Dissociation of nicotine tolerance from tobacco dependence in humans.

Chronic functional tolerance to nicotine generally is believed to be associated with processes responsible for tobacco dependence. The dose-related effects of nicotine (0-20 microg/kg by nasal spray) on subjective, cardiovascular, and performance responses were compared among four groups varying in current or past dependence: dependent smokers (21 cigarettes per day for 20 years; n = 45), nondependent smokers (three cigarettes per day for 14 years; n = 12), former dependent smokers (mean of 7 years quit after smoking 25 cigarettes per day for 19 years; n = 17), and life-long nonsmokers (n = 19). Chronic tolerance was determined by a shift to the right, or flattening, of the dose-response curve relative to the curve for nonsmokers. Responses were corrected for plasma nicotine concentration to rule out dispositional tolerance. Chronic tolerance was observed for most subjective responses, but little or none for cardiovascular and performance effects. Tolerance was substantial and virtually identical between dependent and nondependent smokers, whereas tolerance of former smokers was intermediate between nonsmokers and dependent smokers. Identical chronic tolerance between dependent and nondependent smokers indicates that tolerance is not a linear function of smoking exposure and does not require presence of dependence. Thus, the wide variability in daily smoking rate among smokers cannot be attributed to differences in tolerance and must involve other processes of adaptation to nicotine. The modest reversal of tolerance in long-time former smokers suggests that such tolerance reversal is either limited or extremely slow after extended abstinence, despite loss of dependence. These results suggest there is no close link between nicotine tolerance and dependence and question the utility of tolerance as one of the criteria for defining dependence.

Greater sensitivity to subjective effects of nicotine in nonsmokers high in sensation seeking.

The personality characteristic of sensation seeking is associated with risk of smoking, perhaps because of greater initial sensitivity to nicotine. Young healthy nonsmokers (N = 37) were administered 0, 10, and 20 microg/kg nicotine by nasal spray in 3 separate sessions, and subjective responses were assessed. Sensation-Seeking Scale (SSS) scores were then correlated with these responses. A comparison group of smokers (N = 55) was included to determine whether sensation seeking was associated specifically with initial sensitivity to nicotine or with general sensitivity regardless of past nicotine exposure. SSS subscales, particularly Experience Seeking and Disinhibition, were correlated with subjective responses to nicotine in nonsmokers but generally not in smokers. These findings indicate that sensation seeking is associated with greater initial sensitivity to nicotine's subjective effects and may provide directions for further study of individual-differences characteristics that predispose people to the risk of becoming smokers.

Sex differences in the acute effects of cigarette smoking on the reinforcing value of alcohol.

Alcohol consumption acutely increases smoking behavior, but the reverse relationship, the acute effects of smoking on alcohol intake, largely has been ignored. We examined whether smoking acutely increases the reinforcing value of alcohol, first in the absence of recent alcohol intake and then following an alcohol pre-load. Healthy, social-drinking smokers (n = 11 men, 14 women) engaged in a computerized task involving concurrent schedules of reinforcement for beer (FR10, 3 oz (90 ml) per reinforcement) or money (FR5 to FR30, $0.20 per reinforcement) during two sessions, one following day-long ad lib smoking and the other following overnight smoking abstinence. During each session, subjects performed the task in two sets of trials, one before and one after consumption of an alcohol pre-load, with 60 min between sets. To standardize the alcohol pre-load, all subjects were led to believe that they had earned 9 oz (270 ml) of beer after the first trial set, which they then consumed before the second set of trials. Compared to responding during the abstinent session, responding for alcohol during the smoking session was no different before the alcohol pre-load (trial set one) but was significantly greater following the alcohol pre-load (trial set two), although only in men and not women. Subjective sedation after the alcohol pre-load was attenuated during the smoking session in both men and women, but attenuated sedation due to smoking was related to subsequent alcohol-reinforced responding only in men. Additional research is needed to determine the extent to which these effects in men are pharmacological in nature or are conditioned responses to smoking or to consuming a preferred alcoholic beverage.

Importance of environmental distractors in the effects of nicotine on short-term memory.

This study examined the role of environmental context in mediating the effects of nicotine on short-term memory performance (i.e., working memory). Male and female smokers (n = 12, overnight tobacco abstinent) and nonsmokers (n = 11) were administered nicotine (20 ug/kg) and a placebo (0 ug/kg) by means of a measured-dose nasal spray procedure on separate days. Participants were tested on a variant of S. Sternberg's (1966) memory search task. Half of the memory task sets involved the presentation of an auditory environmental distraction. Improvements in short-term memory performance with nicotine were primarily seen in smokers and in the presence of the distracting stimuli. These results suggest that environmental conditions, such as the presence of a distracting stimulus, may play an important role in mediating the effects of nicotine.

Acute reinforcing effects of low-dose nicotine nasal spray in humans.

Tobacco smoking behavior is reinforced by nicotine intake, but there has been little human research examining self-administration of nicotine per se, isolated from tobacco. In this study, 10 smokers (5 men, 5 women) who wanted to quit smoking sampled 0 (placebo), 0.75, and 1.5 ug/kg/spray nicotine via nasal spray during separate lab sessions before engaging in a free choice session, involving ad lib access to all three spray doses. Subjects also ad lib smoked during another session. For the group as a whole, neither nicotine spray dose was self-administered significantly more than placebo during the free choice session, suggesting low abuse potential. However, 4 of 10 subjects self-administered 1.5 ug/kg/spray on more than 50% of all sprays (vs. 33% chance) and were designated nicotine "choosers," while the others were "nonchoosers." Choosers responded to initial nicotine spray exposure during sampling sessions with greater positive subjective effects (similar to their responses to tobacco smoking), smoked more during the ad lib smoking session (i.e., self-administered more nicotine via tobacco smoking), and tended to be more heavily dependent smokers. They did not report greater withdrawal relief or less aversive effects from nicotine, suggesting their greater nicotine choice reflected greater positive reinforcement rather than negative reinforcement. These results are consistent with the few existing studies demonstrating that acute nicotine intake per se, in the absence of tobacco, may be reinforcing in some smokers.

Nicotine preference in smokers as a function of smoking abstinence.

Overnight smoking abstinence increases desire to smoke and intensity of smoking behavior in smokers, but it is not completely clear that this reflects an increase in reinforcement from the psychoactive effects of nicotine per se. We examined choice of nicotine vs. placebo via nasal spray (Study 1) and nicotine vs. nonnicotine cigarette puffs (Study 2) in separate groups of smokers during each of two sessions, following overnight abstinence vs. no abstinence. In each study, subjects followed a forced choice procedure in which they were instructed to self-administer six sprays/puffs from between the two nasal sprays/cigarettes every 15 min for 2 h following initial exposure to each. In Study 1, choice of nicotine spray (1.5 micrograms/kg per spray) increased significantly following abstinence vs. no abstinence (47 +/- 6% vs. 34 +/- 5%, respectively, p < 0.05). This shift in choice was more pronounced in the subset of smokers (choosers, n = 9 out of 24) who selected nicotine on more than 50% of choices on the abstinent day. Choosers exhibited greater responses to initial nicotine exposure on positive (e.g., pleasant, vigor) but not aversive (e.g., jittery, uneasy) subjective measures, suggesting that greater positive reinforcement from nicotine per se predicted subsequent choice. In Study 2, abstinence similarly increased choice of nicotine vs. nonnicotine cigarette puffs (82 +/- 6% vs. 64 +/- 8%, p < 0.05), although nearly all subjects (12 of 13) preferred the nicotine cigarette following abstinence. These results indicate that choice of nicotine per se, isolated from tobacco smoke, increases significantly after overnight tobacco abstinence.

Influence of training dose on nicotine discrimination in humans.

Non-human research indicates that drug discrimination results may depend largely on the specific training conditions, including initial training dose. It has recently been shown that humans can discriminate among different doses of nicotine delivered by nasal spray. In this study, we examined the influence of training dose on subsequent behavioral discrimination of a range of nicotine doses. Male (n = 17) and female smokers (n = 16) were randomly assigned to "low" (10 micrograms/kg) versus "high" (30 micrograms/kg) nicotine training dose groups and trained reliably to discriminate this dose from placebo (0) on day 1 (> or = 80% correct identification). All but six subjects (four in low, two in high) learned this discrimination and continued on to day 2, in which both groups received 0, 5, 10, 20, and 30 micrograms/kg in ascending order (30 min between dosings) and were tested for generalization with their training dose using quantal and quantitative behavioral discrimination tasks. Subjective responses via traditional self-report measures were also assessed. Nicotine-appropriate responding on day 2 was significantly greater in low- versus high-dose groups, especially at 5 micrograms/kg. However, this difference due to training dose was seen more in women than in men. Discrimination behavior was associated with subjective effects of head rush in males, and with head rush and decline in urge to smoke in females. These results show that discriminative stimulus effects of nicotine are not fixed properties of the drug, but can be influenced by training conditions, and that effects associated with this discrimination may differ between men and women.

Subjective and cardiovascular responses to nicotine combined with alcohol in male and female smokers.

Nicotine and alcohol are often consumed concurrently by smokers. Each drug alone produces significant subjective and cardiovascular responses, but the effects of the two drugs in combination have rarely been examined. Smokers who were moderate alcohol drinkers (n = 18, 9 males and 9 females) participated in four sessions, involving acute administration of nicotine/placebo and alcohol/no alcohol. Subjects abstained overnight from tobacco and alcohol prior to each session. Nicotine (20 micrograms/kg per presentation) or placebo was administered by measured-dose nasal spray every 30 min for 2 h following consumption of diet tonic water with or without alcohol (0.5 g/kg). Subjective (visual analog scales, Profile of Mood States, Addiction Research Center Inventory) and cardiovascular (heart rate, systolic and diastolic blood pressure) responses were assessed after each nicotine/placebo administration. Nicotine increased head rush, dizzy, and most stimulant effects (i.e. jittery, tension, and arousal and decreased fatigue and relaxed), while alcohol increased intoxication, head rush, dizzy, and jittery, with no other stimulant effects. Nicotine and alcohol generally produced additive subjective and cardiovascular effects when consumed together, although nicotine attenuated sedating and intoxicating effects of alcohol alone. Furthermore, there were several interaction effects on subjective measures involving gender. Nicotine plus alcohol tended to attenuate some subjective effects due to one drug or the other alone in men but enhanced the effects of either alone in women. These findings indicate that nicotine and alcohol generally have additive subjective and cardiovascular effects, but that men and women differentially respond on some subjective measures to the combination of alcohol and nicotine.

Gender, dietary restraint, and smoking's influence on hunger and the reinforcing value of food.

Smoking may enhance satiety following meal consumption, thereby reducing subsequent eating (i.e., between-meal snacks), especially in women high in dietary restraint. Female smokers (n = 20, 10 high and 10 low restraint) and male smokers (n = 10) participated in two sessions, involving overnight abstinence from food and smoking (smoking abstinence day) or from food only (smoking day), in a within-subjects design. The reinforcing value of food was determined by the number of responses made to obtain food reinforcers (100-kcal snack portions) vs. money using a concurrent schedules computer task. Subjects were given a small caloric load on each day followed by access to food vs. money. On the smoking day, subjects were allowed to smoke every 30 min during the session as well as ad lib before the session. Self-reported hunger was also assessed upon arrival (after fasting) and following the caloric load during each session. Results indicated no effect of smoking on initial hunger rating, after fasting, but hunger ratings following the caloric load declined significantly more during smoking vs. abstinence days for all subjects, consistent with an enhancement of postmeal satiety due to smoking. There was no overall main effect of smoking on food-reinforced responding. However, responding for food was significantly less during the smoking vs. abstinence days for high-restraint females only and not for low-restraint females or for males. These findings indicate that smoking's acute influence on reducing food intake does not reflect a broad gender difference but may be specific to dietary restraint.

Acute tolerance to nicotine in smokers: lack of dissipation within 2 hours.

Greater understanding of development and dissipation of acute tolerance to nicotine may help explain temporal patterns of nicotine self-administration in smokers. The time course of dissipation of acute tolerance to nicotine was examined in 16 smokers (8M, 8F) participating in four sessions differing on pretreatment exposure or time interval prior to nicotine (20 micrograms/kg) challenge: placebo 30 min before, or nicotine (20 micrograms/kg) 30, 60, or 120 min before challenge. Nicotine and placebo were administered by measured-dose nasal spray. The measurement battery consisted of subjective, cardiovascular, thermal pain detection, and behavioral performance measures. Results demonstrated significant acute tolerance (i.e. smaller responses to nicotine challenge following nicotine versus placebo pretreatment) for most subjective measures and for heart rate. Acute tolerance dissipated with lengthening inter-dose interval for two subjective measures, dose strength and arousal, but there was no tolerance dissipation for other measures. In contrast, nicotine pretreatment resulted in acute sensitization of finger temperature (vasoconstriction) response, which dissipated with lengthening interval. No acute tolerance was observed for thermal pain detection or performance measures. These findings demonstrate that acute tolerance develops quickly to some subjective and cardiovascular effects of nicotine. However, acute tolerance to most effects did not dissipate over 2 h, suggesting that, following acute tolerance development during initial exposure, most smokers generally obtain similar magnitude of effects from each subsequent nicotine exposure (i.e. cigarettes smoked later in the day).

Nicotine discrimination in male and female smokers.

Discriminative stimulus effects of nicotine were evaluated in humans using formal behavioral drug discrimination procedures. Male and female smokers (n = 9 each) were trained on day 1 to reliably discriminate 0 versus 12 micrograms/kg nicotine administered by measured-dose nasal spray. All subjects were able to reach criterion performance (at least 80% correct). Generalization of responding across nicotine doses of 0, 2, 4, 8, and 12 micrograms/kg (approximately 0-0.8 mg for typical subject) was then examined on day 2. Nicotine-appropriate responding was linearly related to dose, and subjects were able to distinguish the smallest dose (2 micrograms/kg) from placebo. Although there were no differences between males and females in behavioral discrimination, subjective effects were correlated with nicotine discrimination in females but not in males. These findings indicate that humans are able to discriminate among low doses of nicotine per se, that males and females may differ in the stimuli used to discriminate nicotine, and that drug discrimination procedures may be more sensitive than traditional subjective effects measures in distinguishing among low doses of nicotine.

Chronic and acute tolerance to subjective, behavioral and cardiovascular effects of nicotine in humans.

Understanding tolerance to effects of nicotine in humans may elucidate processes involved in the onset and maintenance of tobacco dependence. Subjective, behavioral and cardiovascular responses to nicotine were examined as a function of past history of nicotine exposure (i.e., smokers vs. nonsmokers, chronic tolerance) and of immediately preceding nicotine exposure (acute tolerance). Dose-effect relationships between nicotine (0-2 micrograms/kg via measured-dose nasal spray) and each response were determined in male and female smokers (n = 17) and nonsmokers (n = 18), with different doses presented on different days. Each day, subjects also received a challenge dose of 20 micrograms/kg 30 min after the previous dosing to assess acute tolerance. Plasma nicotine concentrations were 30% lower in nonsmokers compared with smokers and analyses were adjusted to control for this difference. Results showed significant changes in nearly all responses as a function of nicotine dose. Dose-effect curves were shifted to the right or dampened in smokers relative to nonsmokers for most subjective and some behavioral responses, consistent with chronic tolerance, but there was less evidence of chronic tolerance to other behavioral effects or to cardiovascular responses. A pattern of acute tolerance generally similar to that of chronic tolerance was observed across response domains (i.e., clear acute tolerance to subjective measures but less to behavioral or cardiovascular effects). These results support the notions that regular use of nicotine is associated with chronic functional tolerance and that repeated nicotine exposure during a single episode produces acute tolerance. A similar pattern of chronic vs. acute tolerance suggests similarity of mechanisms responsible for both "types" of tolerance. However, variability in tolerance magnitude across subjective, behavioral and cardiovascular response domains indicates that different mechanisms may be responsible for these different effects of nicotine.

Comparison of acute subjective and heart rate effects of nicotine intake via tobacco smoking versus nasal spray.

Nicotine is the primary psychoactive constituent of tobacco smoke, but it is not clear whether the reinforcing effects of cigarette smoking can be attributed solely to nicotine intake. In this study, two groups of male and female smokers participated in three sessions involving intermittent exposure to moderate low, or no nicotine doses via controlled tobacco smoking ("smoke," n = 20) or measured-dose nasal spray ("spray," n = 16). Visual analog scales of subjective effects (VAS) and heart rate (HR) were obtained within 5 min of each dosing. Plasma nicotine levels indicated comparable dosing between methods. For both methods, there were significant nicotine dose effects for most subjective measures and HR. More importantly, the pattern of effects across doses was virtually identical between methods, as nicotine intake via smoking or spray significantly increased HR and the VAS scales of Head Rush and Dizzy, decreased Hunger and Desire to Smoke, and had no effect on Comfortable, Jittery, or Relaxed. These results suggest that rapid nicotine uptake by novel methods may provide effects very similar to nicotine intake by smoking.

Chronic and acute tolerance to subjective effects of nicotine.

Tolerance to subjective effects of nicotine may induce novice smokers to increase the magnitude and frequency of their nicotine self-dosing. In this study, smokers (n = 8) and nonsmokers (n = 7) participated in three sessions involving presentation of 0, 7.5, or 15 micrograms/kg nicotine 30 min for 2 h via measured-dose nasal spray, with different doses presented on separate days. Subjective responses were assessed using visual analog scales (VASs) of jittery, light-headed, relaxed, dizzy, and head rush, and the Profile of Mood States (POMS) scales of vigor, confusion, fatigue, tension, and the composite scale of arousal. Smaller responses in smokers vs. nonsmokers were viewed as evidence for chronic tolerance. In addition, on each day subjects received a fifth, challenge dose of 30 micrograms/kg 30 min after the previous dosing. Smaller responses to the challenge dose as a function of increasing prior nicotine dosing during Trials 1-4 were viewed as evidence for acute tolerance. Results showed significant changes in most measures as a function of nicotine dose, and the dose-response curves for most VAS and POMS scales tended to be shifted to the right, or dampened, in smokers relative to nonsmokers, consistent with chronic tolerance. However, smokers and nonsmokers tended to respond to nicotine in opposite directions for POMS scales of vigor and arousal, perhaps reflecting withdrawal relief in smokers. Acute tolerance on a few selected VAS and POMS scales was apparent for both smokers and nonsmokers.(ABSTRACT TRUNCATED AT 250 WORDS)

Nasal spray nicotine replacement suppresses cigarette smoking desire and behavior.

The effects of short-term nasal spray nicotine replacement in suppressing desire to smoke and ad libitum cigarette smoking behavior were evaluated in male and female smokers. In study I, 10 male and 10 female smokers received intermittent doses of 0, 7.5, 15, and 30 micrograms/kg nicotine by way of measured-dose nasal spray, with each dose on a separate day. Self-reported desire to smoke was significantly suppressed by each nicotine dose compared with placebo, but there were no significant differences among nicotine doses or between men and women. In study II, eight male and eight female smokers received 0, 15, and 30 micrograms/kg nicotine intermittently and were allowed to smoke their preferred brands of cigarettes ad libitum. Similar to study I, nicotine replacement significantly suppressed number of cigarettes smoked, number of puffs, and carbon monoxide boost and increased latency to smoking, but there were almost no significant differences between the two nicotine doses. Magnitude of smoking suppression attributable to 15 micrograms/kg tended to be greater in men than in women. However, plasma nicotine concentrations were significantly higher after 15 and 30 micrograms/kg versus placebo, suggesting only partial compensation in smoking behavior with short-term nasal nicotine replacement. These findings support the idea that short-term nicotine replacement decreases smoking desire and behavior, but the findings indicate that smoking behavior is partly influenced by factors other than nicotine regulation.

Increased desire to smoke during acute stress.

Conditions which promote smoking urges, or desire to smoke, are believed to be important in maintaining smoking behaviour, yet little controlled research has examined acute situational factors which increase desire to smoke. In this study, 16 male and 16 female smokers either smoked or sham-smoked with an unlit cigarette after brief abstinence during two sessions, one involving a stressful computer task and the other a non-stress task. Desire to smoke was greater during the stress vs. non-stress task for sham-smokers (p less than 0.01). Furthermore, although smoking desire decreased markedly after smoking in the smoking smokers (p less than 0.001), even this group tended to report greater desire to smoke during stress (p less than 0.10). There were no differences between males and females. These findings indicate that exposure to stressors increases desire to smoke, and suggest that such situations may be influential in maintaining smoking behaviour in smokers not attempting to quit.

"Paradoxical" effects of smoking on subjective stress versus cardiovascular arousal in males and females.

Cigarette smoking has sometimes been found to decrease subjective stress while simultaneously increasing cardiovascular arousal, contrasting effects referred to as the "nicotine paradox." The present study assessed acute effects of cigarette smoking on subjective stress vs. cardiovascular arousal in minimally deprived male and female smokers who smoked (n = 16) or sham smoked (unlit cigarette, n = 15) and a comparison group of male and female nonsmokers (n = 12) who sham smoked only. All subjects participated in two sessions (high- or low-challenge computer task) in which they smoked or sham smoked prior to each of two 20-min task trials. Results showed reduced subjective stress in smoking smokers compared with sham-smoking smokers during the high- but not low-challenge task. However, this stress reduction occurred only immediately after smoking and dissipated midway through each trial. In males, smoking appeared to reduce stress below that of nonsmokers, while smoking in females attenuated stress only partially to the level of nonsmokers. In contrast with the attenuated stress effects, cardiovascular arousal (especially heart rate) was increased immediately after smoking during both tasks and did not appear to be directly related to subjective changes. These findings suggest that the stress-reducing effects of smoking may be transient, situationally specific, partly gender dependent, and dissociated from the effects of smoking on cardiovascular arousal.

Effects of nicotine on subjective arousal may be dependent on baseline subjective state.

The often disparate and contrasting effects of nicotine on subjective arousal in smokers may be due in part to differences in presmoking subjective state. In Study 1, on each of 2 days, 10 male smokers were divided into high- and low-baseline subgroups on the basis of median split of resting predrug baseline subjective arousal. Then, subjects received intermittent nicotine (15 mu/kg) or placebo via measured-dose nasal spray, with drug conditions counterbalanced between days. In Study 2, 32 male and female smokers were similarly divided into high- and low-baseline subgroups on subjective arousal prior to either smoking or sham-smoking (n = 16 each) during a single session. Results were virtually identical between studies in showing that subjective arousal responses to nicotine (Study 1) or smoking (Study 2) were significantly inversely related to baseline arousal level; those initially low in arousal showed large increases following nicotine or smoking whereas those high in arousal showed little change. No such baseline dependency of responses was seen following placebo or sham smoking. Baseline dependency of cardiovascular responses to nicotine or smoking was also evaluated in similar fashion to determine generalizability of these effects to nonsubjective responses. In each study, systolic blood pressure response was related to baseline level but there was no effect of baseline level on heart rate and diastolic blood pressure responses. Implications of these results for explaining differential rewarding effects of smoking are discussed.