Kenneth A. Perkins - US grants

Smokers generally have lower body weights than non-smokes and tend to gain weight after smoking cessation. The weight gain that occurs when smokers quit is a major reason many smokers give for not abstaining and is a significant cause of smoking relapse following cessation. This proposal is designed to investigate which aspects of the energy balance equation--caloric intake or expenditure--are involved in nicotine's effects on body weight. The focus will involve both the chronic effects of smoking status and the acute effects of nicotine on caloric intake, including perceived appetite, caloric consumption, satiety, and taste sensitivity and preference, and on caloric expenditure, including leisure time activity and fatigue, resting metabolic rate (RMR), and diet- and activity-induced thermogenesis (DIT, AIT). Study I will examine differences between 20 smokers and 20 non-smokers in reported daily food intake, ratings of sensitivity and preference for graded samples of sweet, salty, sour and bitter food, caloric consumption during a standard meal, and appetite and satiety ratings before and after the meal. This study will also investigate nicotine's effects on appetite and taste sensitivity and peference ratings by comparing smokers' ratings before and after receiving 1 mg. nicotine via inhalation with those before and after receiving placebo. Study II will examine the dose-response and cumulative effects of nicotine on RMR by presenting during 3 separate sessions 0 mg. (placebo), 1 mg., or 2 mg. nicotine every 30 minutes for 2 1/2 hours (5 presentations) to each of 20 smokers. Study III will investigate differences between 80 smokers and 40 non-smokers in RMR and DIT by presenting a caloric load or water, and will examine the acute effects of nicotine on RMR and DIT in smokers by administering nicotine or placebo following the caloric load or water. Nicotine's effect on DIT may relate to the efficiency of caloric storage in smokers. Finally, Study IV will investigate differences between 80 smokers and 40 non-smokers in reported leisure time activity and in AIT, and will examine in smokers the acute effects of nicotine on AIT and fatigue during a lighit workload. Nicotine's effect on AIT may indicate whether the caloric expenditure of daily activities is increased when performed while smoking. The results of these studies may offer directions for future research in the development of adjunct treatment for smoking cessation to prevent weight gain and thus reduce the likelihood of smoking relapse.

Smokers generally have lower body weights than non-smokes and tend to gain weight after smoking cessation. The weight gain that occurs when smokers quit is a major reason many smokers give for not abstaining and is a significant cause of smoking relapse following cessation. This proposal is designed to investigate which aspects of the energy balance equation--caloric intake or expenditure--are involved in nicotine's effects on body weight. The focus will involve both the chronic effects of smoking status and the acute effects of nicotine on caloric intake, including perceived appetite, caloric consumption, satiety, and taste sensitivity and preference, and on caloric expenditure, including leisure time activity and fatigue, resting metabolic rate (RMR), and diet- and activity-induced thermogenesis (DIT, AIT). Study I will examine differences between 20 smokers and 20 non-smokers in reported daily food intake, ratings of sensitivity and preference for graded samples of sweet, salty, sour and bitter food, caloric consumption during a standard meal, and appetite and satiety ratings before and after the meal. This study will also investigate nicotine's effects on appetite and taste sensitivity and peference ratings by comparing smokers' ratings before and after receiving 1 mg. nicotine via inhalation with those before and after receiving placebo. Study II will examine the dose-response and cumulative effects of nicotine on RMR by presenting during 3 separate sessions 0 mg. (placebo), 1 mg., or 2 mg. nicotine every 30 minutes for 2 1/2 hours (5 presentations) to each of 20 smokers. Study III will investigate differences between 80 smokers and 40 non-smokers in RMR and DIT by presenting a caloric load or water, and will examine the acute effects of nicotine on RMR and DIT in smokers by administering nicotine or placebo following the caloric load or water. Nicotine's effect on DIT may relate to the efficiency of caloric storage in smokers. Finally, Study IV will investigate differences between 80 smokers and 40 non-smokers in reported leisure time activity and in AIT, and will examine in smokers the acute effects of nicotine on AIT and fatigue during a lighit workload. Nicotine's effect on AIT may indicate whether the caloric expenditure of daily activities is increased when performed while smoking. The results of these studies may offer directions for future research in the development of adjunct treatment for smoking cessation to prevent weight gain and thus reduce the likelihood of smoking relapse.

Chronic and acute tolerance to nicotine reflects physiological or behavioral adaptation and may relate to the onset and persistence of smoking behavior, as well as to development of tobacco dependence. Litt1e research has examined tolerance to nicotine in humans, largely due to methodological problems in attempting to present reliable bolus doses of nicotine. This proposal is designed to investigate chronic and acute tolerance to cardiovascular (heart rate, systolic and diastolic blood pressure, pulse amplitude), subjective (self-reported arousla and symptoms), antinociceptive (lactencies to heat and pain thresholds during a thermal stimulus), and behavioral (handsteadiness and fingertapping task performance) responses to nicotine in humans. All studies will employa measured-dose nasal spray nicotine delivery procedure we have developed. Chronic tolerance will be determined by comparing responses of smokers vs. nonsmokers (i.e. subjects distinctly different in their past history of exposure to nicotine). To identify acute tolerance, responses to a "challenge" nicotine dose-response and time course effects of a single niicotine presentation in smokers vs. nonsmokers. Its aims will be to document differences in chronic tolerance and determine the optimum inter-dose interval for subsequent studies of acute tolerance. Study II will examine the effect of dose amount on acute tolerance in smokers and nonsmokers. Study III will vary the intrval between dose presentations to examine attenutation of acute tolerance. The last tow studies will focus on the environmental specificity of this nicotine tolerance. Study V will exmaine the conditioned effects of exposure to non-nicotine stimuli associated with smoking (e.g. sight, smell of smoke) on chronic and acute tolerance to nicotine. Results may proivde directions for the study of mechanisms responsible for tolerance, as well as for investigations of physiological and behavioral aspects of nicotine depenence and smoking relapse.

Success rates of treatment for smoking cessation have generally not improved substantially over the past decade. Currently, there is much interest in devising nicotine replacement strategies which provide smokers relief from tobacco withdrawal and thus improve cessation. Despite widespread use of nicotine polacrilex (gum), long-term abstinence rates are still well below 50%. Other new methods are being developed (e.g. transdermal nicotine patch), but it is not yet clear whether they will be better than gum. Thus, additional means of nicotine replacement may be necessary to enhance smoking cessation. The present small grant application is designed to obtain information on the possible utility of a measured-dose nasal spray nicotine delivery procedure, which was developed in our lab as a tool for basic research, in enhancing smoking cessation. This application involves the development of a new treatment technique and represents a new research direction for us, both priority categories for small grants. Three studies using male and female volunteer smokers are planned. Study I involve presenting 0, 7.5, 15, and 30 ug/kg nicotine intermittently to smokers ad then observing amount of cigarette smoking to determine the dose-response effect of nicotine replacement via this method on suppression of ad lib smoking. Study II will determine whether nicotine spray is self-administered to a substantial degree by smokers desiring to quit, and whether intake of the spray relieves tobacco withdrawal. In addition, this study will compare plasma nicotine concentrations, withdrawal relief, and other subjective effects of nicotine spray vs. tobacco smoking to determine the completeness of the nicotine replacement and its effects in comparison to smoking. Finally, Study III will employ this nasal spray procedure to provide nicotine vs. placebo in conjunction with behavioral treatment for smoking cessation to determine the short-term acceptability of nicotine replacement with this method in aiding abstinence. Study III is not designed t be a formal assessment of clinical outcome, given the extensive effort and expense required for such as study, but rather will provide an indication as to whether such a clinical trial is warranted and practical. The knowledge gained from these studies should provide a clear indication as to whether this nasal spray nicotine procedure shows promise as a clinical aid to smoking cessation. If it does show promise (i.e. suppresses smoking in the lab, is self-administered, relieves withdrawal, and provides no practical or safety concerns), we would then propose a larger, more comprehensive evaluation of its clinical utility, including a longer-term clinical trial of cessation.

Despite a decline in prevalence of cigarette smoking, it remains the single most important preventable cause of disease morbidity and mortality. Notably, this decline has been much less apparent in women compared with men, and young women are now more likely than men to be smokers. Female smokers are less likely to quit smoking and less successful if they do quit, compared with male smokers. The substantial concern of women about weight gain after quitting is probably a major reason for this gender difference in cessation. Even though amount of weight gain is modest, weight control efforts in conjunction with smoking cessation have been proposed to prevent this weight gain, under the assumption that this will enhance success of cessation. Moreover, many female smokers who quit place themselves on diets to minimize weight gain with cessation. However, recent research results indicate that weight control efforts are associated with no better, and possibly worse, rates of smoking abstinence than smoking cessation interventions without weight control. Given the concern about weight gain and the active weight control efforts by women in conjunction with smoking cessation, a thorough evaluation of whether weight control treatments are helpful or harmful in improving smoking cessation in women is clearly needed. A more effective alternative may be adding cognitive therapy to enhance ability to copy with modest weight gain. The primary focus of this proposal is to examine the influence of dietary manipulations on tobacco withdrawal and smoking cessation in female smokers concerned about weight gain. Two lines of investigation are planned: 1) basic laboratory and inpatient studies to examine the interaction between food intake and smoking or withdrawal under controlled conditions, and 2) a clinical outcome study to determine whether implementation of adjunct weight restriction treatment vs. cognitive therapy to reduce weight-related concerns may enhance or impair success of smoking cessation efforts. The specific aims are: 1) Examine whether smoking following caloric intake prolongs satiety and reduces subsequent eating (i.e. snacking), and whether this effect is specific to nicotine per se. 2) Evaluate restricted (i.e. dieting) vs ad lib intake of highly- preferred, high-calorie foods on smoking withdrawal, desire to smoke, and mood under controlled inpatient conditions during one week of smoking abstinence. 3) Assess salivary habituation to taste, a measure related to food hedonics and intake, as function of abstinence from smoking or nicotine to determine if attenuated habituation is associated with increased food intake. 4) Determine smoking abstinence rates in women wanting to quit who are given standard 6-week behavioral smoking cessation counseling plus one of three adjunct treatments: a) weight restriction (dieting), b) cognitive therapy aimed at decreasing concern about weight gain, or c) no adjunct. Results of these studies will improve our understanding of the influence of concurrent dieting during smoking cessation on tobacco withdrawal, mood, and cessation, and they will provide specific directions for development of effective adjunct treatments for smoking cessation with female smokers concerned about weight gain.

Reinforcement from most drugs, including nicotine, depends largely on their interoceptive stimulus effects. Although traditional subjective measures may help, clearer understanding of these effects, and factors that influence them, requires use of behavioral drug discrimination procedures. Knowledge of the discriminative stimulus effects of nicotine may be critical in understanding its dependence potential and in evaluating new treatments for nicotine dependence. In the first 2.5 years of this project, we have established a procedure for assessing nicotine discrimination I humans using a measured-dose nasal spray delivery system and have begun to examine factors influencing this discrimination, such as between-subjects differences (e.g.. Sex, smoking status) and within-subjects factors (e.g. training conditions). The research proposed in the present application directly extends this line of investigation to key questions concerning the relationship between nicotine discrimination and reinforcement, mechanisms underlying nicotine discrimination, and common environmental factors which may, acutely influence nicotine discrimination. More specifically, we plan to: 1) identify the lowest reliably discriminable nicotine doses (discrimination threshold) in smokers and nonsmokers; 2) compare effects of central plus peripheral nicotine blockage (via mecamylamine) with effects of peripheral blockade only (via trimethaphan) to verify that nicotine discrimination is dependent on its central effects; 3) systematically evaluate alterations in the discriminative stimulus effects of nicotine due to situational conditions that commonly accompany nicotine intake via smoking in the natural environment, including concurrent drug consumption (alcohol, caffeine) and concurrent engagement in light physical activity; and 4) determine the relationship between nicotine choice (a measure of reinforcement) and nicotine discrimination following each of these manipulations. Findings from the first study may assist efforts to identify thresholds for nicotine reinforcement and development of dependence, an objective with important implications for prevention and treatment of nicotine dependence. Results of this program may also ultimately assist in the development of new treatments for smoking cessation by: providing a means for testing new medications to alter nicotine's reinforcing effects; confirming that these effects are centrally-mediated; and by determining the influence of situational factors of these effects, thus providing a better understanding of how these factors may impact on nicotine reinforcement, maintenance of smoking, and smoking relapse.

This protocol is designed to examine the discriminative stimulus effects of nicotine in male and female subjects using a measured-dose nasal spray method of nicotine adminstration. It is proposed that humans can discriminate among nicotine doses, that this effect is due to the effect of nicotine on the CNS. The underlying hypothesis is that this discrimination is related to nicotine self-administration in subjects who smoke cigarettes.

This protocol is designed to examine the discriminative stimulus effects of nicotine in male and female subjects using a measured-dose nasal spray method of nicotine adminstration. It is proposed that humans can discriminate among nicotine doses, that this effect is due to the effect of nicotine on the CNS. The underlying hypothesis is that this discrimination is related to nicotine self-administration in subjects who smoke cigarettes.

smoking cessation; nicotine; drug tolerance; tobacco abuse; inhalation drug administration; clinical research; human subject;

Nicotine replacement therapy (NRT) is the common pharmacological treatment for smoking cessation. There appear to be individual differences in the degree to which some formulations of NRT are clinically efficacious. Because of the vastly different speed of nicotine delivery between transdermal (TN) and nasal spray nicotine (NS), some of this individual differences in efficacy may relate to different effects of these products on neurochemical responses. Differences in dopamine transporter genotype, SLAGA3-9 ("protected") versus SLC6A3- *("predisposed"), are related to smoking status, perhaps because of differential effects of nicotine on the dopaminergic reward system. A smoking cessation study (project #2) is planned as part of the main center application to examine whether dopamine transporter genotype may predict differential outcome with TN versus NS treatment. This project includes assessment of the reinforcing value of smoking prior to starting NRT. The present pilot study extends and complements the clinical study by examining under controlled conditions whether the reinforcing value of smoking in response to acute exposure to TN versus may be differentially reduced between smokers of one genotype or the other. In this pilot project, we propose to: 1) Compare the reinforcing value of smoking following acute pre- treatment with TN, NS, and placebo between smokers with the SLC6A3- 9 versus SLC6A3-* dopamine genotypes. We predict that the reinforcing value of smoking will be decreased more by NS versus TN (main effect of NRT type) and that this decrease will differ as a function of genotype (genotype x NRT type interaction). The reinforcing value of smoking will be decreased by NS, but not TN, in SLC6A3-* smokers, while the reinforcing value of smoking will be decreased by either NS or TN in SLC6A3-9 smokers. 2) Compare acute objective mood response to TN, NS, and placebo between dopamine genotypes. Although of secondary, we predict that positive subjective responses (e.g. "alert", "relaxed") will be increased by NS more in smokers with SLC6A3-* versus SLC6A3-9 genotypes, while differences are expected between groups in mood responses to TN (genotype x NRT interaction). Result of this pilot may help explain possible different clinical efficacy of TN and NS between genotypes and aid in the identification of smokers more likely to benefit from one of the other formulation of NRT (i.e. tailor pharmacotherapy).

DESCRIPTION: (Adapted from the Investigator's Abstract) Men and women may differ in factors that reinforce smoking behavior: self-administration of nicotine per se is often less robust in women, women are less sensitive to many effects of nicotine, and nicotine replacement is less effective for smoking cessation in women. Nicotine therefore may be a less reinforcing consequence of tobacco smoking in women vs. men. Other results suggest that non-nicotine aspects of smoking (e.g. sensory effects) may be more reinforcing in women. In this revision of "Sex Differences in Nicotine Reinforcement: Human/Animal" (DA 12655), we will examine sex differences in the influence of nicotine and non-nicotine factors on self-administration (SA) behavior. A unique feature of this proposal is a parallel series of studies exploring these questions using an animal (rat) model of nicotine self-administration. Procedures in the human and animal lines of research will allow independent manipulation of nicotine and non-nicotine factors. Our specific aims are to: 1) Examine differences in smoking (human) or i.v. nicotine (rat) self-administration in females as a function of menstrual/estrus cycle phase and compare this SA behavior to males. Results will determine the influence of cycle phase on SA, which may help explain observed sex differences, and critically inform the design of all subsequent research in this project as to whether cycle phase must be controlled. 2) Examine sex differences in the influence of nicotine dose on SA behavior in humans and animals. Nicotine clearly is the primary psychoactive ingredient reinforcing smoking behavior. However, nicotine may be less important in regulating this behavior in females. We will explore this possibility by determining whether self-administration behavior is less affected by manipulations of nicotine dose in females. 3) Examine sex differences in the influence of non-nicotine, drug-related stimuli on SA in humans and animals. Males' behavior may be more tightly controlled by nicotine and females' relatively more influenced by non-nicotine cues accompanying drug. Results will determine the reinforcing effect of smoking stimuli that have been largely ignored in past human research and provide directions for future study of conditioned reinforcement of smoking. Findings will clarify whether, and to what extent, nicotine and non-nicotine factors differentially reinforce SA behavior in females versus males. Similarities between species would bolster the relevance of the animal findings for human smoking reinforcement and allow an animal model by which to subsequently (and more invasively) investigate mechanisms for these sex differences. Results will increase our understanding of tobacco dependence in women and suggest approaches to developing improved smoking cessation treatments for women, among other future directions. This program may also provide directions for the study of sex differences in pharmacological and non-pharmacological reinforcement from other abused drugs, with potential relevance for broadly improving substance abuse treatment in women.

Individual variation in sensitivity to drugs (i.e., acute responsiveness to drug effects) may help explain vulnerability to onset and persistence of drug abuse, including nicotine dependence. In the previous funding period of this research program, the results identified and characterized tolerance to nicotine in tobacco smokers, defined as reduction in functional sensitivity to nicotine due to smoking history. In this competing renewal, this line of investigation will be extended in two directions: 1) examination of genetic and personality (primarily novelty-seeking) factors that are associated with variation in nicotine responses and reinforcement; and 2) focus on an earlier point in the dependence process-initial nicotine exposure. Variation of this "initial" sensitivity to nicotine likely accounts for some of the differences in the reinforcing effects of nicotine upon initial exposure and, thus, smoking onset. Because nicotine's reinforcing effects likely are related to its dopaminergic actions, genes involved in moderating these actions may be critically important in understanding vulnerability to nicotine dependence. The primary genotypes to be examined involve variants on the SLC6A3 ("dopamine transporter" gene)--specifically presence ("-9") or absence ("-*") of the -9 repeat allele. Nicotine administration will be carefully controlled to allow determination of dose-response relationships for each genotype on acute subjective, behavioral, and physiological effects of nicotine (i.e. "sensitivity"), as well as on nicotine reinforcement (i.e. self-administration). Two hundred never-smokers will be examined, approximately half with each variant, instead of smokers in order to rule out confounds due to nicotine tolerance and withdrawal. It is hypothesized that nicotine sensitivity and reinforcement will be greater in never-smokers with the -* versus -9 alleles of SLC6A3. Because the personality characteristic of novelty-seeking may help clarify the influence of dopamine genotype, comparisons will be made between nicotine sensitivity and reinforcement as a function of novelty-seeking. Secondary analyses will examine responses as a function of DRD2 ("dopamine receptor density") genotypes and explore the possibility of gene-gene interactions. This research will be the first to comprehensively examine factors associated with individual variability in initial nicotine sensitivity and reinforcement (i.e., in nicotine-naive individuals). Results will provide directions for future research on vulnerability to tobacco dependence and for targeted efforts to prevent smoking onset.

DESCRIPTION (provided by applicant): The Society for Research on Nicotine and Tobacco (SRNT) was founded in 1994 to address the need for coordinated scientific discourse on research related to the many direct effects of nicotine and tobacco, the use of tobacco products in our society, and the prevention and treatment of tobacco dependence. It is still the only national organization primarily devoted to promoting the conduct of research on nicotine and tobacco and disseminating findings from this research. SRNT is a multidisciplinary organization including members whose interests range from neuroscience to clinical and prevention interventions to tobacco policy. SRNT will hold its ninth annual meeting in February 2003 at the Sheraton New Orleans Hotel. We are requesting partial support for this and four subsequent annual meetings from NIDA, with NCI and CDC as secondary funders, through the conference grant mechanism. At the annual meetings, a multidisciplinary group of scientists, many of whom are funded by NIDA, NCI, and other NIH institutes, will present talks, posters, symposia, and other sessions that highlight the latest research on nicotine and tobacco. This research will cover the broadest possible scope of the influence of nicotine and tobacco on public health, including neuroscience, clinical pharmacology, treatment, prevention, epidemiology, and health policy. Theme lectures by three distinguished researchers will highlight developments in the three general interest areas: basic research, clinical, and public health/epidemiology. The work of new investigators will be highlighted via special oral sessions and awards programs. In addition, just prior to the 2003 annual meeting, we plan to hold a 1-day special topics meeting on global collaborations in nicotine and tobacco research (although support for that meeting is not being requested here). Overall, the SRNT annual meeting serves a valuable function by providing a forum for dissemination and discussion of the latest findings in nicotine and tobacco research and the opportunity for cross-fertilization of ideas across research areas. Partial support of the meeting by NIDA, NCI, and CDC would further highlight these agencies' commitment to the importance of nicotine and tobacco research.

DESCRIPTION (provided by applicant): Systematic study of placebo effects could help us better understand nicotine dependence and, perhaps, provide directions for altering these effects to help people quit smoking, still the most important preventable cause of morbidity and mortality. However, nicotine research contains very few studies of placebo effects, particularly with the balanced-placebo design. Also, little is known about how the contexts of the drug use situation and method of drug administration influence placebo effects with any drug. Both factors may be critical to understanding nicotine intake. In particular, negative affect enhances responses to nicotine and may enhance placebo effects, and placebo effects may depend on whether nicotine is administered in the substance use versus medication use context. Nicotine offers a rare opportunity to study the influence of drug formulation since it is widely used both as a substance of abuse (smoking) and as a medication (nicotine replacement therapy, NRT). This project will be virtually the first to comprehensively examine placebo effects in smoking, as well as another form of nicotine (NRT). Moreover, to our knowledge, this project will be the first to examine how the critical situational context of negative affect (specifically depressed mood) alters the placebo effects of any drug. We will employ the balanced-placebo design to systematically examine the placebo effects of nicotine within the substance use context of cigarette smoking (study 1) and within the medication use context of nasal spray NRT (study 2). Each of these lab-based studies will examine these effects during negative affect and neutral affect. We will also assess placebo effects across several dimensions, aside from self-report measures, including the behavioral response of facial affect and the psychophysiological response of acoustic startle. We will also determine whether placebo effects extend to actual drug use behavior (i.e. reinforcement) by measuring self-administration of smoking (study 1) or NRT (study 2). Our main goal is to more clearly understand the contextual factors that influence the occurrence and magnitude of these placebo effects. We hypothesize that placebo effects will be enhanced under negative versus neutral affect, and we will explore whether these effects differ between smoking and NRT. Results will enhance our understanding of contextual influences on placebo effects in nicotine intake, specifically by determining whether they are altered by the affective state of the individual and by the form of drug intake. Findings will provide directions for further research into contextual factors and perhaps into avenues for countering placebo effects in the substance use context of smoking and for enhancing placebo effects in the medication use context of NRT. Secondary analyses may identify important individual characteristics associated with placebo responses, aiding in the prediction of which smokers ultimately are likely to benefit most from manipulation of placebo effects.

DESCRIPTION (provided by applicant): The Society for Research on Nicotine and Tobacco (SRNT) was founded in 1994 to address the need for coordinated scientific discourse on research related to the many direct effects of nicotine and tobacco, the use of tobacco products in our society, and the prevention and treatment of tobacco dependence. It is still the only national organization primarily devoted to promoting the conduct of research on nicotine and tobacco and disseminating findings from this research. SRNT is a multidisciplinary organization including members whose interests range from neuroscience to clinical and prevention interventions to tobacco policy. SRNT will hold its ninth annual meeting in February 2003 at the Sheraton New Orleans Hotel. We are requesting partial support for this and four subsequent annual meetings from NIDA, with NCI and CDC as secondary funders, through the conference grant mechanism. At the annual meetings, a multidisciplinary group of scientists, many of whom are funded by NIDA, NCI, and other NIH institutes, will present talks, posters, symposia, and other sessions that highlight the latest research on nicotine and tobacco. This research will cover the broadest possible scope of the influence of nicotine and tobacco on public health, including neuroscience, clinical pharmacology, treatment, prevention, epidemiology, and health policy. Theme lectures by three distinguished researchers will highlight developments in the three general interest areas: basic research, clinical, and public health/epidemiology. The work of new investigators will be highlighted via special oral sessions and awards programs. In addition, just prior to the 2003 annual meeting, we plan to hold a 1-day special topics meeting on global collaborations in nicotine and tobacco research (although support for that meeting is not being requested here). Overall, the SRNT annual meeting serves a valuable function by providing a forum for dissemination and discussion of the latest findings in nicotine and tobacco research and the opportunity for cross-fertilization of ideas across research areas. Partial support of the meeting by NIDA, NCI, and CDC would further highlight these agencies' commitment to the importance of nicotine and tobacco research.

Current treatments for smoking cessation fail most of the time, and robust new treatments, including medications, are sorely needed. Because ofthe substantial costs and time involved in clinical trials, medications subjected to these trials must be those with the greatest promise of success. The purpose of medication screening studies is to quickly and cheaply evaluate the clinical potential of medications, so that promising drugs proceed to clinical trials and unpromising drugs do not. However, there is no human screening procedure for medications in which results are clearly predictive of smoking cessation outcome in clinical trials with those medications. This proposal aims to improve procedures for human screening of potential medications for smoking cessation prior to clinical trials of the efficacy of those medications. Logically, studies on human screening of cessation medications should simulate, within practical limitations, clinical trial procedures. Thus, emphasis should be placed on smoking abstinence as the primary index of medication response, as there are no other clear short-term predictors of long-term abstinence. We will examine sensitivity to medication effects as a function of two methods used to increase the motivation and likelihood of abstinence in smokers participating in a short-term screening study: 1) ?natural? motivation due to treatment seeking status of participants, and 2) ?artificially supported? motivation using monetary incentives contingent on smoking abstinence. We will assess 160 treatment-seeking smokers and 160 non-treatment seeking smokers, half of whom will receive monetary reinforcement on a daily basis contingent on being abstinent (verified by expired-air Co <= 8 ppm) and half of whom will not receive reinforcement far abstinence. In these groups, we will compare effects of 5 days? exposure to 21 mg nicotine versus placebo patch, using a within-subjects cross-over design. Our main dependent measures will be days of smoking abstinence and continuous 5-day abstinence (dichotomous outcome), with cigarettes/day, craving, withdrawal, negative affect, and ADHD symptoms as secondary measures. We hypothesize that differences between nicotine vs placebo patch will be greater in treatment seekers than non-seekers, and in those receiving abstinence reinforcement vs no reinforcement. Secondarily, we will examine changes in the magnitude of nicotine effects as a function ofthe duration of exposure to medication across days within the 5-day treatment period, to identify the point of peak early medication effects. Assessment of self-report measures will be conducted in the natural environment, as well as the lab, to determine the influence of method of assessment on medication response. We will also examine individual differences in nicotine responses. Results will provide immediate directions for improving screening evaluations of cessation medications. Future directions include testing the utility of this improved screening procedure with novel medications, the long-range objective. This research will ultimately help us better understand how to more quickly and efficiently evaluate potential medications for smoking cessation, a goal with very high public health significance.

DESCRIPTION (provided by applicant): A critical reinforcing effect of cigarette smoking is believed to be acute relief of negative affect (anxiety, sadness, irritability, etc.). Smoking clearly relieves negative affect caused by smoking abstinence (i.e. withdrawal), and negative affect after quitting smoking increases the risk of relapse. However, it is not clear that smoking acutely relieves negative affect from "sources" other than abstinence, such as environmental stressors, which smokers commonly experience in the natural environment. Due to limitations inherent in clinical research, this question may best be addressed with well-controlled laboratory research. What is needed is a lab study that includes more than one source of negative affect so that results across different sources can be compared within the same subject sample, using the same measures of negative affect, and under the same experimental procedures. This is the important and novel objective of the current proposal: to examine the degree to which the relationship between negative affect and smoking depends on the source of that negative affect. We will employ four different procedures to briefly induce negative mood. Demands of these procedures vary in key ways (e.g. active coping vs. no active coping) and will help us determine the conditions under which smoking is associated with negative affect. In addition, the 200 smoking subjects will be randomly assigned to one of three groups that differ in smoking and/or nicotine exposure (i.e. between-subjects factor), those who: smoke a nicotine cigarette, smoke a denicotinized cigarette, or do not smoke at all. Comparisons among these groups will determine whether nicotine per se or smoking behavior alone, without nicotine (suggesting conditioned effects), is responsible for the associations between smoking and negative affect. Affect will be assessed via multiple response domains: self-report, psycho physiological, and behavioral. Primary specific aims are to examine: 1) whether acute tobacco smoking relieves negative affect as a function of source, 2) whether negative mood induction increases smoking behavior as a function of source, and 3) the association between negative affect relief and subsequent smoking behavior. In a secondary aim, we will: 4) explore individual differences in these effects. If smoking relieves negative affect from all four sources, this will strengthen the commonly held, but rarely demonstrated, notion that smoking does in fact acutely relieve negative affect, under virtually all conditions. However, if smoking relieves negative affect selectively, this finding will suggest that smoking's ability to relieve negative affect is limited to only certain conditions. Finally, if results for affect relief versus smoking behavior are inconsistent (i.e., aim #3), the traditional negative reinforcement explanation for the increase in smoking during negative mood will need to be reconsidered, warranting other explanations. In sum, this research will help address the fundamental question of why cigarette smoking is reinforcing.

This proposal is Project 4 of a P50 application for the proposed Center for Interdisciplinary Research in Nicotine Addiction (CIRNA). Development of robust new medications for smoking cessation is hampered in part by inefficiency in how they are initially screened for efficacy in humans. Building on our prior work, this proposal is aimed at improving the sensitivity of procedures for screening medication efficacy. Within practical limits, such screening should simulate clinical trial methods, including use of smoking abstinence as the primary index of medication response, which may require study participants who are motivated to abstain, at least briefly. In prior research, we found that medication (NRT patch) increased abstinence over one week of use in treatment seekers, those with high intrinsic quit motivation, but extrinsic quit motivation via reinforcement for abstinence made no difference. Although informative, our findings are preliminary until they can be cross-validated with other cessation medications, which is the focus of the current project. Study 1 will examine in 200 smokers whether these results generalize to another effective medication, varenicline, by using the same mixed, cross-over design, with treatment seeking status and abstinence reinforcement as 2x2 between-subjects factors, and varenicline vs placebo as a within-subject factor. We predict that varenicline (vs placebo) will increase abstinence (i.e., show efficacy) over one week in treatment seekers more than in non-treatment seekers, confirming the importance of intrinsic quit motivation for screening. Study 2 will determine whether use of treatment seekers in such screening is both sensitive and specific. Sensitivity will be indicated if our procedure shows efficacy with another medication known to aid cessation in clinical trials, bupropion (i.e., a positive control), while specificity will be indicated if our procedure shows no efficacy in a medication known not to be effective for cessation in clinical trials, in this case modafinil (i.e., a negative control). Treatment seekers (n=100) will receive each medication and placebo in a within-subject cross-over design. We predict that, compared with placebo, bupropion will increase abstinence. Efficacy of modafinil, which is not expected, would question our procedure's specificity. Secondarily, both studies will examine individual differences and medication effects on symptoms of early abstinence (craving, withdrawal, negative and positive affect, smoking reward) to determine possible mechanisms of efficacy. Results will provide immediate directions for improving the screening of novel cessation medications, the project's longrange objective and a goal with very high public health significance.

DESCRIPTION (provided by applicant): "Behavioral Genetics of Mood-Induced Smoking" Controlled laboratory studies reliably show that negative mood manipulations of various kinds acutely increase smoking reinforcement. However, very few studies have identified individual differences that moderate mood-induced smoking, and only one, a recent report by us, has examined genetic associations. The primary aim of this proposal is to validate our prior, preliminary data on genetic associations with increases in smoking due to negative mood, a potentially important novel phenotype for nicotine dependence. Dependent smokers (N=200) will participate in two virtually identical lab sessions, differing only in induction of negative vs. positive mood via a validated procedure to robustly induce mood (one mood per session, sessions in counter-balanced order). They will ad lib smoke their preferred brand of cigarettes (to maximize generalizability) during mood induction each session. Differences in smoking reinforcement (latency and amount of smoking) between the negative and positive mood conditions, i.e. mood-induced smoking, will be related to the dopamine and mu opioid receptor gene variants identified in our preliminary study. These include: dopamine D4 receptor (DRD4 VNTR), dopamine D2 receptor (DRD2 C957T SNP [rs6277] and DRD2/ANKK1 TaqIA SNP [rs1800497]), the dopamine transporter (SLC6A3 VNTR), and the mu opioid receptor exon 1 SNP (OPRM1 A118G [rs1799971]). In secondary aims, we will examine genetic associations with smoking reward, affect, and related measures, as well as other individual differences in mood-induced smoking, including subject sex, depression history, distress tolerance, and severity of nicotine dependence. Our prior study and past productive collaborations between the PI and co-I demonstrate the strong feasibility of this proposal. Results of this innovative project may identify smokers potentially at greater risk for relapse due to negative mood and may guide research on mechanisms behind mood-induced smoking. Our procedures could be used to test the efficacy of medications to attenuate mood-induced smoking, thereby reducing vulnerability of some smokers to mood-related relapse. This project also could be a prototype for future research that combines rigorous behavioral pharmacology methodology and genetics to identify individual variation in drug reinforcement due to situational influences. PUBLIC HEALTH RELEVANCE: Negative mood increases smoking behavior and leads to relapse after a quit attempt. Controlled laboratory studies show that negative mood manipulations of various kinds (e.g. stressors) acutely increase smoking behavior. However, very few studies have identified individual differences in mood-induced smoking, and only one, a preliminary study by us, examined genetic associations with mood-induced smoking. This project will validate our preliminary observations, which may identify smokers particularly vulnerable (or resistant) to smoking relapse due to negative mood. Results may guide research on genetics of environmental influences on smoking behavior and other drug abuse, and perhaps guide research on the mechanisms behind mood-induced smoking.

DESCRIPTION (provided by applicant): "Reinforcement-enhancing effects of nicotine" Nicotine clearly has primary and secondary reinforcing effects in humans and animal models. Very recent research in rodents indicates that nicotine may also have a third reinforcing function;that of reinforcement-enhancing effects, or increasing the reinforcing efficacy of rewards unrelated to nicotine intake. This R21 application seeks to determine whether nicotine via smoking has reinforcement enhancing effects in humans. One hundred smokers, 50 nicotine dependent and 50 nondependent, will participate in 4 experimental sessions, involving: 1) smoking nicotine (0.6 mg) cigarettes or 2) smoking denic (0.05 mg) cigarettes or 3) no smoking, each after overnight abstinence, or 4) smoking their own brand after no overnight abstinence (exploratory condition). In each session, they will respond on a simple operant task for small amounts of money, brief access to preferred music, avoidance of aversive white noise, or no reward (control). Our primary specific aim is to examine the influence of nicotine via smoking on responding for rewards. We hypothesize that reinforced responding will be greater after smoking a nicotine vs a denic cigarette (and vs. no smoking), indicating reinforcement enhancing effects of nicotine per se. Effects of nicotine on responding for some rewards versus others or no reward will indicate that reinforcement enhancement due to nicotine is specific to certain rewards and not a generalized effect of nicotine intake. Reinforcement-enhancing effects of nicotine in nondependent smokers, as well as dependent smokers, would suggest that these effects do not require the establishment of dependence and reflect absolute enhancement of reinforcement, as observed in the rodent studies. Substantial pilot work supports project feasibility and points to the likelihood of these hypothesized results. By contrast, if effects are observed only in dependent and not nondependent smokers, they could reflect withdrawal relief and not true enhancement of reinforcement. A secondary aim is to explore sex differences in the reinforcement enhancing effects of nicotine. This research is highly significant because demonstrating reinforcement-enhancing effects of nicotine in humans would have very important implications for our understanding of nicotine dependence. It would indicate that smoking does not "just" provide reinforcement from direct psychoactive effects of nicotine but rather broadly increases the reinforcing effects of the other rewards in a smoker's environment. Therefore, quitting smoking would result in a loss of this broad reinforcement, in addition to loss of nicotine's psychoactive effects. This broad reinforcement loss could be restored by smoking one cigarette (i.e. a lapse), helping to explain the persistence of smoking behavior. Results would provide directions for improving cessation treatments. This R21 submission fits the requirements of PA-10-069, "NIH Exploratory Developmental Research Grant Program." PUBLIC HEALTH RELEVANCE: "Reinforcement enhancing effects of nicotine" This project will determine whether nicotine via cigarette smoking increases the reinforcing value of other rewards unrelated to smoking, as indicated by recent rodent studies. Dependent and nondependent smokers will work on a computer task to earn various small rewards after smoking nicotine or denic cigarettes or not smoking. This research is highly significant because demonstrating reinforcement-enhancing effects of nicotine in humans would have very important implications for our understanding of nicotine dependence. It would indicate that smoking does not "just" provide reinforcement from direct psychoactive effects of nicotine, but rather broadly increases the reinforcing effects of the other rewards in a smoker's environment. Therefore, quitting smoking could result in a loss of this broad reinforcement, in addition to loss of nicotine's psychoactive effects. This broad reinforcement loss could be restored by smoking a cigarette (i.e. a lapse), helping to explain why a lapse almost invariably leads to relapse after a quit attempt.

DESCRIPTION (provided by applicant): Nearly 50 million Americans smoke cigarettes, the leading preventable cause of death worldwide. Although most report wanting to quit, few are successful during a given quit attempt even with currently available therapeutics. Of dozens of drugs tested in clinical trials for cessation over the last three decades, only 3 have been approved by the FDA (nicotine replacement, varenicline, bupropion). Additional effective medications are needed to help the majority of dependent smokers succeed in quitting permanently. This application uses a streamlined two-stage approach to evaluate the efficacy of a new compound as a medication for smoking cessation. In the first stage, preclinical feasibility studies will be performed based on highly convincing preliminary data in rodent models that are validated predictors of medications for smoking cessation in humans. These will be followed by the second stage, human clinical Phase 2a studies to detect medication evidence of efficacy for smoking cessation. Abstinence due to medication versus placebo will be compared within a well-validated, innovative procedure for initial test of efficacy. We will also assess the mechanisms through which this medication reverses symptoms of abstinence. These clinical studies benefit from a within- subject crossover design as a high throughput method for predicting therapeutic efficacy of smoking cessation drugs in a highly efficient manner. Moreover, a highly innovative component of this application is to test medication efficacy for smoking cessation in both the broader population of healthy dependent smokers and in smokers with schizophrenia, who have very high rates of smoking but limited therapeutic alternatives to quit smoking. The feasibility of this research is substantial, given the investigators' extensive experience conducting very similar preclinical and clinical research. Results of this application could lead to a new medication to treat nicotine dependence, reducing enormous costs to public health and providing perhaps the first effective treatment for cessation in the most vulnerable smokers.

DESCRIPTION (provided by applicant): The lowest (i.e. threshold) nicotine dose in cigarettes that produces tobacco reinforcement and dependence is almost certainly not lower than the threshold dose for discrimination of nicotine's interoceptive stimulus effects from smoking. Despite a half century of animal research on nicotine discrimination and prior human studies of threshold dose for discriminating drugs other than nicotine, no research has clearly assessed this nicotine discrimination threshold in humans via cigarettes because of difficulty controlling nicotine dosing with tobacco intake. Because our lab has, by far, the most experience assessing nicotine discrimination in humans (including threshold dose, with a nicotine formulation other than tobacco), we propose to employ well- validated behavioral discrimination methodology to identify the cigarette nicotine threshold dose for discrimination using nicotine research cigarette (NRC) from the NIDA Drug Supply Program. We will assess threshold doses in a diverse sample of 100 healthy male and female smokers varying in dependence level and menthol preference to generate evidence that informs policy on establishing a maximum nicotine content in tobacco cigarettes that could prevent the onset and maintenance of dependence. We hypothesize that this nicotine threshold dose for discrimination will be lower than the yield of most current commercial brands, which typically exceed 0.4 mg. We also hypothesize that the threshold dose will be lower in nondependent vs. dependent smokers, in men vs. women, and perhaps as a function of cigarette menthol preference, consistent with prior research on differences in nicotine sensitivity. Importantly, this study will also separately assess self-administration of nicotine from these cigarettes to determine the relationship between nicotine discrimination threshold dose and reinforcement threshold dose in smoking. This research is highly significant because limiting nicotine cigarettes to amounts below this threshold dose could minimize risk of nondependent smokers escalating to dependence and make it easier for dependent smokers to quit smoking. As such, this R21 addresses key research objectives of the FDA's Center for Tobacco Products (CTP), notably those involving reducing addiction to tobacco products by modifying nicotine levels, including in potentially vulnerable populations, and adverse health consequences of tobacco use.

DESCRIPTION (provided by applicant): Reinforcement enhancing effects of NRT Nicotine clearly has primary and secondary reinforcing effects, as nicotine is self-administered and stimuli associated with nicotine (cues) can become conditioned reinforcers of responding. Overlooked until recently is non-human research showing that nicotine has a third reinforcing function, that of reinforcement enhancing effects, or increasing reinforcing efficacy of rewards unrelated to nicotine intake. Notably, we recently demonstrated reinforcement enhancing effects, perhaps for the first time in humans, of nicotine intake via tobacco smoking, supporting clinical applicability of these preclinical research findings. Similar effects in both nondependent and dependent smokers and other findings indicated dependence and withdrawal as not necessary for these nicotine effects to occur. Yet, these effects may be specific to only some types of reinforcers, especially positive sensory rewards (visual, auditory, etc.). Also, nicotine' kinetics do not influence its reinforcement enhancing effects in animal models, in contrast to its primary and secondary effects, but reinforcement enhancing effects of rapid versus gradual intake of nicotine per se warrants confirmation in humans. Nicotine via means other than smoking, such as nicotine replacement therapy (NRT), can assess effects of nicotine per se on enhancing reinforcement and determine its clinical predictive value in quitting smokers. NRT also can test if pharmacokinetics influences this reinforcement enhancing effect, via rapid (nasal spray) vs. gradual (patch) nicotine intake. Study 1 will examine influences of nicotine per se (versus placebo) on responding for reinforcers in 60 nondependent and dependent smokers to confirm our results with nicotine via smoking, using our well-validated within-subjects design to increase power. We hypothesize that responding will be greater after NRT (patch or spray) versus placebo, indicating reinforcement enhancing effects of nicotine per se, and we will explore whether these effects differ by type of reward, showing specificity. Study 2 will determine if greater reinforced responding due to NRT early in abstinence predicts days to relapse with NRT in 60 treatment-seeking smokers making a permanent quit attempt. We hypothesize that a greater increase in reinforced responding due to NRT early in cessation will predict longer duration of abstinence. This research is highly significant because demonstrating reinforcement enhancing effects of nicotine per se in humans would have important implications for understanding: an overlooked reinforcing effect of nicotine that may help account for persistence of dependence, some of the efficacy of NRT for aiding smoking cessation, and perhaps potentially similar actions of other therapeutic medications or other drugs of abuse.