Kenneth A. Perkins

Guidelines on nicotine dose selection for in vivo research

RationaleThis review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure.ObjectivesThis review capitalizes on the authors’ collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models.ResultsSeven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses.ConclusionsThe selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose–response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

Cue dependency of nicotine self-administration and smoking

A paradox exists regarding the reinforcing properties of nicotine. The abuse liability associated with smoking equals or exceeds that of other addictive drugs, yet the euphoric, reinforcing and other psychological effects of nicotine, compared to these other drugs, are more subtle, are manifest under more restricted conditions, and do not readily predict the difficulty most smokers experience in achieving abstinence. One possible resolution to this apparent inconsistency is that environmental cues associated with drug delivery become conditioned reinforcers and take on powerful incentive properties that are critically important for sustaining smoking in humans and nicotine self-administration in animals. We tested this hypothesis by using a widely employed self-administration paradigm in which rats press a lever at high rates for 1 h/day to obtain intravenous infusions of nicotine that are paired with two types of visual stimuli: a chamber light that when turned on signals drug availability and a 1-s cue light that signals drug delivery. We show that these visual cues are at least as important as nicotine in sustaining a high rate of responding once self-administration has been established, in the degree to which withdrawing nicotine extinguishes the behavior, and in the reinstatement of lever pressing after extinction. Additional studies demonstrated that the importance of these cues was manifest under both fixed ratio and progressive ratio (PR) schedules of reinforcement. The possibility that nicotine-paired cues are as important as nicotine in smoking behavior should refocus our attention on the psychology and neurobiology of conditioned reinforcers in order to stimulate the development of more effective treatment programs for smoking cessation.

Time to First Cigarette in the Morning as an Index of Ability to Quit Smoking: Implications for Nicotine Dependence

An inability to maintain abstinence is a key indicator of tobacco dependence. Unfortunately, little evidence exists regarding the ability of the major tobacco dependence measures to predict smoking cessation outcome. This paper used data from four placebo-controlled smoking cessation trials and one international epidemiological study to determine relations between cessation success and the Fagerström Test for Nicotine Dependence (FTND), the Heaviness of Smoking Index, the Nicotine Dependence Syndrome Scale, and the Wisconsin Inventory of Smoking Dependence Motives. Results showed that much of the predictive validity of the FTND could be attributed to its first item, time to first cigarette in the morning, and this item had greater validity than any other single measure. Thus the time-to-first-cigarette item appears to tap a pattern of heavy, uninterrupted, and automatic smoking and may be a good single-item measure of nicotine dependence.

Sex differences in nicotine effects and self-administration: review of human and animal evidence.

Although both the human and animal literatures are notable for the general lack of attention paid to possible sex differences in drug self-administration behavior, evidence is accumulating to suggest that males and females may differ in factors that maintain tobacco smoking or nicotine self-administration. Self-administration of nicotine per se may be less robust in women, and women are less sensitive than men to some effects of nicotine that may be reinforcing. Compared to men, smoking behavior of women may be influenced more by non-nicotine stimuli associated with smoking, suggesting greater conditioned reinforcement of smoking in women. Moreover, nicotine replacement, the current standard treatment for smoking cessation, is sometimes less effective in women, further suggesting the need for greater consideration of non-nicotine factors that may maintain womens smoking. Very recent research on rats also indicates sex differences in nicotine self-administration. However, these differences are complex and suggest that nicotine-seeking behavior is composed of several components, including hedonic, incentive-motivational, and conditioning effects; males and females may differ in one or more of these components. Menstrual or estrous cycle phase effects on the maintenance of nicotine self-administration are not particularly apparent in humans or animals, although cycle phase may influence other stages of dependence (e.g., withdrawal symptoms during cessation). Future research should evaluate further the consistency of results across human and non-human species, identify the conditions and procedures under which sex differences are observed, and elucidate the specific components of reinforcement that may differ between males and females. Studies also should examine the possible generalizability of these sex differences to other drugs of abuse. Identification of specific factors responsible for these sex differences may lead to improved interventions for smoking cessation and other substance abuse in women.

Smoking cessation in women. Special considerations.

Women may be at relatively greater risk of smoking-related diseases than men but tend to have less success than men in quitting smoking. The failure of most outcome studies to report results by gender and the lack of statistical power for detecting significant gender differences currently do not allow for many firm conclusions to be drawn about smoking cessation rates in women, but several trends warrant attention and further study.First, the difference in cessation rates for women versus men may be even greater in trials of nicotine replacement therapies (NRT). This suggests that women benefit less from NRT relative to men, although this difference may depend on the particular form of NRT (e.g. inhaler versus gum). On the other hand, some non-NRT medications may reverse the poorer outcome of women, producing quit rates in women comparable with those in men. Gender differences in outcome, as well as overall success rates, with NRT and some of the non-NRT medications appear to be enhanced when treatment includes substantial behavioural counselling. However, while several of the non-NRT medications may be particularly appropriate to consider for treating women trying to quit smoking, adverse effects may limit widespread use of some of these drugs, such as clonidine and naltrexone. Thus, even if the gender differences in outcome with NRT versus non-NRT drugs are confirmed in further research, such findings do not necessarily justify limiting NRT use in women, because such treatment is clearly effective and is likely to be safer and more readily available than non-NRT medications. Nevertheless, study of the mechanisms by which some non-NRT drugs are effective in women may aid our understanding of factors that are more influential in smoking behaviour in women than in men.Secondly, smoking cessation treatment for women must address several other issues that often emerge, and these are most likely to require behavioural counselling that is tailored to these problems. These issues include concern about bodyweight gain, restrictions on medication use in pregnant smokers, variability in mood and withdrawal as a function of menstrual cycle phase, harnessing social support to foster abstinence, and the possibility that smoking-associated environmental cues may be more influential in smoking behaviour in women than men.Greater attention to gender differences in clinical trial outcomes and to addressing concerns of women smokers may aid in the development of substantially improved smoking cessation interventions for women.

Sex Differences in Long-Term Smoking Cessation Rates Due to Nicotine Patch

Compared to men, women may be at greater risk for smoking-related diseases and have greater difficulty quitting smoking. Sex differences in medication response could guide treatment for smoking cessation to improve womens quit rates. We conducted a meta-analysis of the 14 placebo-controlled nicotine patch trials (N = 6,250) for which long-term (6 months) clinical outcome results could be determined separately by sex. This analysis updated a meta-analysis of 11 of these trials that found no significant sex differences due to nicotine patch. The increase in quitting due to the nicotine vs. placebo patch was only about half as large in women as in men. Pooled absolute quit rates at 6 months for nicotine and placebo patch, respectively, were 20.1% and 10.8% in men, and 14.7% and 10.1% in women. The odds ratio for quitting due to nicotine vs. placebo patch was lower in women (OR = 1.61) than in men (OR = 2.20), with an interaction odds ratio of 1.40 (95% CI = 1.02-1.93, p = .04). This sex difference did not vary significantly by whether or not formal counseling was provided. Poorer outcomes in women vs. men treated with nicotine patch suggests that increasing the quit rates of women smokers may require supplementing patch treatment or use of other medications.

The self-report of punitive childhood experiences of young adults and adolescents

A questionnaire designed to assess childhood disciplinary experiences was administered to a large sample of university students. The responses of these subjects indicated many of these predominantly middle-class young adults had experienced disciplinary activities that could be considered abusive. The results provide prevalence data on child abuse histories in a nonclinical sample and were seen as supporting the idea that physical abuse of children is widespread and not restricted to groups identified on the basis of clinical service or social deviance. Regardless of the criterion for physical abuse applied to the data, most respondents who met a criterion for having been abused failed to label themselves as having been abused. Additionally, correlations between severe physical punishment and abuse-related domains were shown to obtain in these nonclinical samples in a manner consistent with descriptions of abusive families in the clinical literature. A second study conducted with truly abused and nonabused adolescents established the validity of the questionnaire approach used in this research, and the two studies indicated the feasibility of conducting research on physical child abuse in natural collectivities of nonclinical subjects.

Varenicline Improves Mood and Cognition during Smoking Abstinence

BACKGROUND Neuronal nicotinic acetylcholine receptors (nAChRs) are a key target in medication development for various neuropsychiatric disorders, including nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, is a new, efficacious medication for nicotine dependence. Its effects on the affective and cognitive dimensions of nicotine withdrawal have yet to be well characterized. METHODS Sixty-seven treatment-seeking smokers were administered varenicline (x 21 days) and placebo (x 21 days) in a double-blind within-subject crossover design. Following medication run-up (Days 1-10), there was a 3-day mandatory smoking abstinence phase (Days 11-13) during which subjective symptoms and cognitive performance were assessed. Participants were reexposed to a scheduled smoking lapse (Day 14) and followed for days to lapse (Days 15-21) in each medication period. RESULTS In the varenicline period, compared with placebo, withdrawal symptoms (p = .04), smoking urges (p < .001), and negative affect (p = .01) during manditory abstinence were significantly lower, and levels of positive affect (p = .046), sustained attention (p = .018), and working memory (p = .001) were significantly greater. Varenicline also significantly reduced subjective rewarding effects of the scheduled smoking lapse (e.g., satisfaction, relief, liking; p = .003). Medication effects on days to lapse following the scheduled smoking lapse were dependent on treatment order (p = .001); among participants who received placebo in the first period, varenicline increased days of abstinence in the follow-up period. CONCLUSIONS These data identify novel affective and cognitive effects of varenicline and may have implications for medication development for other neuropsychiatric conditions.

Importance of nonpharmacological factors in nicotine self-administration.

There is mounting evidence that nonpharmacological factors critically modulate the effects of several drugs of abuse both in humans and experimental animals. This paper reviews research from this laboratory on one factor that influences the degree to which nicotine is self-administered: environmental stimuli that form the context within which nicotine is taken. The results suggest that the direct, pharmacological actions of nicotine are necessary but not sufficient to explain either the high rates of self-administration exhibited by laboratory animals or cigarette smoking by humans, and that future investigations on the neurophysiological effects of nicotine that underlie smoking behavior must take into account the environmental context within which the behavior occurs.

The Effect of Nicotine on Energy Expenditure during Light Physical Activity

The metabolic effects of nicotine have been implicated in the relation between smoking and lower body weight. This study examined whether the nicotine-induced increase in the metabolic rate observed at rest is also present during physical activity. We compared the energy expenditure of 10 male smokers receiving nicotine (15 micrograms per kilogram of body weight) with that of 10 male smokers receiving placebo on two occasions, each including a period of rest and a period of exercise on a modified bicycle ergometer at workloads designed to simulate and standardize light daily activity. All had abstained from cigarette smoking the night before the study. The excess energy expenditure attributable to nicotine was more than twice as great during exercise (difference between groups, 0.51 kJ per kilogram per hour, or 12.1 percent of the metabolic rate at rest; P less than 0.001) than during rest (0.23 kJ per kilogram per hour, or 5.3 percent of the metabolic rate at rest; P less than 0.05). In contrast, the expenditure was not affected by placebo during exercise or rest in the smokers or in a comparison group of 10 non-smokers, indicating that smoking status has no long-term metabolic effect in the absence of short-term nicotine intake. We conclude that the relatively small metabolic effect of nicotine when the subject is at rest is enhanced during light exercise. Our data also suggest that the weight gain that often follows smoking cessation may be influenced not only by nicotine intake but also by the level of physical activity a smoker typically engages in while smoking.