Plasma nicotine,plasma β-endorphin and mood states during periods of chronic smoking,abstinence and nicotine replacement

Nicotine is known to release neuroendocrine substances which may subsequently reinforce smoking behavior by improving mood states. The purpose of this study was to examine changes in plasma-endorphin and mood states during periods of chronic smoking, abstinence from smoking, and abstinence while chewing nicotine gum. A modified A-B-A-C design was used. Normal male volunteers were randomly assigned to an experimental or control group. Over a 12-day protocol, experimental subjects smoked ad libitum for 2 days, were abstinent for 4 days, resumed smoking for 2 days, and then chewed nicotine gum for the final 4 days. Control subjects smoked ad libitum throughout the entire protocol. Results indicated that changes in plasma-endorphin levels were not related to changes in the four smoking conditions. Plasma nicotine and mood states were related, such that dysphoric moods increased during abstinence from smoking in comparison to the control group. To investigate further the relationships between nicotine,-endorphin and reinforcement for smoking, it may be necessary to characterize endogenous opioid peptide release in the central nervous system during smoking.     

Lack of association between the dopamine D2 receptor gene allele DRD2*A1 and cigarette smoking in a United Kingdom population

The dopamine D2 receptor gene contains a TaqI repeat fragment length polymorphism creating two alleles DRD2*A1 and DRD2*A2. It has been previously suggested that the lesser allele, DRD2*A1, is more prevalent in individuals who are susceptible to impulsive/addictive/compulsive behaviour, for example, alcoholics, polysubstance abusers and tobacco smokers. We genotyped a series of 104 smokers and 117 non smokers and compared the allele frequencies between the groups. A subset (n = 87) of the smoking population also completed the Classification of Smoking by Motives questionnaire and were given scores for five criteria that drive smoking: automatic, dependence, sedative, stimulant and indulgence. Another subset (n = 52) completed the Fagerstrom Tolerance Questionnaire and were given scores for nicotine dependence. We did not find any increase in allele A1 frequency when comparing smokers to non smokers. Furthermore, neither measure of dependence was affected by possession of the A1 allele; the only difference between DRD2*A1 bearing and DRD2*A2 homozygous individuals in terms of smoking motives was found in the scores for indulgence; the former having a moderately reduced score (by 17%, p < 0.05). We conclude that, in the individuals studied, the dopamine D2 receptor TaqI locus does not affect the drive to smoke. This may be caused by the locus being unrelated to impulsive/addictive/compulsive behaviour, the polymorphism being in linkage disequilibrium with another distinct locus or, alternatively, smoking may represent a behaviour that is not directly comparable to impulsive/addictive/compulsive behaviours previously associated with the DRD2*A1 allele.     

Nicotine elimination and tolerance in non-dependent cigarette smokers

Although most smokers are nicotine-dependent, recent studies suggest that some very light smokers (chippers, who smoke fewer than five cigarettes per day) may smoke for decades without developing dependence. It was considered that slowed nicotine elimination and/or reduced nicotine tolerance might underlie chippers' ability to maintain smoking at such low levels. To evaluate this hypothesis, we studied the elimination kinetics and pharmacodynamics of nicotine in chippers and matched regular smokers. Plasma nicotine levels and cardiovascular responses were observed for several hours after subjects were administered uniform doses of tobacco smoke. Chippers did show less chronic nicotine tolerance, but only on some response measures. Their rates of nicotine elimination equaled those of regular smokers. This finding, when coupled with other data about chippers' smoking patterns and nicotine absorption, establish that chippers cannot maintain substantial plasma nicotine levels between cigarettes, and thus suggest that attempts to maintain minimal trough levels of nicotine do not underlie chippers' smoking.     

Naltrexone reduces the relative reinforcing value of nicotine in a cigarette smoking choice paradigm

Rationale Human behavioral pharmacology studies can examine how medications that target different neurotransmitter systems influence different aspects of smoking. Naltrexone and bupropion have been shown to alter ad lib smoking behavior; however, medication effects on nicotine reward in a cigarette choice paradigm have yet to be investigated.Objective This study explored the effects of an acute dose of naltrexone, bupropion, or placebo on the relative reinforcing value of nicotine from cigarette smoking using new nicotine and de-nicotinized (Quest, 0.6 and 0.05 mg = denicotinized) cigarettes.Methods In a double-blind, within-subjects design, 26 dependent smokers participated in three experimental cigarette smoking sessions following pretreatment with either naltrexone (50 mg), bupropion (300 mg), or placebo. After medication administration and 2 h of monitored deprivation from cigarettes and food, participants rated their responses to the initial exposure to the cigarettes and then participated in four choice sessions over a 2-h period during which they could take four puffs from either cigarette.Results The relative reinforcing value of nicotine, as measured by the number of nicotine puffs chosen out of 16, was significantly lower following naltrexone compared to placebo. There were no effects of an acute dose of bupropion on nicotine choices.Conclusions These results suggest that naltrexone may reduce the relative reinforcing effects of nicotine via cigarette smoking and support ongoing investigation of opioid antagonists as potential smoking cessation pharmacotherapies.     

Transdermal nicotine: reduction of smoking with minimal abuse liability

Cigarette consumption as well as the physiologic, performance and subjective effects of the nicotine patch were evaluated in ten subjects who smoked ad libitum while residing on a residential research ward for 30 days. Nicotine transdermal systems (patches) delivering a total of 0, 22 or 44 mg per 24 h were applied daily at a constant dose during each 7-day condition; the order of dosing conditions was varied according to a randomized, double-blind, crossover design. Nicotine patches significantly but modestly reduced spontaneous smoking and significantly increased venous plasma nicotine levels. Self ratings of patch liking, satisfaction with cigarettes and the ability to identify the patch condition did not change as a function of the nicotine dose, indicating minimal abuse liability. There were no consistent changes in the puffing pattern measures; however, in all patch conditions, subjects with extensive histories of illicit drug use smoked cigarettes faster than subjects with histories of occasional drug use. Small changes in resting heart rate, pulse and blood pressure occurred when the nicotine patch was worn. Thus large changes in venous plasma nicotine levels engender only modest changes in ad libitum cigarette consumption, measures of abuse liability and cardiovascular effects. These findings are consistent with the notion that the addictive and toxic effects of nicotine are partially determined by the rate of drug administration.     

Measuring smoking-related preoccupation and compulsive drive: evaluation of the obsessive compulsive smoking scale

Rationale

Tobacco use for many people is compulsive in nature. Compelling theories of how smoking becomes compulsive exist but are largely based on extrapolation from neuroscience findings. Research on smokers is impeded, in part, by a lack of instruments that specifically measure compulsive smoking.

Objective

This study evaluated the measurement structure and validity of the Obsessive Compulsive Smoking Scale (OCSS), a ten-item questionnaire designed to measure compulsive smoking.

Methods

Participants were 239 daily smokers (≥1 cigarette/day), including 142 students at a public university in Chicago and 97 veterans treated at the VA Boston Healthcare System. The OCSS and questionnaires measuring current and past smoking, cigarette craving, automatic smoking, and nicotine dependence were administered.

Results

Factor analysis with maximum likelihood extraction and oblique rotation revealed two correlated underlying factors, interpreted as “Preoccupation with Smoking” and “Compulsive Drive.” The measurement structure was consistent across students and veterans, and confirmed in an independent sample of adults (n?=?95). Veterans exhibited higher OCSS scores (full scale and subscales) than students. Across groups, higher OCSS scores were positively correlated with smoking intensity, craving, and nicotine dependence. OCSS full-scale and compulsive drive scores, but not smoking preoccupation scores, were inversely correlated with past month smoking reduction and minutes since last cigarette.

Conclusions

The OCSS is a valid and reliable inventory for measuring the degree to which daily smokers are preoccupied with smoking and engage in compulsive tobacco use, and may be useful for advancing understanding of core smoking phenotypes or for tailoring cessation therapies.     

Reevaluating the nicotine delivery kinetics hypothesis

Rationale

The view of smoking as an addiction to nicotine implies that nicotine is an addictive drug and a primary reinforcer. However, nicotine other than in tobacco does not appear to be very rewarding for smokers. This potential anomaly to the nicotine addiction thesis is resolved by the proposition that the reward associated with smoking depends on “high-nicotine boli.” According to the nicotine delivery kinetics hypothesis, smoked nicotine reaches the brain in 5–10 s in high concentrations, which provide reinforcing “hits” of nicotine to the brain.

Objectives

Because of its essential role in the nicotine addiction thesis, this review set out to examine the current empirical basis of the nicotine delivery kinetics hypothesis.

Materials and methods

We reviewed studies that bear on two questions: First, does nicotine from cigarettes reach the brain significantly faster than from other nicotine delivery devices? Second, is there a relationship between delivery kinetics and any rewarding effects of nicotine?

Results

There is little empirical support for the nicotine delivery kinetics hypothesis. Several studies found that arterial nicotine levels associated with smoking are much lower than predicted by the nicotine delivery kinetics thesis and not higher than with other nicotine delivery devices. More importantly, comparisons of nicotine delivery devices with varying speeds of delivery do not suggest any correlation between nicotine delivery profile and subjective reward.

Conclusions

This review indicates that the wide endorsement of the nicotine delivery kinetics hypothesis is unjustified. Critical research is required to resolve the anomalies within the nicotine addiction theory of smoking.

     

Which smokers report most relief from craving when using nicotine chewing gum?

Seventy-seven smoker clinic clients who managed at least 2 weeks of smoking abstinence while chewing 2 mg nicotine gum reported the degree to which the gum reduced their craving for cigarettes, their daily gum consumption and the extent of urges to smoke despite the gum. Greatest relief from craving by the gum was reported by smokers with higher pre-abstinence expired-air carbon monoxide (CO) concentrations and higher stimulant and dependent scores on a smoking motivation questionaire but not greater usual daily cigarette consumption. Gum consumption correlated positively with expired-air CO, usual daily cigarette consumption, and stimulant and dependent smoking scores. Despite the gum, urges to smoke and difficulty not smoking were reported and the severity of these was associated with indulgent, stimulant and dependent smoking scores but not CO or usual daily cigarette consumption. The results are discussed in terms of the possible role of pharmacological and non-pharmacological factors in craving.     

Pre-abstinence smoke intake and smoking motivation as predictors of severity of cigarette withdrawal symptoms

Twenty-nine cigarette smokers completed a smoking motivation questionnaire and had expired-air carbon monoxide (CO) and plasma nicotine concentrations measured prior to abstaining from smoking for 24 h. Before and after the abstinence period, the subjects rated mood and physical symptoms known to be affected by cigarette abstinence (e.g. irritability, restlessness). Scores on the dependent smoking subscale of the smoking motivation questionnaire correlated significantly with overall withdrawal severity, craving, and increased irritability. Indulgent smoking scores correlated positively with increased hunger. Pre-abstinence plasma nicotine concentration significantly pedicted craving, hunger, restlessness, inability to concentrate and overall withdrawal severity, while expired-air CO predicted craving and restlessness only. Usual daily cigarette consumption did not significantly predict any withdrawal effects. The data indicate that pre-abstinence measures of smoking motivation and smoke intake may provide a guide to withdrawal severity on smoking cessation and that smokers with a high pre-abstinence nicotine intake experience the greatest discomfort.     

High dose transdermal nicotine therapy for heavy smokers: safety,tolerability and measurement of nicotine and cotinine levels

Transdermal nicotine has been shown to relieve nicotine withdrawal and to double smoking cessation rates compared to placebo in clinical trials. A 21 or 22 mg/day dose provides a steady state serum nicotine that is less than obtained from smoking. Limited information is available about higher nicotine patch doses. To define better the optimal dosing of nicotine patch therapy, we undertook an open-label study to determine the safety and tolerability of 44 mg/day dose for smoking cessation in subjects smoking 20 cigarettes per day. Forty smokers received 44 mg/day of transdermal nicotine for 4 weeks followed by 4 weeks of 22 mg/day. Of the 40 subjects enrolled, 38 (95%) completed the 4 weeks of 44 mg patch therapy and 36 (90%) completed the entire 8 weeks of patch therapy. Non-smokers at week 4 had a mean serum nicotine level of 23.4±11.7 ng/ml and cotinine of 152.2±87.3 ng/ml. Percent replacement was calculated by dividing the steady state level at week 4 by the baseline level while the subjects were smoking their usual number of cigarettes. Percent nicotine replacement for non-smokers at week 4 (while on 44 mg nicotine patch) averaged 158%±108.4, and for cotinine was 112.0±73.8. For nicotine, 33% of non-smokers at week 4 had 100% nicotine replacement and for cotinine 63% 100% replacement. Biochemically confirmed point prevalence smoking cessation rates were 65% and 55% at weeks 4 and 8 of patch therapy, respectively, and self-reported smoking cessation at 3 months was 50%. The most common effect was skin irritation at the patch site. A single subject was admitted for myocardial infarction following step-down from 44 to 22 mg of replacement nicotine. The subject was not smoking and the adverse event was deemed to be not related to the patch therapy. Sleep complaints were reported in 33% of subjects during the 44 mg phase. Other complaints were infrequent. We conclude that 44 mg per 24-h nicotine patch therapy in heavy smokers is safe, tolerable, and without significant adverse events.     

Effect of smoke-free cigarettes on 24 h cigarette withdrawal: a double-blind placebo-controlled study

In a double-blind randomised trial, 40 cigarette smokers used either nicotine-containing or placebo smoke-free cigarettes during 24 h abstinence from smoking. Subjects in the nicotine group experienced smaller increases in irritability and difficulty concentrating and fewer urges to smoke than those who received placebo. Nicotine smoke-free cigarettes were rated as more satisfying, more helpful and more effective in relieving craving than placebo. After 24 h use nicotine smoke-free cigarettes provided average blood nicotine levels of 6.3 ng/ml, i.e., 29.2% of smoking levels. The most frequent side effects were irritation of the throat and coughing. Overall, side effects were rated as not serious. Although the smoke-free cigarette in its present form is not very efficient in delivering nicotine, it was effective in alleviating initial tobacco withdrawal. It is possible that by providing both nicotine and behavioural replacement it may be particularly useful in the first stages of stopping smoking. The product is worth further investigation.     

Nicotine or tar titration in cigarette smoking behavior?

A significant problem in assessing the relative relevance of nicotine and tar yield for compensatory smoking after switching from high to low yield cigarettes is that nicotine and tar yield are highly intercorrelated across conventional cigarettes and that the tar/nicotine ratios vary only within a modest range. A better differentiation between the impacts of nicotine and tar yield was expected by comparing in a laboratory experiment a new low nicotine/medium tar cigarette (Next) with conventional low nicotine/low tar (ultra-light) cigarettes and with medium nicotine/medium tar cigarettes with respect to nicotine absorption and physiological effects. Twelve females, habitually smoking medium type cigarettes (0.7 mg nicotine) participated in the study. Neither the number of cigarettes smoked under field conditions nor the puffing behavior during the laboratory experiment differed between the three types of cigarettes. In the laboratory, Next produced only very small increases in plasma nicotine and changes in cardiovascular or EEG measures, whereas the effects of the medium cigarettes were in the expected range and those of the ultra-light cigarettes about halfway in between. The nicotine absorption/nicotine yield and the CO absorption/CO yield ratios were similar for Next and the habitual cigarettes, but about twofold higher for the ultra-light cigarettes. This suggests that gustatory and olfactory sensations, which are supposed to be more dependent on tar than on nicotine yield, may play a greater role for the regulation of smoking behavior than hitherto believed.     

Effects of nicotine on hunger and eating in male and female smokers

We tested whether the inverse relationship between smoking and body weight may be due in part to nicotine's acute effects on reducing hunger and eating. On four mornings, male and female smokers (n=10 each), abstinent overnight from smoking and food, received one of three nicotine doses (7.5, 15, and 30 µg/kg) or placebo (0) via nasal spray every 30 min for 2 h. Self-reported hunger and satiety (fullness) and craving for cigarettes were obtained after each dose presentation. Subjects subsequently ate ad lib from a large array of food items varying in sweet taste and fat content. For both males and females, nicotine had no effect on self-reported hunger, but cigarette craving was decreased. Rather than being decreased, caloric intake during the meal was unexpectedlyincreased following nicotine compared with placebo. Cigarette craving increased after the meal, and this increase was unaffected by nicotine dose. There were virtually no differences between males and females in any effects of nicotine. These results indicate that nicotine may not acutely suppress appetite in fasting smokers and suggest that other actions of nicotine or smoking may account for the lower body weights of smokers.     

Studies on lung N-methyltransferases,a pharmacological approach

Summary Phenylethanolamine N-methyltransferase (PNMT) was identified as the primary, high affinity N-methylating enzyme for phenylethanolamine (PEA) in rat, dog and Rhesus monkey lung. Human and rabbit lung, however, do not contain this enzyme but possess a more non-specific or general N-methyltransferase with a relatively low affinity for PEA and for which -phenethylamine (-PE) is also a substrate. The former but not the latter enzyme is markedly inhibited by micromolar concentrations of the PNMT antagonist, SK & F 64139. This evidence indicates that certain species differences exist for the enzyme system(s) available for the N-methylation of phenethylamine-type compounds in pulmonary tissue.     

Examining the relation between usual-brand nicotine yield,blood cotinine concentration and the nicotine-“compensation” hypothesis

Eight data sets relating usual-brand nicotine yield (FTC method or equivalent) to blood cotinine concentration are reviewed with respect to the so-called nicotine-compensation hypothesis, i.e., that all smokers achieve a specific level of nicotine in their blood, regardless of the FTC nicotine yield of the cigarette smoked. The data from the studies reviewed here indicate wide variability in blood cotinine concentrations over the range of FTC nicotine yields and that the nicotine-compensation hypothesis is not supported. On average, blood cotinine concentrations are found to be roughly midway between complete compensation (all smokers absorb equal amounts of nicotine regardless of FTC nicotine yield) and the value expected if there was no compensation (i.e., smokers absorb an amount of nicotine exactly equal to the FTC yield). As a result of individual smoking-behavior differences (number of cigarettes smoked, puff volume, puff frequency inhalation volume and depth, etc.), the data indicate that, on average, smokers achieve roughly 50% lower blood cotinine concentrations than predicted by the nicotine-compensation hypothesis.     

Acute effects of nicotine on hunger and caloric intake in smokers and nonsmokers

The inverse relationship between smoking and body weight may be due in part to nicotine's effects on reducing hunger and eating. Male smokers and nonsmokers (n=10 each), abstinent overnight from smoking and food, participated in four sessions, involving consumption of a liquid caloric load or water followed by nicotine (15 µg/kg) or placebo via nasal spray every 20 min for 2 h. Hunger and satiety (fullness) ratings were obtained prior to each dose presentation. At the end of the two sessions involving the caloric load (simulating breakfast), subjects were also presented with typical lunch/snack food items varying in sweet taste and fat content for ad lib consumption. Results indicated that, for both smokers and nonsmokers, the hunger-reducing effects of nicotine occurred only following caloric load consumption, and there was no effect of nicotine on hunger after water consumption. Smokers unexpectedly reported greater satiation than nonsmokers following the caloric load regardless of nicotine or placebo condition. Nicotine also resulted in less caloric intake during the meal, and the decrease was not specific to consumption of sweet, high-fat foods. These results indicate that nicotine reduces appetite, possibly helping to explain the influence of smoking on body weight.     

The effect of nicotine on the swimming speed of pre-trained rats through a water alley

Summary In sessions of ten runs each, swimming time of rats through a 4 m long water alley was measured. Four doses of nicotine (0.05; 0.1; 0.2; 0.4 mg/kg given intraperitoneally 30 minutes before testing) were tested in sessions with a braking load on the tails of the animals either in all 10 runs of a session, or in every second run, or in none of the 10 runs. Regardless of the swimming condition, nicotine produced a considerable, and at doses of 0.1 mg/kg and over, significant decrease of performance in the first two runs. From the third to the 10th run, the changes caused by nicotine were smaller and differed depending on the swimming conditions.A dose of 0.1 mg nicotine/kg improved performance in the without-load-sessions and the without-load-runs of the alternating sessions, while both 0.1 and 0.2 mg/kg improved performance of the with-load-runs of the alternating sessions. Performance in the without-load-sessions and the without-load-runs was depressed by 0.4 mg/kg and that in the with-load-sessions by 0.2 and 0.4 mg/kg.     

Effects of nicotine on avoidance conditioning of inbred strains of mice

Summary Avoidance conditioning of inbred strains of mice was used to analyse the effects exerted by genetic factors on the action of nicotine. The experiments were carried out through an automatic programming and recording shuttle box device. The results indicate that the effects of nicotine are strain dependent. A facilitating effect on avoidance conditioning was observed in 6 of the 9 inbred strains, the strains characterized by a low performance showing generally the highest degree of facilitation. In two strains with a very high level of performance there was an impairing effect of nicotine on avoidance performance.     

Neuroendocrine reactivity to nicotine in smokers

The present study explored neuropeptide responses to nicotine from smoking. Habitual smokers smoked research cigarettes of known strength under controlled laboratory conditions while blood samples were withdrawn unobtrusively for subsequent biochemical analysis. To provide a metric that reflected total nicotine intake and total neurohormonal output, data were integrated over time. Subjects were relatively unresponsive in the low-nicotine (0.48 mg) condition. In the high-nicotine (2.87 mg) condition, there were significant positive correlations between integrated plasma nicotine and plasma arginine vasopressin (r=+0.985), its carrier protein neurophysin I (r=+0.944), and -endorphin--lipotropin (r=+0.977), but not adrenocorticotropic hormone. Data from an experiment that used an extraction step to remove -lipotropin corroborated the functional relationship between plasma nicotine and -endorphin implied by the original findings. Taking into account recent research on the role of neuropeptides in the modulation of affective states and cognitive function as well as of other CNS activity, the present findings were interpreted as strengthening the hypothesis that nicotine-stimulated neuropeptide release provides positive reinforcement for smoking. Offprint requests to: Bld. 5, Research V.A. Medical Center, Newington, CT 06111, USA     

Neuroendocrine responses to nicotine and stress: enhancement of peripheral stress responses by the administration of nicotine

Habitual smokers frequently report that when they are stressed smoking helps them to relax. One potential explanation for the reported stress ameliorating effect of smoking is that cigarette consumption (nicotine self-administration) may decrease the sympathetic autonomic nervous system activity which is associated with the stress response. In the present study, rabbits prepared with chronic vascular cannulae were used to study the effects of nicotine administation on plasma corticosterone, catecholamine (epinephrine, norepinephrine and dopamine) and glucose responses to physical restraint stress. Nicotine (0.025, 0.05 or 0.10 mg nicotine base/kg body weight) was administered for 10 days prior to the stress test to allow for the development of habituation/tolerance to its acute toxic effects. Independent administration of nicotine, or the application of the physical restraint stressor, resulted in increases in the plasma concentrations of corticosterone, epinephrine, norepinephrine, and glucose. Nicotine administration during restraint stress enhanced the increase in plasma corticosterone and epinephrine, as compared to the responses induced by either factor alone. The results suggest that the stress ameliorating effect of continued cigarette smoking, as reported by habitual smokers, is not due to a reduction in the activity of the peripheral sympathetic autonomic nervous system.