance effects, and the fourth to assess nicotine reinforcement using a choice procedure. Men had greater initial sensitivity than women to some self-reported effects of nicotine related to reward and incentive salience and to impairment in sensory processing, but Men and women did not differ on most other effects. Prior marijuana use was associated with greater nicotine reward, nicotine reinforcement was greater in men versus women among those with prior marijuana use, and having parents who smoked was related to increased incentive salience. However, history of other drug use and parental smoking were not otherwise associated with initial nicotine sensitivity. These findings warrant replication with other methods of nicotine administration, especially cigarette smoking, and in more diverse samples of subjects naive to nicotine. Yet, they suggest that sex differences in initial sensitivity to nicotine reward occur before the onset of dependence. They also suggest, that parental smoking may not increase risk of nicotine dependence in offspring by altering initial nicotine sensitivity, and that cross-tolerance between other drugs and nicotine may not be robust in humans.

Perkins KA; Grottenthaler A; Ciccocioppo MM; Conklin CA; Sayette MA; Wilson AS. Mood, nicotine, and dose expectancy effects on acute responses to nicotine spray. Nicotine & Tobacco Research 11(5): 540-546, 2009. (30 refs.)

Introduction: We recently showed effects of nicotine dose and nicotine expectancy on some responses to cigarette smoking, with generally no influence of induced mood on these effects. The present study extended this line of research to Nicotrol nasal spray, to determine whether formulation (spray vs. smoking) alters responses. Methods: Smokers abstained overnight before each of two virtually identical sessions, involving negative or positive mood induction. They were randomized to one of five groups, four comprising the 2 x 2 balanced placebo design, varying actual and expected dose of nicotine in the nasal spray, and the fifth group a no-spray control. Dependent measures included self-reported affect, craving, withdrawal, and spray ratings of "liking" and "how much nicotine." Analyses were limited to those whose nicotine expectancies were manipulated successfully (N = 48). Results: The following results matched those from our smoking study: expecting nicotine increased liking; expected, but not actual, nicotine dose increased dose perception; neither actual nor expected nicotine dose had much influence on affect or withdrawal; and mood had no influence on these effects. However, both actual and expected nicotine dose decreased craving in response to spray, contrary to our prior study with smoking. Discussion: Formulation made little difference in some effects of nicotine and expectancies, but other effects differed by formulation. Some of these findings, particularly for craving reduction, may have implications for enhancing the acute therapeutic effects of nasal spray and, perhaps, other medications in smokers trying to maintain abstinence after quitting.

Pomerleau OF; Pomerleau CS. Commentary on Haberstick, et al. (2011): Dizziness upon initial experimentation with cigarettes - implications for smoking persistence. (commentary). Addiction 106(2): 400-401, 2011. (8 refs.)

Pomerleau OF; Pomerleau CS; Snedecor SM; Finkenauer R; Mehringer AM; Langenecker SA et al. Substance use, trait measures, and subjective response to nicotine in never-smokers stratified on parental smoking history and sex. Nicotine & Tobacco Research 11(9): 1055-1066, 2009. (71 refs.)

Male and female never-smokers stratified on parental history of smoking were tested for possible differences in susceptibility to the hedonic effects of nicotine. 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. 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. 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.

Richardson CG; Okoli CTC; Ratner PA; Johnson JL. Empirical support for a multi-dimensional model of sensations experienced by youth during their initial smoking episodes. Addiction 105(10): 1827-1834, 2010 , 2010. (32 refs.)

Aims: To examine the dimensionality of sensations experienced during initial tobacco smoking. Design Cross-sectional survey. Setting Thirteen secondary schools located in British Columbia, Canada. Participants Data from 1187 adolescents who responded 'yes' to the question: 'Have you ever tried cigarette smoking, even one or two puffs?'. Measurements: Participants answered questions about their demographic characteristics, tobacco smoking history and sensations experienced during their initial smoking episodes. Findings: The sensations appear to represent the following three separate but modestly correlated dimensions: a pleasant dimension defined by feeling good and relaxed; an unpleasant dimension defined by coughing, feeling sick and nervous; and a 'buzz' dimension defined by feeling high and dizzy. The three factors made statistically significant contributions to the prediction of transition to regular smoking (defined as having smoked at least 100 cigarettes in one's life-time) after adjusting for age, sex and age at first puff. Conclusions: The results suggest that three relatively distinct physiological systems appear to explain the relationship between initial smoking sensations and probability of becoming a regular smoker. Researchers examining sensations experienced during initial tobacco smoking episodes should consider using a three-dimensional profile of symptoms composed of pleasant, unpleasant and buzz dimensions.

Rose JE; Salley A; Behm FM; Bates JE; Westman EC. Reinforcing effects of nicotine and non-nicotine components of cigarette smoke. Psychopharmacology 210(1): 1-12, 2010. (55 refs.)

Nicotine and non-nicotine components of cigarette smoke contribute to its reinforcing effects; however, the specific role of each component in maintaining behavior has not yet been elucidated. To assess the reinforcing effects of nicotine and non-nicotine components of cigarette smoke by presenting a concurrent choice paradigm in which participants had access to intravenous (IV) nicotine infusions vs. saline (placebo) infusions and puffs from denicotinized ("denic") cigarettes vs. air (sham puffs). We also measured the effects on self-administration of prior satiation with each component. Sixteen smokers participated in seven sessions: 1) a baseline smoking assessment, used to tailor the nicotine dose per infusion; 2) two sessions for training discrimination of IV nicotine vs. saline infusions and denic smoke vs. sham puffs; and 3) four sessions assessing choice behavior after different satiation conditions. Denic smoke was self-administered more than any other alternative, including IV nicotine. IV nicotine, however, was preferred over IV saline and sham puffs. Preference for denic smoke vs. IV nicotine was inversely correlated with subjective ratings of "comfort" associated with nicotine. Smoke satiation reduced the number of denic puffs taken during choice periods, while prior nicotine administration did not affect puffing behavior. Smoking withdrawal symptoms were alleviated both by nicotine administration and by denic smoke. In established smokers, non-nicotine aspects of cigarette smoking have potent reinforcing effects. While current smoking cessation pharmacotherapies primarily address the nicotine component of cigarette addiction, future cessation strategies should also be designed to target non-nicotine factors.

Sartor CE; Lessov-Schlaggar CN; Scherrer JF; Bucholz KK; Madden PAF; Pergadia ML et al. Initial response to cigarettes predicts rate of progression to regular smoking: Findings from an offspring-of-twins design. Addictive Behaviors 35(8): 771-778, 2010. (54 refs.)

The aim of this study was to examine the association between initial subjective effects from cigarettes and the rate of progression from first cigarette to regular smoking. Latent class analysis (LCA) was applied to subjective effects data from 573 offspring of twins ranging in age from 14 to 32 years. LCA revealed four classes: 1) High on both pleasurable and physiological responses, 2) Cough only response, 3) High on physiological, low on pleasurable responses, and 4) High on pleasurable, low on physiological responses. Classes of responses were then used to predict time from first cigarette to the onset of regular smoking in a Cox proportional hazards model. Time-varying covariates representing relevant psychiatric and psychosocial factors as well as dummy variables representing the offspring-of-twins design were included in the model. Members of classes 1 and 4 transitioned more rapidly to regular smoking than the classes characterized as low on the pleasurable response dimension. Our findings provide evidence that previously reported associations between pleasurable initial experiences and progression to regular smoking hold true as well for the rate at which that transition occurs. Furthermore, the fact that profiles of responses did not fall into global categories of exclusively pleasurable vs. exclusively negative (physiological) responses suggests the importance of considering both dimensions in combination to characterize risk for smoking-related outcomes.

Shihadeh AL; Eissenberg TE. Significance of smoking machine toxicant yields to blood-level exposure in water pipe tobacco smokers. Cancer Epidemiology, Biomarkers & Prevention 20(11): 2457-2468, 2011. (38 refs.)

Background: The global increase in tobacco smoking with a water pipe (hookah, narghile, or shisha) has made understanding its health consequences imperative. One key to developing this understanding is identifying and quantifying carcinogens and other toxicants present in water pipe smoke. To do so, the toxicant yield of machine-generated water pipe smoke has been measured. However, the relevance of toxicant yields of machine-generated smoke to actual human exposure has not been established. Methods: In this study, we examined whether carbon monoxide (CO) and nicotine yields measured with a smoking machine programmed to replicate the puffing behavior of 31 human participants who smoked a water pipe could reliably predict these participants' blood-level exposure. In addition to CO and nicotine, yields of polyaromatic hydrocarbons, volatile aldehydes, nitric oxide (NO), and "tar" were measured. Results: We found that when used in this puff-replicating manner, smoking machine yields are highly correlated with blood-level exposure (nicotine: r > 0.76, P < 0.001; CO: r > 0.78, P < 0.001). Total drawn smoke volume was the best predictor of toxicant yield and exposure, accounting for approximately 75% to 100% of the variability across participants in yields of NO, CO, volatile aldehydes, and tar, as well as blood-level CO and normalized nicotine. Conclusions: Machine-based methods can be devised in which smoke toxicant yields reliably track human exposure. Impact: This finding indicates the basic feasibility of valid analytic laboratory evaluation of tobacco products for regulatory purposes.

Sjoberg N; Saint DA. A single 4 mg dose of nicotine decreases heart rate variability in healthy nonsmokers: Implications for smoking cessation programs. Nicotine & Tobacco Research 13(5): 369- 372, 2011. (24 refs.)

Introduction: The vast majority of work on the physiological effects of nicotine in humans has been done in smokers or smokers trying to quit. Such studies can be confounded by tolerance, desensitization of receptors, or withdrawal. Because of these difficulties, there is still some dispute as to whether nicotine is proparasympathetic or prosympathetic in humans. To circumvent these difficulties, we assessed the effect of nicotine on autonomic function by measuring changes in heart rate variability (HRV) in nicotine-naive healthy subjects. Methods: Twenty males and 20 females aged between 18 and 25 years received 4 mg oral nicotine lozenge or placebo. HRV was assessed in 15-min periods before, during, and after ingestion. Results: There were no significant changes in any measure after placebo administration. During and after nicotine ingestion, heart rate increased to 78 +/- 2 beats per minute (bpm) from a baseline level of 75 +/- 2 bpm (p < .01). Nicotine significantly increased low frequency (LF; normalized units) from 66 +/- 2 at baseline to 70 +/- 2 at 15-30 min postingestion (p < .01) and decreased high frequency (HF; normalized units) from 28 +/- 2 to 24 +/- 1 (p < .01). LF/HF ratio was therefore substantially increased from 2.9 +/- 0.3 to 3.7 +/- 0.3 (p < .01). Conclusions: A single dose of 4 mg oral nicotine produces a significant reduction in HRV (i.e., a proportional decrease in high-frequency variability) in healthy young nonsmokers consistent with a reduced vagal activity. This has implications for nicotine replacement treatments aimed at cessation of smoking.

Sorensen LT; Jorgensen S; Petersen LJ; Hemmingsen U; Bulow J; Loft S et al. Acute effects of nicotine and smoking on blood flow, tissue oxygen, and aerobe metabolism of the skin and subcutis. Journal of Surgical Research 152(2): 224-230, 2009. (44 refs.)

Background. Nicotine released from tobacco smoke causing reduction in blood flow has been suggested as causative for postoperative wound complications in smokers, but the mechanism remains unknown. Materials and methods. In eight healthy male smokers and eight ex-smokers, the cutaneous and subcutaneous blood flow (QBF, SqBF) was assessed by Laser Doppler and 133Xe clearance. Tissue oxygen tension (TO2) was measured by a LICOX O-2-electrode. Tissue glucose and lactate (Tgluc, Tlact) were assessed by microdialysis. The parameters were studied after intravenous infusion of 1.0 mg nicotine, smoking of one cigarette, arterial occlusion, and reperfusion. Results. Nicotine infusion decreased SqBF from 4.2 +/- 2.0 to 3.1 +/- 1.2 mL/100 g tissue/min (P < 0.01), whereas QBF was 21.7 +/- 8.6 and 22.7 +/- 9.6 Arbitrary Units (AU), respectively (P = 0.21). TO2 increased from 49.3 +/- 12.0 to 53.9 +/- 12.0 mm Hg (P = 0.01). Tgluc and Tlact remained unaffected. Smoking decreased SqBF from 4.2 2.0 to 2.7 +/- 1.2 mL/100 g tissue/min (P < 0.01). QBF decreased from 23.4 +/- 9.2 to 20.3 +/- 7.4 AU (P < 0.01), and TO2 decreased from 53.9 +/- 12.0 to 48.4 +/- 11.1 In Hg (P < 0.01). Following smoking, Tgluc decreased from 0.7 +/- 0.1 to 0.6 +/- 0.1 ng/mL (P < 0.01), and Tlact increased from 0.2 +/- 0.1 to 0.3 +/- 0.2 ng/mL (P < 0.01). The observed alterations were similar in smokers and ex-smokers. Conclusions. Nicotine has a limited vasoactive effect in the skin and subcutis unlikely to be explained by smoking, which distinctly decreases tissue blood flow, oxygen tension, and aerobe metabolism independent of smoking status.

Strong DR; Leventhal AM; Evatt DP; Haber S; Greenberg BD; Abrams D et al. Positive reactions to tobacco predict relapse after cessation. Journal of Abnormal Psychology 120(4): 999-1005, 2011. (36 refs.)

Among chronic smokers, individual differences in subjective reactions to smoking may characterize important facets of nicotine dependence that relate to abstinence-induced craving, withdrawal symptom profiles, and risk for relapse. Although the negative reinforcing properties of smoking have achieved prominent positions in models of relapse (Baker, Brandon, & Chassin, 2004), vulnerability to relapse risk may also arise from seeking positive reinforcement from smoking (Shiffman & Kirchner, 2009). In this study, 183 cessation-motivated smokers provided subjective craving, positive and negative reactions to standardized cigarettes following overnight abstinence. Level of craving, negative mood, and positive mood after overnight abstinence were significantly predictive of withdrawal on quit-day. Increased positive reactions to smoking were uniquely predictive of relapse after quitting (Hazard Ratio = 1.22, p < .001). Individual differences in positive reactions to smoking may be important markers of neurobiological systems that promote dependence and interfere with cessation efforts.

Unverdorben M; Mostert A; Munjal S; van der Bijl A; Potgieter L; Venter C et al. Acute effects of cigarette smoking on pulmonary function. Regulatory Toxicology and Pharmacology 57(2-3): 241-246, 2010. (42 refs.)

Introduction: Chronic smoking related changes in pulmonary function are reflected as accelerated decrease in FEV1 although histologic changes occur in the peripheral bronchi earlier. More sensitive pulmonary function parameters might mirror those early changes and might show a dose response. Methods: In a randomized three-period cross-over design 57 male adult conventional cigarette (CC)smokers (age: 45.1 +/- 7.1 years) smoked either CC (tar:11 mg, nicotine:0.8 mg, carbon monoxide:11 mg [Federal Trade Commission (FTC)]), or used as a potential reduced-exposure product the electrically heated smoking system (EHCSS) (tar:5 mg, nicotine:0.3 mg, carbon monoxide:0.45 mg (FTC)) or did not smoke (NS). After each 3-day exposure period, hematology and exposure parameters were determined preceding body plethysmography. Results: Cigarette smoke exposure was significantly (p < 0.0001) higher in CC than in EHCSS and in NS: (carboxyhemoglobin: CC: 6.4 +/- 1.9%; EHCSS: 1.3 +/- 0.6%; NS: 0.5 +/- 0.3%; serum nicotine: CC: 18.9 +/- 7.4 ng/ml; EHCSS: 8.4 +/- 4.3 ng/ml; NS: 1.2 +/- 1.6 ng/ml). Significantly lower in CC than in EHCSS and NS were specific airway conductance (0.22 +/- 0.09; 0.25 +/- 0.12; 0.25 +/- 0.1 1/cmH(2)O x s; CC vs EHCSS: p < 0.05; CC vs NS: p < 0.01), forced expiratory flow 25% (7.6 +/- 1.7; 7.8 +/- 1.7; 7.9 +/- 1.7 L/s; CC vs EHCSS or NS: p < 0.01). Thoracic gas volume (5.1 +/- 1; 5 +/- 1.1; 5 +/- 1.1 L/min) changed insignificantly. Conclusion: The data indicate acute and reversible effects of cigarette smoke exposures and no-smoking on mid to small size pulmonary airways in a dose dependent manner.

Ursprung WWS; Savageau JA; DiFranza JR. What is the significance of experiencing relaxation in response to the first use of nicotine? Addiction Research & Theory 19(1): 14-21, 2011. (28 refs.)

Individuals who feel relaxed the first time they inhale from a cigarette are more likely to develop nicotine dependence. To determine if the relaxation response is associated only with specific aspects of dependence, a survey was administered to 1405 adolescents aged 14-18 years (mean 15.8 years) from four schools in Massachusetts. Nicotine dependence was measured with the Diagnostic and Statistical Manual (DSM-IV), and the loss of autonomy over tobacco was measured with the Hooked on Nicotine Checklist (HONC) and the Autonomy Over Smoking Scale. A feeling of relaxation was reported by 39.4% of 439 youth who had inhaled from a cigarette. Relaxation was associated with increased risk of current smoking (odds ratio (OR) = 5.7, p < 0.001), daily smoking (OR = 5.7, p < 0.001), a loss of autonomy on the HONC (OR = 5.0, p < 0.001), and a DSM-IV diagnosis (OR = 2.4, p < 0.02). In regression analyses, relaxation was not associated with psychological reliance on tobacco after controlling for nicotine withdrawal symptoms, and cue-induced craving. This study extends the literature by demonstrating that relaxation is associated with DSM-IV nicotine dependence, nicotine withdrawal, and aspects of cue-induced craving.

Vansickel AR; Cobb CO; Weaver MF; Eissenberg TE. A clinical laboratory model for evaluating the acute effects of electronic "cigarettes": Nicotine delivery profile and cardiovascular and subjective effects. Cancer Epidemiology, Biomarkers & Prevention 19(8): 1945-1953, 2010 , 2010. (41 refs.)

Background: Electronic "cigarettes" are marketed to tobacco users as potential reduced exposure products (PREP), albeit with little information regarding electronic cigarette user toxicant exposure and effects. This information may be obtained by adapting clinical laboratory methods used to evaluate other PREPs for smokers. Methods: Thirty-two smokers participated in four independent Latin-square ordered conditions that differed by product: own brand cigarette, "NPRO" electronic cigarettes (NPRO EC; 18 mg cartridge), "Hydro" electronic cigarettes (Hydro EC; 16 mg cartridge), or sham (unlit cigarette). Participants took 10 puffs at two separate times during each session. Plasma nicotine and carbon monoxide (CO) concentration, heart rate, and subjective effects were assessed. Results: Own brand significantly increased plasma nicotine and CO concentration and heart rate within the first five minutes of administration whereas NPRO EC, Hydro EC, and sham smoking did not. Own brand, NPRO EC, and Hydro EC (but not sham) significantly decreased tobacco abstinence symptom ratings and increased product acceptability ratings. The magnitude of symptom suppression and increased acceptability was greater for own brand than for NPRO EC and Hydro EC. Conclusions: Under these acute testing conditions, neither of the electronic cigarettes exposed users to measurable levels of nicotine or CO, although both suppressed nicotine/tobacco abstinence symptom ratings. Impact: This study illustrates how clinical laboratory methods can be used to understand the acute effects of these and other PREPs for tobacco users. The results and methods reported here will likely be relevant to the evaluation and empirically based regulation of electronic cigarettes and similar products.

Vansickel AR; Poole MM; Stoops WW; Hays KE; Upchurch MB; Glaser PEA et al. Stimulant-induced changes in smoking and caloric intake: Influence of rate of onset. Pharmacology, Biochemistry and Behavior 92(4): 597-602, 2009. (30 refs.)

Rate-of-onset modulates the subject-rated effects of stimulants. Results of two studies from our laboratory demonstrate that immediate-release methylphenidate increases smoking and decreases caloric intake. Whether rate-of-onset influences the effects of methylphenidate on smoking and eating is unknown. The present experiment examined the influence of a range of doses of immediate- (7.5-30 mg) and sustained-release (18-72 mg) methylphenidate as well as placebo on smoking and eating. Eight cigarette smokers participated. A double-dummy drug administration procedure Was used to maintain the double blind because immediate-release methylphenidate produces peak plasma concentrations 1.5-2 h and the sustained-release formulation produces peak plasma concentrations 6-8 h after oral administration. Smoking and eating were assessed for 4 h across the predicted peak effects of both methylphenidate formulations. Measures of smoking included total cigarettes, puffs. and carbon monoxide levels. Snacks and decaffeinated beverages were available ad libitum and caloric intake was monitored during the four-hour smoking session. Immediate- and sustained-release methylphenidate increased smoking and decreased caloric intake. The effects of methylphenidate generally did not vary as a function of formulation. The results of this study may have important implications for the treatment of disorders that require Stimulant medications. Smoking should be monitored in patients that are prescribed stimulant medications, regardless of the formulation type.

Veid J; Karttunen V; Myohanen K; Myllynen P; Auriola S; Halonen T et al. Acute effects of ethanol on the transfer of nicotine and two dietary carcinogens in human placental perfusion. Toxicology Letters 205(3): 257-264, 2011. (61 refs.)

Many mothers use, against instructions, alcohol during pregnancy. Simultaneously mothers are exposed to a wide range of other environmental chemicals. These chemicals may also harm the developing fetus, because almost all toxic compounds can go through human placenta. Toxicokinetic effects of ethanol on the transfer of other environmental compounds through human placenta have not been studied before. It is known that ethanol has lytic properties and increases the permeability and fluidity of cell membranes. We studied the effects of ethanol on the transfer of three different environmental toxins: nicotine, PhIP (2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine) and NDMA (N-nitrosodimethylamine) in placental perfusion. We tested in human breast cancer adenocarcinoma cell line MCF-7 whether ethanol affects ABCG2/BCRP, which is also the major transporter in human placenta. We found that the transfer of ethanol is comparable to that of antipyrine, which points to passive diffusion as the transfer mechanism. Unexpectedly, ethanol had no statistically significant effect on the transfer of the other studied compounds. Neither did ethanol inhibit the function of ABCG2/BCRP. These experiments represent only the effects of acute exposure to ethanol and chronic exposure remains to be studied.

Ward RD; Barrett ST; Johnson RN; Odum AL. Nicotine does not enhance discrimination performance in a temporal bisection procedure. Behavioural Pharmacology 20(1): 99-108, 2009. (39 refs.)

Recent reports of selective disruption of stimulus control by drug administration and other disruptive operations in temporal discrimination procedures may be interpreted as a disruption of attention to the temporal sample stimuli. This experiment assessed the effects of nicotine, a compound that has been widely shown to increase measures of attention, on temporal discrimination performance. Pigeons responded under a psychophysical choice procedure in which responses to one key color were correct after presentation of four shorter sample durations and responses to another key color were correct after presentation of four longer sample durations. Performance under nicotine was characterized by using a model that differentiates the effects of nicotine on stimulus control, bias, and sensitivity of temporal discrimination. Nicotine selectively decreased the measure of stimulus control, but did not systematically affect the measures of timing. Mecamylamine (1.0 mg/kg) failed to antagonize the disruptive effects of nicotine. These results suggest that disruption of temporal discrimination performance in this preparation may not have been dependent on the specific pharmacology of nicotine and underscore the importance of quantitative separation of the effects of various manipulations on stimulus control from effects on timing.

Wardle MC; Munafo MR; de Wit H. Effect of social stress during acute nicotine abstinence. Psychopharmacology 218(1, special issue): 39-48, 2011. (41 refs.)

Relapse to smoking is often precipitated by stress, yet little is known about the effects of nicotine withdrawal on responses to acute stress, or whether nicotine replacement reverses withdrawal-induced changes in stress response. The aim of the present study is to use an effective social stressor, the Trier Social Stress Test (TSST), to study subjective, cardiovascular and hormonal responses to stress during withdrawal, and examine whether nicotine replacement moderates responses to stress during withdrawal. Forty-nine current regular smokers were randomly assigned to smoke as normal (SM), 12-h abstention with placebo patch (PL), or 12-h abstention with nicotine patch (NIC). They participated in a single session using the TSST, during which subjective affect, heart rate (HR), mean arterial blood pressure (MAP) and salivary cortisol were measured. The TSST produced expected increases in subjective negative affect, HR, MAP, and cortisol. Groups did not differ in subjective or cardiovascular responses, but the PL group exhibited larger stress-induced increase in cortisol than the other groups. The increased cortisol response might indicate a greater hormonal stress response during nicotine withdrawal. Alternatively, considering that cortisol also provides negative feedback to the stress system, and blunted cortisol responses are predictive of smoking relapse, the lower cortisol responses in the NIC and SM groups might indicate chronic dysregulation of the stress system. In this case, restoration of cortisol response by nicotine treatment to the lower levels seen during regular smoking may actually represent an undesired side effect of nicotine replacement.

Wise PM; Preti G; Eades J; Wysocki CJ. The effect of menthol vapor on nasal sensitivity to chemical irritation. Nicotine & Tobacco Research 13(10): 989-997, 2011. (57 refs.)

Introduction: Among other effects, menthol added to cigarettes may modulate sensory response to cigarette smoke either by masking "harshness" or contributing to a desirable "impact." However, harshness and impact have been imprecisely defined and assessed using subjective measures. Thus, the current experiments used an objective measure of sensitivity to chemical irritation in the nose to test the hypothesis that menthol vapor modulates sensitivity to chemical irritation in the airways. Methods: Nasal irritation thresholds were measured for 2 model compounds (acetic acid and allyl isothiocyanate) using nasal lateralization. In this technique, participants simultaneously sniff clean air in one nostril and chemical vapor in the other and attempt to identify the stimulated nostril. People cannot lateralize based on smell alone but can do so when chemicals are strong enough to feel. In one condition, participants were pretreated by sniffing menthol vapor. In a control condition, participants were pretreated by sniffing an odorless blank (within-subjects design). Results: Pretreatment with menthol vapor decreased sensitivity to nasal irritation from acetic acid (participants required higher concentrations to lateralize) but increased sensitivity to allyl isothiocyanate (lower concentrations were required). Conclusions: The current experiments provide objective evidence that menthol vapor can modulate sensitivity to chemical irritation in the upper airways in humans. Cigarette smoke is a complex mixture of chemicals and particulates, and further work will be needed to determine exactly how menthol modulates smoking sensation. A better understanding could lead to treatments tailored to help menthol smokers quit by replacing the sensation of mentholated cigarettes.

Wu J. Double target concept for smoking cessation. Acta Pharmacologica Sinica 31(9): 1015-1018 , 2010. (37 refs.)

Tobacco use is estimated to be the largest single cause of premature death in the world. Nicotine is the major addictive substance in tobacco products. After cigarette smoking, nicotine quickly acts on its target, nicotinic acetylcholine receptors (nAChRs), which are widely distributed throughout the mammalian central nervous system and are expressed as diverse subtypes on cell bodies, dendrites and/or nerve terminals. Through the nAChRs in brain reward circuits, nicotine alters dopaminergic (DA) neuronal function in the ventral tegmental area (VTA) and increases dopamine release from VTA to nuclear accumbens (NA), which leads to nicotine reward, tolerance and dependence. After quitting smoking, smokers experience withdrawal symptoms, including depression, irritability, difficulty concentrating or sleeping, headache, and tiredness. Recently, evidence has been accumulated to reveal the molecular and cellular mechanisms of nicotine reward, tolerance and dependence. The outcomes of these investigations provide pharmacological basis for smoking cessation. Here, I briefly summarize recent advancements of our understanding of nicotine reward, tolerance and dependence. Based on these understandings, I propose a double target hypothesis, in which nAChRs and dopamine release process are two important targets for smoking cessation. Dysfunction of nAChRs (antagonism or desensitization) is crucial to abolish nicotine dependence and the maintenance of an appropriate level of extracellular dopamine eliminates nicotine withdrawal syndromes. Therefore, the medications simultaneously act on these two targets should have the desired effect for smoking cessation. I discuss how to use this double target concept to interpret recent therapies and to develop new candidate compounds for smoking cessation.