Brain Nicotine Receptor Density in Veteran Smokers

Despite improvements in tobacco control, the prevalence of Tobacco Dependence (TD) remains
high at 27% among Veterans and 21% among the general U.S. population (~46 million U.S.
adults). Both co-morbid substance use and menthol cigarette preference are important issues
contributing to greater severity of TD. Among smokers, a lifetime history of substance
use/dependence is common and approximately 33% of all smokers use primarily menthol
cigarettes, meaning that roughly 9% of Veterans smoke menthols. In addition to menthol
cigarette usage being prevalent among Veterans, this problem is likely to worsen over time,
because recent military deployments increase the chances of smoking initiation and marketing
of menthol cigarettes is aimed at roughly the age group that comprises the active military.

For substance use/dependence, marijuana (MJ) users are five times more likely than non-MJ
users to smoke tobacco cigarettes, and regular caffeine users are twice as likely as
non-caffeine users to smoke cigarettes. Cigarette smoking contributes greatly to morbidity
and mortality among patients with drug (and alcohol) dependencies, making it vital to
understand better the complex relationship between drug/alcohol dependence and brain nicotine
receptor densities in cigarette smokers.

Based on prior literature and pilot data collected during the previous Merit Review period,
the primary hypotheses for the proposed research are that: 1) Participants who are heavy MJ
users will have higher 4 2* nAChR densities in the thalami (and other brain regions) than
participants who are not heavy MJ users, 2) Participants who are daily heavy caffeine users
will have lower 4 2* nAChR densities in the thalami (and other regions) than participants who
are not heavy daily caffeine users, 3) Densities of 4 2* nAChRs in the thalami (and other
brain regions of interest) will be higher in menthol than non-menthol cigarette smokers, and
4) lesser severity of 4 2* nAChR up-regulation at baseline (along with clinical factors such
as lesser severity of nicotine dependence) will be associated with better treatment outcomes
in a standard smoking cessation program, including an improved likelihood of quitting and/or
decreasing smoking.

To test these hypotheses, cigarette smokers will be recruited through flyers posted at the VA
Greater Los Angeles Healthcare System in areas where smokers are likely to be present.
Participants will undergo the following sequence of procedures: (1) telephone/in-person
screening, (2) a bolus-plus-continuous-infusion 2-FA positron emission tomography (PET)
scanning session, (3) a structural magnetic resonance imaging scan within one week of the
initial PET session, and (4) referral to a standard 12-week smoking cessation program. Rating
scales for the determination of smoking-related symptoms will be collected before and during
the PET scanning procedure. Smoking status and measures of nicotine exposure and metabolism
will be collected during the study using participant reports, exhaled carbon monoxide (CO)
levels, urine cotinine levels, and plasma nicotine, cotinine, and 3'-hydroxycotinine levels.

Inclusion Criteria:

- Must be a Veteran cigarette smoker, living within commuting distance of the VA San
Diego Healthcare System

- Healthy adult Veterans (18 to 65 years old) who are tobacco dependent cigarette
smokers (10 to 40 cigarettes per day) meeting criteria for Nicotine Dependence as
defined by DSM-IV criteria109 and who want to quit smoking.

- Heavy marijuana or caffeine use (defined as using the equivalent of > 2 marijuana
cigarettes per week or the use of at least 3 coffee cup equivalents per day) for at
least the past 6 months or no heavy drug/alcohol use.

- Ability to read, write, and give voluntary informed consent.

- An exhaled CO > 8 ppm during the study screening visit to verify smoking status.

Exclusion Criteria:

- Any Axis I diagnosis (including mood, anxiety, and psychotic disorders) other than
Nicotine, Marijuana, or Caffeine Dependence within the past 1 year.

- A current diagnosis (within the past month) of other substance abuse/dependence
diagnoses (such as cocaine, amphetamine, or opiates). (Length of abstinence will be
verified through participant interview and a chart review at the initial study visit,
which typically includes information about substance abuse treatment history and
objective verification with breathalyzer and/or urine toxicology screens). Occasional
drug/alcohol use not meeting criteria for abuse/dependence will not be exclusionary.

- Any current medication or any history of a medical condition that might affect the
central nervous system at the time of scanning (e.g., current treatment with a
psychotropic medication, or history of severe head trauma with loss of consciousness,
epilepsy, or other neurological diseases).

- The combination of both heavy marijuana and caffeine use.

- Unstable cardiovascular disease, severe liver disease, or renal insufficiency, which
might make tolerating study procedures difficult. Routine history and physical
examination will be performed at the initial screening visit to insure that
participants meet study criteria (Section D4).

- Pregnancy (urine pregnancy tests will be obtained on all women of childbearing
potential) due to the theoretical risk of radiation exposure to the fetus.