A Multi-Modal Investigation of the Smoking Cessation Medication Varenicline: Dopaminergic Modulation of Reward Processing and Cognitive Control
| Status: | Completed |
|---|---|
| Conditions: | Smoking Cessation, Tobacco Consumers |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 55 |
| Updated: | 4/17/2018 |
| Start Date: | November 25, 2008 |
| End Date: | February 26, 2013 |
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.
- 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.
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.
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.
- INCLUSION CRITERIA:
1. between the ages of 18-55.
2. right-handed.
3. in good health.
4. free of active DSM-IV dependence, or dependence in partial remission, on alcohol
or any drug except nicotine. Past active dependence is acceptable provided it is
at least five years in the past and total time of active dependence did not
exceed 4 years. Those with past dependence may not have any current use (past 6
months) of the substance on which they were dependent.
5. able to abstain from alcohol 24hrs before each of the imaging sessions and able
to moderate their caffeine intake 12hrs before each session.
In addition, smokers must:
1. smoke 10 or more cigarettes per day and have smoked for more than 2 years.
2. be able to refrain from smoking for up to 12hrs (at 6 different time points) during
the study.
3. be able to tolerate the nicotine patch.
In addition, non-smokers must:
(1) Not have a history of daily cigarette smoking lasting more than a month and no smoking
within the past 2 years.
EXCLUSION CRITERIA:
1. are not suitable to undergo an fMRI experiment due to certain implanted devices
(cardiac pacemaker or neurostimulator, some artificial joints, metal pins, surgical
clips or other implanted metal parts), body morphology, or claustrophobia.
2. have coagulopathies, history of, current superficial, or deep vein thrombosis,
musculoskeletal abnormalities restricting an individual s ability to lie flat for
extended periods of time.
3. have HIV or Syphilis.
4. regularly use any prescription, over-the-counter or herbal medication that may alter
CNS function, cardiovascular function, or neuronal-vascular coupling.
5. have any current, or a history of, neurological illnesses including, but not limited
to, seizure disorders, frequent migraines or on prophylaxis, multiple sclerosis,
movement disorders, history of significant head trauma, or CNS tumor.
6. have any current, or a history of, major psychiatric disorders, substance-induced
psychiatric disorders, suicidal ideations and/or suicide attempts, or currently under
antidepressant or antipsychotic medication treatment.
7. are cognitively impaired or learning disabled.
8. have significant cardiovascular or cerebrovascular conditions.
9. have moderate to severe renal impairment.
10. are diabetic.
11. have any other major medical condition that in the view of the investigators would
compromise the safety of an individual during participation.
12. pregnant, planning to become pregnant, or breastfeeding.
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