Nicotine Tolerance Research Articles

Calcium-Acting Drugs Modulate Expression and Development of Chronic Tolerance to Nicotine-Induced Antinociception in Mice

Initial studies in our laboratory suggested that tolerance to nicotine is thought to involve neuronal adaptation not only at the level of the drug-receptor interaction but at postreceptor events such as calcium-dependent second messengers. The present study was undertaken to investigate the hypothesis that L-type calcium channels and calcium-dependent calmodulin protein kinase II are involved in the development and expression of nicotine tolerance. To that end, the effects of modulation of L-type calcium channels (through the use of inhibitors or activators) as well as calcium-dependent calmodulin protein kinase II inactivation were studied in a mouse model of tolerance where mice were infused with nicotine in minipumps (24 mg/kg/day) for 14 days. In addition, the activity of calcium-dependent calmodulin protein kinase II in the lumbar spinal cord region obtained from nicotine-tolerant mice was measured. Our data showed that chronic administration of L-type calcium channel antagonists nimodipine (1 and 5 mg/kg) and verapamil (10 mg/kg) prevented the development of tolerance to nicotine-induced antinociception. In contrast, chronic exposure of BAYK8644 [(+/-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester], a calcium channel activator, enhanced nicotine's tolerance. Moreover, a significant increase in both dependent and independent calcium-dependent calmodulin protein kinase II activity was seen in the spinal cord in nicotine-tolerant mice. Finally, spinal administration of 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-phenylpiperazine (KN-62), a calcium-dependent calmodulin protein kinase II antagonist, reduced the expression of tolerance to nicotine-induced antinociception in mice. In conclusion, our data indicate that calcium-dependent mechanisms such as L-type calcium channels and calcium-dependent calmodulin protein kinase II activation are involved in the expression and development of nicotine tolerance.

An exploration of self-reported negative affect by adolescents as a reason for smoking: implications for tobacco prevention and intervention programs

Background Negative affect is related to initiation and maintenance of smoking among youth and understanding its role is important when developing effective prevention and cessation programs. This study investigates the relationship between adolescent negative affect and smoking dependence, behaviors, attitudes, and self-efficacy in order to shed light on differences in adolescent smoking maintenance and cessation. Methods 721 smoking youth participated in a cognitive-behavioral smoking cessation program. Reasons for smoking were categorized ( α = 0.87) and youth were placed into one of two groups based on presence or absence of negative affect. One-way repeated measures ANOVA determined if differences existed between the groups on smoking behaviors, attitudes, and self-efficacy. One-way ANOVA determined if differences existed on Fagerström Nicotine Tolerance Dependence (FTND) scores. Results Adolescents indicating negative affect for smoking were significantly more likely to have future smoking intentions and had significantly less self-efficacy to quit smoking than adolescent reporting other reasons. Conclusions This study supports the need to address negative affect among adolescents participating in prevention and cessation programs. An examination of negative affect will provide program developers and facilitators with information to improve their interventions, assist with cessation, and provide an avenue to access other needed health services.

Tolerance to nicotine in mice lacking α7 nicotinic receptors

Previous studies have suggested that a knockout of the gene coding for alpha7 nicotinic receptor subunits influences the behaviour of undrugged mice but not the acute effect of nicotine on locomotor activity. The present studies extend these observations to nicotine tolerance assessed by means of schedule-controlled behaviour. Groups of alpha7-/- and alpha7+/+ mice were trained to press levers under an FR20 schedule of food reinforcement. The acute response rate-depressant effects of nicotine were determined in both genotypes and the mice were then subdivided into groups treated daily with nicotine (1.2 mg/kg/day) or saline. After 39 days of exposure to this regimen, the dose-response curves were re-determined. Knockout of the alpha7 gene had no consistent effect on the lever-pressing behaviour of undrugged mice and did not influence the acute, dose-related, response rate-depressant effect of nicotine (0.2-1.2 mg/kg). When dose-response curves for nicotine (0.4-2.0 mg/kg) were re-determined after daily dosing with the drug, both wild-type and knockout mice developed similar tolerance to nicotine, as shown by approximately 2.5-fold shifts to the right of the dose-response curves. Nicotinic receptors containing the alpha7 subunit do not play a significant role in the regulation of the lever-pressing behaviour studied or in the acute behavioural depressant effect of nicotine and the development of tolerance to that effect. Such results contrast with previous reports suggesting profound impairments in sensitivity to nicotine in nicotinic receptor beta2-/- mice.

Nicotine physical dependence and tolerance in the mouse following chronic oral administration.

Although nicotine dependence and tolerance develop in rats, few studies have examined these processes in the mouse. Establishing such mouse models would eventually allow for an examination of the role of specific nicotinic receptor subtypes in mediating these processes (i.e. through the use of receptor knockouts). The goals of the present study were to establish mouse models of nicotine dependence and tolerance. Mice were chronically exposed to nicotine (0-200 mug/ml) in their drinking solution and assayed for plasma nicotine and cotinine levels, withdrawal signs following nicotine cessation (spontaneous withdrawal) or nicotinic antagonist administration (precipitated withdrawal), or nicotine tolerance. Dependence assays included somatic sign observations (paw tremors, backing and head shakes), tail-flick, plantar stimulation, elevated plus-maze and spontaneous activity. Tolerance was assayed using tail-flick, hot-plate and body temperature tests. Plasma nicotine and cotinine levels were elevated during oral nicotine exposure (15.85 ng/ml and 538.00 ng/ml, respectively) and quickly declined following nicotine cessation (<1 ng/ml and <2 ng/ml, respectively), providing evidence that the oral route was pharmacologically relevant. Nicotine withdrawal increased numbers of somatic signs (spontaneous and mecamylamine-precipitated withdrawal) and/or hyperalgesia (spontaneous withdrawal only). Chronic nicotine exposure also produced tolerance, as indicated by reduced responsivity to acute nicotine in assays of analgesia and hypothermia. These results indicate that chronic oral nicotine produces dependence and tolerance in the mouse. Further, nicotine dependence may be mediated by multiple nicotinic receptor subtypes, since specific nicotinic receptor antagonists failed to precipitate withdrawal.

E-35. Smoking and the sexes

Globally, smoking rates have traditionally been higher for men than for women. In recent decades, however, this sex difference has decreased. The impact of smoking is significant; there are now over 1 million deaths per year among women worldwide due to smoking. Since 1987 lung cancer has surpassed breast cancer as the leading cause of female cancer mortality in the U.S. and is responsible for 87% of all lung cancer deaths in this nation. In developing countries women’s smoking rates are increasing as they are targeted by the tobacco industry. In the U.S., men’s smoking rates have declined from over 50% in the 1950’s to 25.7% in 2002 while women’s smoking rates have declined by a much smaller percent (34% to 21%). The sex difference is even smaller among U.S. teens. While prevalence remains higher for men, the quit ratio, the proportion of ever smokers who are now former smokers (former smokers/ever smokers), is higher in men than women (52% vs. 47%, CDC 1994). In the past few decades smoking has clearly become a “women’s health issue” as defined by those issues “unique” to women or those that disproportionately affect women. To provide selected examples, consider the adverse impact of smoking on the fetus during pregnancy, the causal role of smoking in cervical cancer, and the potential complications of wound healing following reconstructive surgery for breast cancer. Each of these very different experiences creates a window of opportunity to target cessation efforts to women. However, the need for targeted interventions for women has been clouded by conflicting studies regarding sex differences that affect smoking initiation, maintenance of smoking, response to treatment, and relapse. Conflicting evidence exists for sex differences related to physiological, psychological, and behavioral factors. Studies suggest that there are sex differences in nicotine sensitivity, tolerance, and dependence. Women appear to be more dependent on nicotine, have reduced nicotine clearance, and experience greater withdrawal from nicotine. However, other studies suggest that women smoke fewer cigarettes and, while they self-report greater withdrawal symptoms than men, the actual withdrawal profile may be similar. Sex differences have also been found in response to NRT, with women receiving less cessation benefit. However, studies of pharmacological treatments such as bupropion tend to show equivalent results for men and women, perhaps negating the sex difference. At the behavioral level, psychological and social factors such as depression, weight gain concerns, social support, social pressure, self-efficacy, readiness to quit, cue-reactivity, coping styles, and expectancies may all affect initiation to smoking, treatment effectiveness, and relapse. Sex differences have been shown in all of these factors; however, the impact of these differences is not clear. For example, the rate of depression/negative affect is higher in women than men in population studies. While depression/negative affect is correlated with smoking rates, findings are mixed with some studies suggesting a causal role, and others suggesting only association. Weight concerns are also stronger in women than men. While smokers tend to weigh less than nonsmokers and quitting smoking often leads to an average 5-8 pound weight gain, it is not clear how these concerns differentially affect women’s smoking behavior. On the other hand, large population-based surveys have not shown sex differences in the ability to quit smoking and remain abstinent. While some treatment outcome studies have identified sex differences, methodological concerns have obscured the ability to draw firm conclusions. For example, the use of post-hoc analysis, lack of power to identify gender differences, and the lack of analysis of interactions of sex with etbnicity and SES are common methodological shortcomings. Furthermore, treatment outcome studies rely on convenience samples of volunteers and may not be representative of the general population. Over 20 years ago the Surgeon General reported that women may have more difficulty than men giving up smoking (U.S. Department of Health and Human Services, 1980). This controversy has not yet been resolved. Women’s smoking is increasingly a global problem. Increased awareness, funding, and advocacy is needed to reduce the rate of women who are smoking. However, in order to both target women and tailor interventions effectively, more research is needed to understand why women smoke, how to motivate them to quit, and how best to assist their quit attempts and prevent relapse. Finally, cultural differences in women’s smoking behavior, normative patterns and rapidly changing advertising and promotion tactics by the tobacco industry must be incorporated into ongoing and new research.

Concurrent use of tobacco products by California adolescents

Background To describe patterns and correlates of tobacco product use other than cigarettes in adolescents 12–17 years of age. Methods Adolescent respondents ( N = 6090) to the 1999 California Tobacco Survey provided estimates of ever and current use (in last 30 days) of smokeless tobacco, cigars, and bidis, which were examined by cigarette smoking experience, demographics, and known predictors of cigarette use. Results Only 3% of adolescents who never smoked cigarettes experimented with other tobacco products. Among ever smokers who were not current smokers, the rate was 35%. Nearly 60% of current cigarette experimenters had tried another tobacco product, but almost 90% of current established smokers had experimented with one. Over 40% of current established smokers used another tobacco product in the last 30 days. Factors predictive of cigarette smoking were also highly associated with other tobacco use. In ever cigarette smokers, having peers who used other tobacco products was most highly associated with other tobacco use. Problem or risky behaviors, beliefs that cigarettes are safe or beneficial, and receptivity to tobacco promotions were also independently associated with other tobacco product use. Conclusions Adolescent smokers who use other tobacco products may be prone to risky behavior and such use may hasten the development of nicotine tolerance.

Chronic tolerance to nicotine in humans and its relationship to tobacco dependence.

Chronic tolerance to any drug of abuse traditionally has been thought critical to understanding drug dependence. This paper reviews research on chronic pharmacodynamic tolerance to nicotine in humans. An overview of tolerance and a discussion of methodological issues are first presented, followed by examination of cross-sectional comparisons of tolerance between groups differing in smoking history, as well as the few prospective studies of change in tolerance after quitting smoking. The relationship of nicotine tolerance to tobacco dependence is then evaluated. While somewhat modest in size, the literature on chronic tolerance to nicotine in humans is reasonably consistent in showing clear evidence of tolerance to subjective mood effects but little or no tolerance to cardiovascular, performance or other nicotine effects, within the limitations inherent in most human research on tolerance. However, this research also indicates that chronic tolerance to nicotine is not closely associated with tobacco dependence: non-dependent and dependent smokers are equally tolerant; tolerance declines very little even years after quitting; and tolerance before quitting may have no relationship to clinical outcome of a cessation attempt. Recent research from the alcohol and substance abuse fields is consistent with the notion that tolerance has little clinical utility in determining dependence. These results question the relevance of nicotine tolerance to dependence and suggest that research into mechanisms of tolerance, while important for understanding biological adaptation, may not elucidate factors responsible for nicotine dependence. Future research should focus on whether dependence may be related to tolerance or to other, as yet unexamined, effects of nicotine, including conditioned tolerance effects, and on the possibility that tolerance may influence the early onset of dependence in teens even if apparently unrelated to maintenance of dependence in adult smokers.

Tobacco use and baccalaureate nursing students: a study of their attitudes, beliefs and personal behaviours.

To report findings about student nurses' attitudes, beliefs and personal behaviour in relation to tobacco issues. Nurses have the potential to influence clients' behaviours and public policy concerning tobacco use. However, a review of the literature suggests that this is not happening. Further understanding of nursing students' attitudes, beliefs and behaviours regarding tobacco use is needed in order to develop strategies which can positively impact on their future health promotion role. A cross-sectional survey of the total population of baccalaureate nursing students in one Canadian province was employed. Students were asked to complete a self-administered questionnaire, which included questions related to their smoking history; stage of behavioural change, and beliefs and attitudes towards tobacco. Students also completed the Health Promotion Lifestyle Profile (HPLP) and the Fagerström Nicotine Tolerance Scale. Two hundred and seventy-two students (61.9%) responded. Sixty (22.1%) indicated that they smoked daily or in social situations. These smokers were found to have a fairly low level of nicotine dependence and although 91.4% said they wanted to quit, few were actively engaged in the quitting process (16.9%). When comparing the beliefs and attitudes of smoking and non-smoking students, proportionally more of the non-smokers agreed that smokers will need close family/friends to help them quit; that the health of society should be protected by laws against smoking; and that nurses should set a non-smoking example. Non-smokers indicated more health promoting behaviours on items in the HPLP especially on the variables of physical activity, nutrition and stress management. Nurses have the potential to influence clients' behaviours and public policy concerning tobacco use. Developing future nurses with the knowledge and skill to do so needs to be an important emphasis of nursing curricula.

Alkaloid tolerance in Manduca sexta and phylogenetically related sphingids (Lepidoptera: Sphingidae)

Nicotine tolerance is well known for Manduca sexta. It also occurs in several other sphingids of the subfamilies Macroglossinae and Sphinginae. Only members of the subfamily Smerinthinae appear to be more susceptible to nicotine intoxication. Phylogenetic trees have been reconstructed from mitochondrial 16S rDNA and nuclear DNA to map nicotine tolerance.¶The nicotine binding site of both α-subunits of nicotinic acetylcholine receptors (nAChR) have been amplified and sequenced. No apparent amino acid substitution can be seen in the putative nicotine binding site of the α-subunits of nAChR from nicotine tolerant and nicotine sensitive sphingids. Thus, a simple target-site modification can be ruled out as a cause for nicotine tolerance. This finding agrees with feeding experiments: larvae of M. sexta and other sphingids of the Macroglossinae and Sphinginae not only tolerated nicotine, but also many other alkaloids that affect neuroreceptors other than acetylcholine receptors (nAChR, mAChR).¶Only 10 to 20% of nicotine injected into larvae of nicotine-tolerant taxa could be recovered later as free nicotine, nicotine N-oxide or cotinine, i.e., 80 to 90% must have been converted to polar conjugates or degradation products which are not detectable with the methods applied. Usually more than 98% of the recoverable alkaloids were found in the faeces. Excretion reached a maximum 6 h after injection in tolerant taxa. Larvae of Manduca sexta, which were reared on a nicotine-rich diet, showed higher nicotine degradation and faster nicotine elimination than naive larvae. Application of the cytochrome P450 inhibitor SKF 525A (proadifen) reduced the formation of nicotine N-oxide and the rate of alkaloid degradation. Thus, an inducible detoxification mechanism, coupled with a rapid and inducible excretion, appear to be a strategy in Sphingidae that helps them to live on host plants rich in otherwise toxic secondary metabolites.

The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion

The subtypes of nicotinic receptors at which the behavioural effects of nicotine originate are not fully understood. These experiments use mice lacking the β2 subunit of nicotinic receptors to investigate its role in nicotine discrimination and conditioned taste aversion (CTA). Wild-type and mutant mice were trained either in a two-lever nicotine discrimination procedure using a tandem schedule of food reinforcement, or in a counterbalanced two-flavour CTA procedure. Rates of lever-pressing of wild-type and mutant mice did not differ. Wild-type mice acquired discrimination of nicotine (0.4 or 0.8 mg/kg) rapidly and exhibited steep dose–response curves. Mutant mice failed to acquire these nicotine discriminations and exhibited flat dose–response curves. Both wild-type and mutant mice acquired discrimination of nicotine (1.6 mg/kg) although discrimination performance was weak in the mutants. Nicotine initially reduced response rates in wild-type and mutant mice, and tolerance developed to this effect in each genotype. Both genotypes acquired discrimination of morphine (3 mg/kg) with similar degrees of accuracy, and dose–response curves for morphine discrimination in the two genotypes were indistinguishable. Nicotine produced dose-related CTA in both genotypes, but the magnitude of the effect was less in the mutants than in the wild-type controls. It is concluded that nicotinic receptors containing the β2 subunit play a major role in the discriminative stimulus and taste aversion effects of nicotine that may reflect psychological aspects of tobacco dependence. Such receptors appear to have a less crucial role in the response-rate, reducing effects of nicotine and in nicotine tolerance.

Agonists cause endocytosis of nicotinic acetylcholine receptors on cultured myotubes

Regulated trafficking of neurotransmitter receptors in excitable cells may play an important role in synaptic plasticity. In addition, agonist-induced endocytosis of nicotinic acetylcholine receptors (nAChRs) in particular might be involved in nicotine tolerance and addiction. The existing evidence concerning regulated internalization of cell-surface nAChRs is indirect and equivocal, however. In the present study, radioligand binding and fluorescence microscopy were used to show that agonists cause substantial endocytosis of nAChRs on cultured myotubes. Exposure to carbachol or nicotine caused a decrease in the intensity of fluorescent labeling of clusters of cell-surface nAChRs that was blocked by low temperature. Overall, myotubes exposed to carbachol or nicotine bound 50-70% less [(125)I]-alpha-bungarotoxin on the cell surface than untreated cells. The effect of carbachol was significant within 5 min, increased progressively for at least 4 h, and had a sensitivity of 100 nM or less. Exposure to carbachol caused the appearance or dramatic expansion of an intracellular pool of nAChRs, which were localized to discrete, largely perinuclear structures. A pulse-chase labeling protocol allowed the selective labeling and localization of nAChRs that had been internalized from the cell surface. In untreated cells, very little internalization of nAChRs occurred over a period of 3 h, indicating that constitutive endocytosis of receptors over this period was minimal. Exposure to carbachol, however, caused a dramatic increase in the endocytosis of nAChRs. These results provide direct evidence that agonists, including the tobacco alkaloid nicotine, can cause substantial endocytosis of cell-surface nAChRs.

Nicotine withdrawal hyperalgesia and opioid-mediated analgesia depend on nicotine receptors in nucleus accumbens

The nucleus accumbens, as part of the mesolimbic dopaminergic reward pathway, mediates both addiction to and withdrawal from substances of abuse. In addition, activity of substances of abuse such as opioids in the nucleus accumbens has been implicated in pain modulation. Because nucleus accumbens nicotinic receptors are important in nicotine addiction and because nicotinic activity can interact with opioid action, we investigated the contribution of nucleus accumbens nicotinic receptors to opioid-mediated analgesia/antinociception. The response of the nociceptive jaw-opening reflex to opioids was studied in the rat, both before and during chronic nicotine exposure. In nicotine-naive rats, intra-accumbens injection of the nicotinic receptor antagonist mecamylamine blocked antinociception produced by either systemic morphine, intra-accumbens co-administration of a μ- and a δ-opioid receptor agonist, or noxious stimulation (i.e., subdermal capsaicin in the hindpaw); intra-accumbens mecamylamine alone had no effect. The antinociceptive effect of either morphine or noxious stimulation was unchanged during nicotine tolerance; however, intra-accumbens mecamylamine lost its ability to block antinociception produced by either treatment. Intra-accumbens mecamylamine by itself precipitated significant hyperalgesia in nicotine-tolerant rats which could be suppressed by noxious stimulation as well as by morphine. These results indicate that nucleus accumbens nicotinic receptors play an important role in both opioid- and noxious stimulus-induced antinociception in nicotine-naive rats. This role was attenuated in the nicotine-dependent state. The suppression of withdrawal hyperalgesia by noxious stimulation suggests that pain can ameliorate the symptoms of withdrawal, thus suggesting a possible mechanism for pain-seeking behavior.

Nicotine regulates alpha7 nicotinic receptor subunit mRNA: implications for nicotine dependence.

Recent evidence suggests that alpha7 subunit-containing nicotinic receptors (nAChRs) within the ventral tegmental area (VTA) are involved in the processes underlying nicotine tolerance and withdrawal. The current study used in situ hybridization histochemistry with multiple radiolabelled probes to amplify mRNA signal, to examine the distribution of alpha7 nAChR subunit mRNA both in control brains and following chronic nicotine treatment (1.5 and 30.0 mg/kg/day). Low levels of alpha7 transcript were detected within substantia nigra pars compacta (SNpc), substantia nigra pars reticularis (SNpr) and VTA. Higher levels of alpha7 transcript were found within the cortex and hippocampus. Following chronic nicotine treatment, levels of alpha7 subunit mRNA were significantly elevated in SNpc, SNpr and VTA, but were unchanged in cortex and hippocampus.

Tolerance to repeated nicotine administration on performance, subjective, and physiological responses in nonsmokers.

When administered acutely to nonsmokers, nicotine's effects on performance are inconsistent, perhaps because of suboptimal dosing or initial dysphoria that could interfere with performance. The purpose of this study was to determine if a range of nicotine doses administered for 8 days to nonsmokers would enhance psychomotor and cognitive abilities and to document the development of nicotine tolerance or sensitization. Twelve male volunteers, who reported ever smoking five cigarettes or less, participated in 8 consecutive experimental days in which they were administered four doses of nicotine polacrilex gum each day in this order: 0, 2, 4, and 8 mg. Performance, subjective, and physiological measures were assessed before and after each dose. Plasma nicotine concentration ranged from 6.9 to 11.5 ng/ml following the 8 mg dose. Nicotine increased rate of responding and decreased response time on working memory (digit recall); however, accuracy was impaired. Nicotine also decreased accuracy on visual scanning and attention (two-letter search), and the 8 mg dose impaired gross motor coordination (circular lights). Tolerance did not develop to the performance impairing effects of nicotine. Nicotine produced dose-related increases in ratings of dysphoria and negative mood, including tension, anxiety, nervousness, turning of stomach, and sedation. Tolerance developed to some, but not all, of these aversive effects. Tolerance also was not observed to the increased cardiovascular measures. Although tolerance developed to some of the aversive effects of nicotine, performance enhancement was not observed. These data do not support the hypothesis that nicotine-induced performance enhancement contributes to the reinforcing effects of tobacco use during the early stages of dependence development.

Late adolescent female smoking.

Although there have been intense efforts to reduce the prevalence of cigarette smoking in the past three decades, smoking continues to be a critical public health problem. An area of particular concern is the increasing number of young women who are smoking. Gender specific research usually does not examine factors affecting smoking behaviours. Information on late adolescent female smoking is not readily found in the literature. The aims of this study were to explore the smoking patterns and processes of late adolescent females and to explore factors which may or may not be helpful in assisting them to stop smoking. A qualitative ethnographic approach was used to uncover the perceptions of 25 adolescent girls of their behaviour. Data were collected using tape-recorded semi-structured interviews and a questionnaire. Items for the questionnaire were derived from the Manitoba Youth Smoking Survey and from the Fagerstrorn Nicotine Tolerance Scale. Qualitative analysis resulted in four stories about smoking: the start story, the smoking story, the quit story, and the looking to the future story. Although many of the findings are congruent with the existing literature, much of the data reflected the purposive nature of smoking in late adolescent girls. Study findings support the need for holistic approaches to health promotion to ameliorate factors affecting smoking behaviour.

Smoking behaviour and compensation: a review of the literature.

Compensation or compensatory smoking, accurately defined, deals with the question of whether switching to cigarette brands with different smoke yields is associated with a change in smoke uptake proportional to the change in machine-derived yields. The issue of compensation is important because it bears on whether switching to "lighter" brands means lower overall smoke intake or not. The present review investigated whether and to what extend low yield cigarettes are smoked more intensively. In addition, published data on whether nicotine, "tar", or any other smoke constituent or property influence compensational smoking are summarized. The studies on compensation were classified as follows: (1) studies on smoking behaviour in relation to cigarette yields (with and without brand switching); (2) studies on compensation for nicotine (switching between cigarettes which differ "only" in their nicotine yield, nicotine supplementation, manipulation of renal nicotine excretion, administration of nicotine agonists or antagonists); (3) studies on compensation for other factors (influence of tar, taste, irritation, draw resistance). In order to quantify the degree of compensation, an index is defined and applied to selected brand switching studies. This compensation index determines, in relative units, the degree to which a smoker responds to a change in smoke yields with a change in smoke uptake measured by suitable biomarkers. The role of vent blocking is also briefly discussed. Most of the studies which compare the smoking behaviour when smoking cigarettes with different smoke yields supply evidence for "partial" compensation, suggesting that cigarettes with lower yields are smoked more intensively than those with higher yields. These studies also show that a change in the daily number of cigarettes is not a common mechanism of compensation. Effective vent blocking during smoking is a rare event and can therefore also be regarded as an uncommon mechanism of compensation. Evaluation of a suitable subset of brand-switching studies revealed an average compensation of 50-60% of the nicotine yield. Compensation tended to be more complete when changing to cigarettes with higher yields than when changing to cigarettes with lower yields. In general, brand-switching studies do not supply information on the underlying causal factors responsible for compensatory smoking. Results of the nicotine supplementation studies are not conclusive: some report evidence of nicotine titration, others do not. A general problem with this type of investigation is that continuous nicotine application does not mimic the spike-wise application with cigarette smoking, and may lead to nicotine tolerance. There is limited evidence that cigarettes were smoked more intensively when the urinary clearance of nicotine was increased. A small number of studies provide some evidence that smoking intensity increased after smokers were administered a nicotine antagonist. Several reports indicate that tar, taste and sensory properties of the smoke as well as the draw resistance of the cigarette may play a role in compensatory smoking. Low-yield cigarettes usually have reduced pressure drops which smoke researchers have suggested leads to increased puff volume. This effect seems to be independent of the smoke yield of the cigarette. There is also some evidence that some smokers maintain a consistent pattern of smoking which works independent of any changes in nicotine or tar yields, taste or design features of the cigarette ("functional autonomy"). The available data suggest that smokers partially compensate for a different smoke yield. While the factors and their interaction responsible for compensational smoking are not fully understood, there are data suggesting that a subgroup of smokers may partially compensate for nicotine. Even in this subgroup of smokers, however, the relative importance of the pharmacological versus

Behavioral factors predicting serum cotinine concentrations of male smokers in a Japanese community.

Cigarette-derived toxic substances are inhaled along with the nicotine that is absorbed to satisfy the smoker's physical demand. Therefore, serum cotinine, a metabolite of nicotine, may be considered to be an indirect marker of absorption of the other toxic substances from smoking. However, few studies have examined factors related to serum cotinine concentrations in natural settings. The authors, therefore, have studied relations among patterns of smoking behavior and serum cotinine concentrations of community residents. Subjects were 60 smoking men living in the town of Yamasaki, Hyogo Prefecture, Japan. Number of daily cigarettes, depth of inhalation, hours from the last cigarette smoked and the total nicotine tolerance score were significantly, while neither nicotine-yields nor butt length of a discarded cigarette was correlated with serum cotinine concentrations. Multiple regression analysis confirmed that depth of inhalation and hours from the last cigarette smoked were independently significant. This finding suggests that attention only to self-reported daily number of cigarettes smoked may not be sufficient to detect smokers who are actually at high risk. Healthcare workers should also pay attention to smokers' patterns of smoking, particularly depth of inhalation.

Altered behavioral sensitivity of Ca 2+-modulating drugs after chronic nicotine administration in mice

Numerous studies have demonstrated that tolerance develops to the physiological and behavioral effects of nicotine in animals after chronic administration of the drug. However, the mechanisms underlying tolerance to nicotine are not well known. There are several lines of evidence which support a role for Ca 2+ in nicotine's acute pharmacological effects. The objective of the study was to determine whether Ca 2+ plays a role in the development of tolerance to nicotine by investigating the behavioral activity of several Ca 2+ modulating drugs after systemic (BAY K 8644: (±)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester) and intrathecal administration (BAY K 8644, Ca 2+ and thapsigargin) in nicotine-tolerant mice. The ability of BAY K 8644 to induce motor impairment and hypomotility after i.p. injection was decreased in nicotine-tolerant mice. In addition, tolerance to Ca 2+, thapsigargin, and BAY K 8644-induced antinociception after i.t. injection also developed in nicotine-tolerant mice. ED 50 values for BAY K 8644 and thapsigargin increased from 3.7 to 12 μg/mouse and 0.83 to 19.7 μg/mouse, respectively. The greatest tolerance developed to the effects of thapsigargin with an ED 50 value that increased from 0.83 to 20 μg. Furthermore, chronic nicotine injections did not alter [ 3H]nitrendipine binding in the brain. These results suggest the involvement of Ca 2+-dependent mechanisms in nicotine tolerance in mice. © 1997 Elsevier Science B.V. All rights reserved.

Influence of smoking and cessation of smoking on neuromuscular effects of atracurium

Smokers are more sensitive to atracurium than non-smokers [1]. During chronic exposure to nicotine tolerance develops and abstinence results in a with-drawal syndrome [2]. Therefore we studied how smoking and cessation of smoking influence the neuromuscular blockade (NMB) induced by atracurium. Following ethical committee approval and informed patient consent 26 healthy patients were studied. Group CONTR did not smoke at all. The smokers were divided into two groups: Group ABST did not smoke during the operation day and group SMOKE was allowed to smoke liberally before anaesthesia. The abstinence time was recorded. Anaesthesia was induced with thiopentone 5 mg kg−1 and fentanyl 2 μg kg−1. Supramaximal train-of-four stimuli were applied to the ulnar nerve at the wrist at 20 s intervals to monitor the EMG response of the first interosseus muscle of the hand. Atracurium 0.5 mg kg−1 was administered immediately after calibration of the Relaxograph® (integrated evoked compound action potential). Normothermia and normocapnia were maintained. Onset time to 90% block, maximal NMB, duration of clinical NMB, and the duration time of consecutive 0.1 mg kg−1 doses of atracurium were recorded. ANOVA and Student's t-test were used to compare data between groups. P<0.05 was considered significant. Data expressed as mean (SD) are shown in Table 12.Table 12: (abstract 45). Influence of smoking on neuromuscular block

Nicotine tolerance in chromaffin cell cultures: acute and chronic exposure to smoking-related nicotine doses.

Nicotine tolerance and dependence are key aspects of tobacco addiction; however, the cellular mechanisms underlying these phenomena are poorly understood. Adrenal chromaffin cells release catecholamines upon exposure to nicotine and with repeated exposure this response exhibits nicotine tolerance. Using bovine adrenal chromaffin cells in culture, we have demonstrated acute and chronic nicotine tolerance at doses relevant to that in the blood and tissues of smokers (10(-7) M to 10(-6) M). Chromaffin cells are preexposed to low doses of nicotine for time periods ranging from 10 min to 7 days and then subsequently challenged with a maximally stimulating dose of nicotine (10(-5) M) for 10 min, all at 37 degrees C. Preexposure to nicotine results in a depression of 45Ca uptake and catecholamine release upon subsequent nicotine challenge. Acute tolerance or desensitization of nicotine-stimulated catecholamine release begins to occur in minutes after preexposure to 10(-6) M nicotine at 37 degrees C. The depression of catecholamine release upon preexposure to nicotine is both dose and temperature dependent and is not seen with potassium-evoked release. Chronic exposure to 10(-7) M nicotine for 3 days led to a depression of the secretory response to approximately 70% of control responses. There was a trend toward recovery of full response by days 5 and 7 of 10(-7) M nicotine preexposure. Nearly complete depression of the nicotine-evoked release occurs within the first day of exposure to 10(-6) M nicotine and persists for at least a week of nicotine exposure at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)