Jed Rose, Ph.D. - US grants

The role of nicotine as a reinforcing agent in tobacco will be investigated as a function of several key variables: 1) smoking deprivation and satiation; 2) conditioned stimuli accompanying inhalation of nicotine; 3) other constituents in tobacco (tar); and 4) situationally induced anxiety (performing while being videotaped). While manipulating these influences systematically in the following experiments, nicotine's reinforcing value will be measured behaviorally using a smoke mixing device that allows subjects to adjust the nicotine delivery of each puff they take. Preferred nicotine levels, puffing and volume of smoke taken in will comprise the dependent measures of smoking. Our goal is to pinpoint the critical pharmacological and psychological variables mediating smoking satisfaction. In so doing, less harmful substitutes may be developed which preserve the reinforcers sought by smokers, and reduce the health risks to which they are currently exposed.

The main goal of the proposed research is to determine how the pharmacologic actions of nicotine and the sensory/behavioral aspects of cigarette smoking contribute to tobacco dependence. In the proposed work, the pharmacologic effects of smoking will be delivered using intravenous (i.v.) nicotine infusions; conversely, the non-nicotine components of the smoking habit will be conveyed using de-nicotinized cigarettes. By dissociating and independently varying these two key components, we will gain a better understanding of the reinforcement processes maintaining smoking behavior. Laboratory studies will assess the determinants of nicotine self-administration and preference between nicotine and non-nicotine components of cigarette smoke. We will measure how preference for nicotine is affected by nicotine replacement in the form of nicotine skin patches. The ability of nicotine and non- nicotine smoke components to satiate smoking behavior will also be assessed. The relative roles of peripheral and central nervous system nicotinic receptors will be examined using different nicotinic antagonists. In addition to participating in the laboratory studies, subjects will be able to enroll in a smoking cessation program using nicotine skin patch therapy. Responses to i.v. nicotine and to the sensory/behavioral cues in the laboratory studies will be correlated with the clinical response to nicotine replacement treatment. The results will lead to a better understanding of the role of pharmacologic and sensory/behavioral cues in nicotine addiction and smoking cessation.

The goal of this research is to elucidate the mechanisms by which dopaminergic (DA) and cholinergic (ACh) neurotransmitter systems interact in the neural bases of cognitive function. In previous studies, Dr. Levin has documented the interactions of DA and ACh drugs given systemically. The current proposal is to investigate critical neural pathways which underlie these DA-ACh interactions. Sites to be studied are those which are important for cognitive function and where DA and ACh systems are anatomically connected. These include the septal nucleus, the nucleus basalis and the ventral tegmental area. These studies will help achieve the goal of elucidating basic mechanisms of DA-ACh interactions in cognitive behavior. This is important to further develop basic understanding of the neural bases of cognitive function. Since no neural system acts alone, it is important to understand how they act together.//

The proposed research will characterize the effects of nicotine and cigarette smoking on regional cerebral blood flow (rCBF). The goals are to identify brain regions involved in the reinforcement processes that underlie tobacco dependence. Two studies will be conducted with cigarette smokers to identify rCBF effects of nicotine and to measure changes in these effects after subjects receive a pharmacologic treatment that blocks smoking reward. In Study 1, eighteen smokers will receive nicotine-containing smoke, de-nicotinized smoke that contains negligible nicotine but which provides significant tar and sensory' aspects of smoking, or sham smoke, which contains neither tar nor nicotine. rCBF will be measured before and after each condition using O15 positron emission tomography (PET). Doses of nicotine will be individualized to match subjects' preferred level of self-administered nicotine during ad lib smoking. The de-nicotinized cigarette smoke will be used to control for the non-nicotine constituents of tobacco smoke and to assess the influence of conditioned reinforcement on rCBF. In Study 2, rCBF effects of nicotine and cigarette smoke will be assessed before and after subjects receive a pharmacologic treatment which previously has been shown to attenuate craving and facilitate abstinence from cigarettes. This treatment entails administration of the nicotinic antagonist mecamylamine in combination with the nicotine skin patch. Changes in rCBF will be correlated with treatment outcome. The results of these studies will help guide future research toward brain regions likely to be involved in nicotine craving and reward, and should ultimately improve our understanding and treatment of tobacco dependence.

The main goal of the proposed research is to determine how the central nervous system actions of nicotine and the sensory/behavioral aspects of cigarette smoking contribute to tobacco dependence. By dissociating and independently varying the pharmacologic effects of nicotine and of the smoking habit, we will gain a better understanding of the reinforcement process mediating nicotine dependence.

DESCRIPTION: (Applicant's Abstract) The proposed research will determine how pre-treatment with nicotine or the nicotinic antagonist mecamylamine modifies the subsequent responses to cigarette smoking. Subjective, cardiovascular, and hormonal indices as well as cognitive performance will be measured before and after different doses of nicotine are presented in cigarette smoke. In Study 1, tolerance induced by pre-exposure to nicotine (with nicotine skin patches) will be assessed by measuring the subsequent responses to controlled doses of nicotine delivered in cigarette smoke. In Study 2, tolerance to nicotine induced by cigarette smoking will be compared to tolerance resulting from transdermal nicotine administration. A follow-up study (Study 3) will seek to relate individual differences in daily smoking patterns to differences in the susceptibility to tolerance produced by nicotine. Study 4 will examine blockade of the various responses to cigarette smoke after oral administration of mecamylamine. Because administration of nicotine and mecamylamine each attenuate subsequent responses to cigarette smoking, Study 5 will characterize the effects of combined nicotine/mecamylamine administration, which has shown considerable promise in smoking cessation treatment. Ad lib smoking behavior and responses to controlled doses of cigarette smoke will be measured during a two week period, to assess the extent to which nicotine and mecamylamine, administered separately or in combination, reduce the rewarding actions of inhaled nicotine and promote extinction of cigarette smoking behavior. Subsequently, participants will quit smoking using nicotine replacement and abstinence will be correlated with the degree to which different effects of cigarette smoking were attenuated by nicotine or mecamylamine treatment. The results of these studies will contribute to the understanding of factors mediating the reinforcing actions of nicotine that underlie tobacco dependence, and shed light on the mechanisms of action of effective smoking cessation treatments.

APPLICANT'S ABSTRACT: The proposed research will delineate the subjective, cardiovascular and behavioral interaction between alcohol and nicotine. Moreover, a novel pharmacologic approach for smoking cessation and alcoholism treatment involving administration of nicotine and the nicotinic antagonist mecamylamine will be explored. In Study 1, the acute interactive effects of controlled doses of alcohol and cigarette smoke will be measured in the laboratory. Subjective and cardiovascular effects as well as indices of cognitive performance will be measured before and after different doses of alcohol are consumed and nicotine-containing vs de-nicotinized cigarettes are smoked. In Study 2, the interactions between alcohol and nicotine administered in skin patches will be assessed. Study 3 will investigate the role of nicotinic neurotransmission in alcohol reward by measuring the effects of controlled doses of alcohol following administration of the nicotinic antagonist mecamylamine. Studies 4 and 5 will evaluate the efficacy of nicotine/mecamylamine treatment for smoking cessation among heavy drinkers, and will also determine whether ad lib alcohol consumption is suppressed by this treatment. In a randomized, double-blind trial, subjects will receive eight weeks of treatment using either combined nicotine/mecamylamine administration, nicotine alone, mecamylamine alone or placebo. Alcohol consumption and relapse to smoking will be assessed during treatment and at a six-month follow-up. Study 6 will evaluate the efficacy of nicotine/mecamylamine treatment in patients undergoing treatment for alcohol dependence. Smoking behavior as well as relapse to alcohol will be monitored over eight weeks. The results of these studies will contribute to the understanding of factors mediating the reinforcing actions of concurrent alcohol/nicotine use and will extend the generality of effective smoking cessation treatments to individuals exhibiting excessive alcohol use or dependence. In addition, this research may lead to the development of nicotinic treatments that reduce alcohol consumption among heavy drinkers and promote abstinence from alcohol in alcoholics.

The Administrative Core will manage the overall operations of the center and will be responsible for coordinating the activities of the various components to promote the cohesive functioning of the center as a whole. This will include monitoring progress on all projects and scheduling the allocation of other resources to ensure their efficient use while maintaining a steady demand on these resources. The administrative core will also monitor and control expenditures of all center projects as well as handle budget projections. In addition, this core will coordinate interactions with the External Advisory Committee and the Data Safety Monitoring Board. Moreover, the Administrative Core will organize monthly meetings of the Executive Committee, consisting of project directors as well as other key center personnel. These meetings will foster communication between the project and core leaders and facilitate key decision making activities to guide the center?s progress to achieve our scientific and training objectives. In addition to overseeing and coordinating the research projects, the Administrative Core will also orchestrate training and education of students and post-doctoral fellows, and disseminate findings to treatment providers, public policy makers and the lay public. In this manner, the Center can serve as national resource to promote improved smoking cessation treatment throughout the nation?s health care system. The dissemination of this knowledge will help reduce, and ultimately end, the enormous burden of death and disease caused by cigarette smoking.

DESCRIPTION (provided by applicant): In this NIDA P50 application, we propose to establish a new Center for Excellence dedicated to the development of more effective smoking cessation treatments. Current smoking cessation treatments are ineffective for the majority of smokers, and new strategies are urgently needed. We propose to build upon the successful translational research center we have established over the last two decades to continue the process of discovering novel and more efficacious treatments. We have initiated the development of a unique adaptive treatment strategy, which alters treatment according to the characteristics of individual smokers (e.g., genotype) and the initial response to nicotine replacement therapy (NRT) prior to the target quit-smoking date. In this innovative approach to NRT, nicotine patch treatment is initiated two weeks before the quit date, which has been shown to double rates of continuous smoking abstinence over those obtained using conventional NRT that begins on the quit date. By monitoring ad lib smoking during the two-week prequit period, we can adapt treatments so that smokers who do not respond favorably, in terms of a reduced ad lib smoking, may be offered rescue treatments that increase their chances of success. This adaptive treatment strategy will be pursued in a tightly interwoven set of preclinical and clinical projects and cores. The preclinical studies (Project 4) will screen novel candidate treatments in a rodent model of nicotine self administration and identify critical mechanisms of action. Proof-of-concept human studies (Project 2) will evaluate the effects of novel candidate treatments on ad lib smoking and stress-induced craving and smoking behavior. The neuroimaging study (Project 3) will seek to elucidate the brain mechanisms underlying the efficacy of cessation treatments, in order to identify treatments that may prove successful in smokers for whom NRT alone is not effective. Large-scale clinical trials will be conducted (Project 1) to evaluate the efficacy of candidate treatment suggested on the basis of preclinical and clinical results from the other projects. All of the studies using human subjects will be facilitated by our already-established multi-site human subjects recruitment network (Recruitment/ Screening Core). An Education Core will convey the knowledge gained in the research projects to trainees, scientists, and the public at large. Our Center will continue to serve as a national resource for the development of innovative and more effective smoking cessation treatments, and will also be a unique educational resource for researchers, clinicians, and policymakers dedicated to the improvement of public health through the promotion of smoking cessation. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the leading and preventable cause of disease and death in the U.S. This health burden can be reduced substantially by quitting smoking, and yet current smoking cessation treatments have only limited effectiveness. The proposed Center will develop and evaluate promising smoking cessation treatment strategies that are adapted to the needs of individual smokers. By promoting more effective smoking cessation treatment, this Center has the potential to have a major positive impact on public health. CENTER CHARACTERISTICS:

Current smoking cessation treatments are ineffective for the majority of smokers. Thus there is an urgent need to develop more effective treatment strategies. This project will comprise two large-scale randomized controlled clinical trials designed to evaluate the efficacy of an enhanced adaptive treatment strategy for smoking cessation. The essence of our unique approach to adaptive treatment is to begin treatment with state-of-the-art nicotine replacement therapy (NRT), which is initiated 2 weeks before a target quit-smoking date. We will subsequently adapt the treatment approach based on smokers'initial response to NRT and other baseline variables assessed prior to the target quit date. Our overarching hypothesis is that we will enhance cessation outcomes by adapting phannacologic treatments based on individual subject characteristics and ad lib smoking during the time when smokers are receiving pre-cessation NRT. Study 1, to be conducted in years 1-3, will evaluate a specific two-phase adaptive treatment algorithm. We will initiate pre-cessation nicotine patch treatment 2 weeks before a target quit-smoking date. If, after one week's exposure to NRT, participants do not show a favorable therapeutic response (assessed by the early outcome marker of reduced ad lib smoking before the quit date), they will be randomized to receive "rescue treatments with bupropion SR (Zyban), varenicline (Chantix), or will remain on NRT (control). Study 2, to be conducted in years 4-5, will evaluate an additional candidate medication, using the same adaptive treatment strategy as in Study 1. The selection of the candidate treatment will be based on available preclinical and clinical evidence from the other center projects as well as findings from other laboratories, using criteria described in the Research Plan. Candidate medications will include the neurosteroids DHEA and pregnenolone, other GABAergic, glutamatergic, or monoaminergic agents as well as nicotinic subtype selective ligands. Clinical trial decisions and results will be enhanced by information on individual subject characteristics, including quit success genotypes, dependence level, gender, as well as psychiatric and substance use comorbidities. Combined information from these baseline characteristics and smoking during pre-cessation NRT are likely to provide powerful predictors of which medication and treatment regimens are most likely to succeed for different smokers. The knowledge gained from these studies will provide an important new therapeutic approach to guide health care providers in delivering the most effective cessation treatments that are best adapted to the needs of each smoker.

This Clinical Trials project will evaluate several innovative, personalized and adaptive approaches to smoking cessation treatment. We developed and validated the first evidence-based algorithm for tailoring smoking cessation treatment to smokers? baseline characteristics and their initial therapeutic response to treatment with our previous 4 years of NIDA support. We will build on this progress by exploring three novel therapeutic approaches that seek to benefit the following distinct populations of smokers: 1) women concerned about weight gain after quitting smoking, who have been shown in previous studies to be especially prone to relapse after quitting smoking. We will evaluate the efficacy of lorcaserin, a 5-HT2C agonist that is FDA-approved for weight loss, which has been shown by our Center?s Preclinical Studies to reduce nicotine self-administration. A sample of women concerned about post-cessation weight gain will be randomized to receiving lorcaserin vs. placebo capsules; 2) smokers for whom the inhalational aspects of smoking are important, a need that is not well addressed by conventional nicotine replacement therapy (NRT). Electronic nicotine delivery systems (?ENDS?) provide replacement of both nicotine and key inhalational aspects of smoking behavior and have shown promise in smoking cessation treatment. In a sample of smokers who report inhalational aspects of smoking to be important to them, we will evaluate the efficacy of ENDS alone or in combination with NRT compared to NRT alone; and 3) smokers who express concern about negative mood consequences of quitting smoking, which confers greater risk of relapse. In these smokers, we will evaluate the efficacy of amitifadine, a triple serotonin-norepinephrine-dopamine reuptake blocker that has antidepressant effects. Amitifadine has also been found in our Center?s Preclinical Studies to reduce nicotine self-administration. Smokers will be randomized into three groups receiving one of the two active doses of amitifadine or placebo. In each of the above clinical trials, participants will be evaluated after the first week of treatment, using a laboratory-based paradigm to identify and validate early markers of treatment outcome. These measures include ad lib smoking, mood, craving and withdrawal symptoms, and the ability to refrain from smoking in a simulated smoking lapse paradigm. We will correlate treatment outcome with these measures of the initial response to treatment. Additionally, we will correlate abstinence outcomes with smokers? baseline characteristics, including demographic variables, smoking history, and genetic markers identified in prior studies. By validating markers predictive of treatment outcome, we will both facilitate the rapid screening of novel candidate treatments and help identify which treatments will be most likely to help specific subpopulations of smokers achieve long-term smoking abstinence. Together with evaluating the efficacy of the candidate treatments described above, this project will likely contribute valuable new therapeutic approaches and a framework to help guide their dissemination to targeted subpopulations of smokers.

DESCRIPTION (provided by applicant): E-cigarettes and related technologies offer an important potential avenue for reducing the death and disease resulting from cigarette smoking. However, relatively few controlled investigations have been conducted to assess the influence of e-cigarette contents on product use and concurrent smoking of conventional cigarettes. It is important to determine how the contents of e-cigarettes influence their use and whether the absence of constituents in e-cigarettes that are present in conventional cigarettes provides a barrier to acceptability for smokers who may have become dependent on these constituents in conventional cigarettes. Continued use of conventional cigarettes along with e-cigarettes, which currently characterizes a substantial proportion of e- cigarette use, will attenuate any harm reduction associated with switching from combustible cigarettes to e- cigarettes. Cigarette addiction critically involves a dependence on nicotine, but it is likely that other tobacco constituents contribute to dependence. Mounting evidence implicates non-nicotine tobacco alkaloids, or NNTAs (including anabasine, anatabine, nornicotine and myosmine) in tobacco dependence. These alkaloids have been shown to augment the reinforcing effects of nicotine in animal models and to affect craving in human smokers. E-cigarettes contain variable quantities of nicotine and NNTAs, but there is virtually no information available concerning the role of e-cigarette nicotine or NNTA content in influencing the concurrent use of cigarettes and e-cigarettes, when smokers attempt to make a transition from conventional combustible cigarettes to e-cigarettes. Additionally, it is not known whether the presence of nicotine and NNTAs in e- cigarettes may sustain dependence, making it difficult to relinquish these products, as well as potentially increasing their use among adolescents. The proposed study will assess the effects of e-cigarette nicotine and NNTA content on cigarette smokers who will be randomized to conditions that manipulate the nicotine and NNTA content of e-cigarettes. Dependence and concurrent use of e-cigarettes and cigarettes will be assessed by a battery of self-report, biochemical, and behavioral indices. The findings from this project will have direct application to regulatory decision-making of the FDA. In so doing, the findings will facilitate the mission of FDA to effectively curb tobacco addiction and make tobacco-related death and disease part of America's past.