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CENTURY
Yale University
School of Medicine
SAC-203
Connecticut
Mental Health Center
34 Park Street
New Haven, CT 06519

Phone:
203-974-7591

Fax:
203-974-7606

E-mail:
infocentury@yale.edu

CENTURY/TTURC Press Release

Tobacco Dependence & Risk Factors for Treatment Failure

Principal Investigator: Stephanie O'Malley

Grant Period: 9/01/04 to 8/31/09

Overall Project Description: In this competitive renewal, we will continue to investigate the underlying mechanisms of and develop novel interventions (pharmacological and behavioral) for treatment resistant smokers. We will build upon and extend research findings from our ongoing TTURC research which suggests that in addition to female gender and the presence of subclinical alcohol drinking and depressive symptoms, abstinence-mediated anxiety and weight concern may also confer resistance to smoking cessation treatment. While traditionally these risk factors have been studied independently, this TTURC research will address at least two of these risk factors simultaneously and involve a strong transdisciplinary approach that incorporates preclinical behavioral/ molecular, human laboratory studies, pharmacological treatment and imaging techniques. Methods for insuring transdisciplinary collaboration and synthesis of findings will be articulated for the center as a whole and within each project. In taking this approach we will arrive at a more complete synthesis of why these groups are at greater risk and how they can be more effectively treated. The following specific aims have been achieved and will continue in the TTURC:

• To conduct a series of programmatic research studies that will lead to a greater understanding of the underlying reasons that these high risk groups find it difficult to quit tobacco use and how to more effectively treat them.
• To channel research efforts into a transdisciplinary team approach where the theories and methods of each discipline will be brought to bear on the problem of treatment resistance and the results will be synthesized at a level that transcends disciplinary boundaries.
• To provide career development activities for advanced undergraduate students, graduate students, medical students, and junior investigators from different disciplines that will expose them to transdisciplinary research on tobacco/nicotine and will potentially influence some to pursue transdisciplinary careers in nicotine/tobacco research.

Specific projects include:

• Project 1: Animal Models to Understand Risk Factors for Treatment Resistance
• Project 2: Imaging Nicotinic and GABAergic Markers in Tobacco Smokers
• Project 3: Modeling Smoking Lapse Behavior for Drug Development
• Project 4: Targeted Interventions for Weight Concerned Smokers

Specific Projects

Project 1: Animal Models to Understand Risk Factors for Treatment Resistance

Many current smokers show several risk factors that make smoking cessation more difficult. We propose to study the biological basis underlying how risk factors might lead to relapse to smoking. Some predictors of treatment failure for smoking cessation include weight concerns, heavy alcohol use, and female gender. This proposal will use animal models to determine how nicotine affects biological processes related to these risk factors, and will focus on how neuronal nicotinic acetylcholine receptors (nAChRs) can affect behavioral and biochemical responses related to these risk factors. These experiments will make use of pharmacological studies in normal rodents as well as experiments with mice lacking the beta2 subunit of the nAChR, transgenic lines with selective expression of these nAChRs in particular brain regions and knockout mice lacking the neuropeptides CART, galanin and NPY which have previously been generated. The aims of this project are: 1) to follow up on previous studies identifying second messenger pathways affected by nicotine treatment by using viral vector and local infusion strategies, identifying functional effects of these molecular changes on behaviors related to nicotine addiction; 2) to determine the relationship between nicotine, food intake, expression of hypothalamic peptides and appetitive behaviors in normal mice and rats undergoing behavioral paradigms following nicotine treatment, and in knockout mice lacking hypothalamic peptides related to feeding (the effect of naltrexone on these parameters will also be investigated); 3) to identify sex differences in these behavioral and neurochemical effects; 4) and to determine the concurrent and independent effects of chronic ethanol and nicotine treatment on biochemical and behavioral responses in appetitive behaviors. These experiments will contribute to the scientific background necessary for designing new strategies for treatment of smokers resistant to current cessation methods.

Principal Investigator: Marina Picciotto. Ph.D.

Co-Investigator: Jane Taylor, Ph.D.

Project 2: Imaging Nicotinic & GABAergic Markers in Tobacco Smokers

The nature of tobacco smoking and nicotine addiction is different between women and men. In particular, women appear to be less sensitive and more tolerant to the pharmacological effects of nicotine. Women also exhibit a poorer response to nicotine replacement therapies; are more vulnerable to smoking-related diseases (e.g. cancer and cardiovascular disease) and to subsyndromal mood disorders (depression and anxiety). Studies in animals and humans have linked subsyndromal anxiety and depressive symptoms to chronic nicotine exposure. In brain, nicotine binds to nicotinic acetylcholine receptors (nAChR) and initiates the release of most major neurotransmitters such as the major inhibitory neurotransmitter, gamma aminobutyric acid (GABA). High-affinity nicotinic agonist binding is elevated in animals chronically treated with nicotine and also in postmortem brain from tobacco smokers. The consequences of the regulatory changes in the nAChR, on GABAergic function are currently not well understood. In the present application, we propose 1) To determine if there are sex differences in high affinity nicotinic agonist binding to beta2-containing nAChR (beta2-nAChR) in men and women never smokers and recently abstinent smokers 2) To determine if cortical GABA and GABAA-benzodiazepine (GABAA-BZR) receptors are decreased in a sex-specific manner in actively dependent tobacco smokers compared to never smokers, and 3) To determine if there is a sex-specific elevation in cortical GABA levels over the first week of abstinence from smoking. Nicotine-induced adaptations in cortical beta2-nAChR, GABA and GABAA-BZR may underlie the anxiety and/or depressive symptoms often observed in women smokers. An understanding of the regulatory effects of smoking and acute abstinence on these key neurochemical targets in brain, may lead to the identification of better pharmacotherapies for smoking cessation in men and women smokers.

Principal Investigator: Julie Staley, PhD

Co-Principal Investigator: Graeme Mason, PhD

Project 3: Modeling Smoking Lapse Behavior for Drug Development

For the current proposal, we are planning to continue with the development of a novel self-administration paradigm to examine how known precipitants of relapse (i.e., nicotine deprivation, smoking availability, and alcohol) facilitate lapse behavior for the purpose of medication screening. The first occurrence of smoking during a cessation attempt is a critical transition, as the vast majority of abstinent smokers who experience a lapse return to baseline levels of smoking. This transition represents an important target for medication development and as a result, we have decided to focus our models on early lapse behavior. To date, there has been limited work developing lapse/relapse models of smoking (Chornock et al., 1992; Juliano & Stitzer, 2003), and to our knowledge, only one study has examined medication effects with such a model (King & Meyer, 2000).

Building on our previous work developing innovative self-administration models to assess medication effects (O'Malley et al., 2000), we are proposing to conduct a series of paradigmatic studies to develop smoking lapse models that incorporate multiple factors that precipitate relapse behavior and then to assess the sensitivity of these models with medications known to affect the models' primes. The two human laboratory models that we are proposing to investigate for this project will examine the influence of multiple primes (i.e., nicotine deprivation, smoking availability, alcohol) on two primary aspects of early lapse behavior: 1) ability to resist the first cigarette and 2) subsequent smoking . The Nicotine Deprivation Model will model the influence of nicotine deprivation + smoking availability on early lapse behavior. The Alcohol Model will model the influence of alcohol + smoking availability on early lapse behavior. Study 1 will extend our pilot work developing the Alcohol Model , to examine the sensitivity of this model to a medication known to attenuate the effects of the alcohol (naltrexone). Study 2 will identify the optimal nicotine deprivation window to use in the Nicotine Deprivation Model . Study 3 will examine the sensitivity of the Nicotine Deprivation Model by investigating the ability of nicotine patch and bupropion to attenuate the ability of nicotine deprivation to prime smoking lapse behavior. Human laboratory models of smoking lapse behavior would facilitate translational work in medication development by providing an intermediary step between preclinical studies and clinical trials. Ultimately, these smoking lapse paradigms could be utilized by us and others in the scientific community to screen promising pharmacological agents.

Principal Investigator: Sherry McKee

Project 4: Targeted Interventions for Weight Concerned Smokers

Current pharmacological treatments for smoking cessation, including nicotine replacement therapies and bupropion, are modestly successful in assisting smokers to quit {George, 2004 #1958}. Moreover, certain barriers limit the success of smoking cessation attempts and even prevent some smokers from attempting to quit, particularly the issue of post-cessation weight gain. A number of ideas have been proposed to explain why weight concerned individuals may have more trouble quitting smoking, including the possibility that attempting to simultaneously control two behaviors, food intake and smoking, leads to failure. However, few laboratory studies have examined the effects of food and tobacco deprivation together, and no pharmacological treatments have been specifically targeted to the concerns of this population. Because current therapies only partially reduce the risk of weight gain and associated concerns, a better understanding of these effects could facilitate the development of more effective treatments for smoking cessation in a weight concerned population. Treatments that attenuate post-cessation weight gain will reduce an important barrier to quitting and motivate smokers who are concerned about this issue to make a quit attempt. In turn, if they are successful, they should accrue important benefits, including reducing their life time exposure to tobacco.

In our original grant, we conducted a dose ranging study of naltrexone in combination with transdermal nicotine replacement therapy. In this study, we found that low dose naltrexone in combination with the nicotine patch reduced weight gain in those who succeeded in smoking cessation, and improved smoking cessation outcomes in a subset of participants who smoked to control their weight. These findings suggest that low dose naltrexone may provide a novel, highly translatable strategy for addressing the needs of weight concerned smokers.

To further investigate these findings, two avenues of investigation are planned: 1) a clinical trial in weight concerned smokers testing the efficacy of low dose naltrexone on weight gain and smoking cessation; and 2) a human laboratory study designed to understand the interactive effects of food and tobacco deprivation on smoking behavior. This study will compare the effects of food deprivation and tobacco deprivation to the effects of tobacco deprivation alone on efforts to resist smoking and ad lib smoking.

Principal Investigator: Stephanie O'Malley