A Multi-Modal Investigation of the Smoking Cessation Medication Varenicline: Dopaminergic Modulation of Reward Processing and Cognitive Control
Condition: Tobacco Use Disorder; Nicotine Dependence
MeSH terms: Tobacco Use Disorder
Study type: Observational

Summary: 
      Background:

        -  Chronic nicotine exposure through cigarette smoking affects the level of the brain
           chemical dopamine. Smokers who attempt to quit experience lower levels of dopamine,
           which increases anxiety and triggers nicotine cravings that make quitting more
           difficult.

        -  Varenicline (Chantix) is a smoking cessation medication that is designed to reduce
           nicotine craving and withdrawal by slightly increasing levels of dopamine in the brain.
           Research has shown that varenicline is a safe, well-tolerated, and effective treatment
           for nicotine dependence, but researchers are interested in learning more about how it
           affects the brain and its function. Functional magnetic resonance imaging (fMRI) and
           electroencephalography (EEG) will help researchers study the brain s response to
           nicotine and varenicline.

      Objectives:

      - To explore how varenicline affects brain function and behavioral performance in current
      smokers and healthy volunteers.

      Eligibility:

      - Individuals between 18 and 55 years of age who are either current smokers (10 or more
      cigarettes per day) or healthy nonsmoking volunteers.

      Design:

        -  The study will involve nine testing and research visits over 5 to 6 weeks. The first
           visit will provide an initial assessment and training on the tasks that will be
           completed during the study.

        -  Six testing visits will involve fMRI and EEG measurements of brain activity. Each visit
           will contain two 2-hour scanning sessions, and each session will involve thinking tests.
           During these visits, participants will receive varenicline and placebo tablets, and wear
           nicotine patches and placebo patches that do not contain nicotine. Participants will not
           be told which tablet or patch they are given. This is a crossover study so all
           participants eventually get nicotine and placebo, as well as varenicline and placebo.

        -  Two other visits involve different thinking tasks. These visits will not require fMRI or
           EEG scans.
    

Detailed description: 
      Objective. Chronic nicotine exposure is thought to lead to alterations in the dopamine (DA)
      system that leaves smokers in a hypo-dopaminergic state during periods of abstinence.
      Varenicline (Chantix), a new efficacious smoking cessation medication, is thought to lead to
      a modest but sustained increase of DA release thereby reducing nicotine craving and
      withdrawal. While numerous studies have shown that varenicline is a safe, well-tolerated, and
      effective pharmacological treatment for nicotine dependence, studies exploring the
      neurophysiological impact of this drug in the human brain have not been conducted. This
      protocol will utilize an array of reward processing and cognitive control tasks to explore
      the effects of subtle DA manipulations (induced by smoking cessation, transdermal nicotine,
      and varenicline) on brain function and behavioral performance. Brain function will be
      assessed using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG).

      Study Population. There will be two study populations: 1) healthy nicotine-dependent adults
      who smoke 10 or more cigarettes per day; and 2) healthy non-smoking, non-drug dependent
      controls. Participants must be generally healthy, right-handed, male or
      non-pregnant/non-lactating females between the ages of 18-55.

      Design. After being medically cleared and giving informed consent, each participant will
      complete several imaging visits (6 visits, on separate days) before and after taking
      varenicline. Two of these visits will take place before varenicline administration
      (baseline), two visits after a two-week varenicline dosing period (post-varenicline), and
      another two after a two-week placebo-pill period (post-placebo-pill). Each set of two scans
      will involve the randomized, double blind administration of a nicotine transdermal or placebo
      patch. fMRI and EEG data will be collected after patch application and will involve several
      tasks designed to probe brain regions in a corticolimbic circuit that may mediate aspects of
      reward-processing, learning, attention, goal-directed behaviors, and drug abuse.

      Outcome Measures. This study involves assessing neurophysiological and behavior differences
      between cohorts (smokers vs. non-smokers) and conditions (nicotine vs. placebo-patch;
      baseline vs. varenicline vs. placebo-pill). The primary outcome measures used to ascertain
      these differences will be: 1) percentage change in fMRI BOLD signal during performance of
      cognitive control and reward processing tasks; 2) change in ERP component (e.g.,
      error-related negativity) amplitudes; 3) behavioral measures during task performance
      including reaction times and error rates; 4) scores on mood, personality, and smoking
      questionnaires; and 5) variations in genes related to nicotinic receptors and DA functioning.
    

Time perspective: Other
Keywords: Smoking Cessation; Dopamine; Cognitive Control; Reward Processing; Varenicline