Neural Substrates in Nicotine Withdrawal

Tolcapone, an FDA-approved treatment for Parkinson's disease, improves cognitive performance
in healthy controls with COMT val/val genotypes, putatively by increasing prefrontal
dopamine levels. We propose a within-subject double-blind cross-over neuroimaging study of
short-term (11 days) treatment with tolcapone (vs. placebo).

Thirty chronic smokers (15 with val/val genotypes and 15 with val/met or met/met genotypes)
will undergo blood oxygenation level dependent (BOLD) fMRI during the two medication
periods:

1. after 24 hours of monitored abstinence while on tolcapone, and

2. after 24 hours of monitored abstinence while on placebo (medication order
counterbalanced with at least a 10-day washout).

The BOLD fMRI data will be acquired while subjects perform a working memory task (Fractal
N-back), a sustained attention task (Continuous Performance Task; CPT), and a response
inhibition task (Go/No-Go). The primary outcome is medication effects (within subject) on
task-related BOLD activation after 24 hours of abstinence. Changes in behavioral
performance and subjective symptoms will be examined in relation to brain activity changes.

The proposed study will provide a critical mechanistic understanding of the role of COMT in
abstinence-induced cognitive symptoms that promote smoking relapse. Information obtained in
this study may further establish cognitive performance measures as endophenotypes for
nicotine dependence.

Inclusion Criteria:

- Smokers who are between 18 and 65 years of age who self-report smoking at least 10
cigarettes (menthol and non-menthol) per day for at least the last 6 months.

- Healthy as determined by the Study Physician, based on a medical evaluation including
medical history and physical examination, psychiatric evaluation, and liver function
tests (LFTs and GGT enzyme levels).

- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the combined consent and HIPAA form.

- Women of childbearing potential must consent to use a medically accepted method of
birth control while participating in the study (e.g., condoms and spermicide, oral
contraceptive, Depo-provera injection, contraceptive patch, tubal ligation) and have
3 months of regular menstrual cycles.

- Capable of providing a Carbon Monoxide (CO) breath test reading greater than 10 parts
per million (ppm) at the medical screening visit.

Exclusion Criteria:

Smoking behavior

- Current enrollment or plans to enroll in another research or smoking cessation
program in the next 3 months.

- Provide a CO reading less than or equal to 10ppm at the medical screening visit.

- Plans to use nicotine substitutes (gum, patch, lozenge, e-cigarette) while enrolled
in the study.

Alcohol/Drug Exclusion:

- History (past 2 years) or current diagnosis of substance abuse and/or currently
receiving treatment for substance abuse (alcohol, THC, cocaine, PCP, amphetamines,
methamphetamines, MDMA/ecstasy, opiates, methadone, benzodiazepines, tricyclic
antidepressants, and barbiturates).

- Current alcohol consumption that exceeds 21 standard drinks/week over the last 6
months.

- Positive urine drug screen (for substances listed previously) at the medical
screening visit or either testing day.

- Breath Alcohol Concentration (BrAC) assessment greater than or equal to 0.01 at
medical screening visit or either testing day.

Medication Exclusion Criteria:

Current use or recent discontinuation (within last 28 days) of any medication including
the following:

- Any form of psychotropic medications including: Antipsychotics; Mood-stabilizers
(e.g., lithium, valproic acid, carbamazepine/tegretol); Anti-depressants (tricyclics,
SSRI's, MAOI's, nonselective MAOIs, Wellbutrin, St. John's Wort);
Anti-anxiety/Anti-panic agents; Anti-obsessive agents; Prescription stimulants (e.g.,
Provigil, Ritalin); Diet Pills/Anorectics; Systemic Steroids; Daily medication for
chronic pain (e.g., opiates) or muscle spasms; Daily use of over the counter
stimulants in pill form (e.g., ephedrine)

- Anti-coagulants (e.g., Warfarin)

- Any heart medications (e.g., dobutamine, isoproterenol)

- Daily medication for asthma

- Parkinson's disease medications (e.g., levodopa, methyldopa, apomorphine)

- Sympathomimetic (e.g., albuterol, pseudoephedrine)

- Other smoking cessation medications (Wellbutrin/Zyban, Chantix/varenicline)

Medical Exclusion Criteria:

- Women who are pregnant, planning a pregnancy within the next 3 months, or lactating.

- History or current diagnosis of any Axis 1 disorder as identified by the MINI (Mini
International Neuropsychiatric Interview) or self-report. For major depression, only
a current diagnosis will be exclusionary.

- History or current diagnosis of Attention-Deficit Hyperactivity Disorder (ADHD).

- Serious or unstable disease (e.g., cancer within the past 6 months [except squamous
cell carcinoma], HIV, Parkinson's disease).

- History of epilepsy or a seizure disorder.

- History or current diagnosis (last 6-months) of abnormal rhythms and/or tachycardia
(>100 beats/minute); history or current diagnosis of COPD, cardiovascular disease
(stroke, angina, coronary heart disease); heart attack in the last 6 months;
uncontrolled hypertension (SBP>150 or DBP>90).

- History or current kidney and/or liver failure (including transplant), disease, or
impairment (e.g., cirrhosis); history or current diagnosis of hepatitis (excluding
hepatitis A); liver function tests more than 20% outside of the normal range;
Gamma-glutamyl Transpepsidase (GGT) values greater than 20% outside the normal range.

- Allergy to the study medication, tolcapone (Tasmar).

- History of severe, uncontrolled muscle movements (e.g., uncontrolled jerking,
twitching) or a certain severe muscle problem (rhabdomyolysis).

- Low or borderline intellectual functioning - determined by receiving a score of less
than 90 on the Shipley Institute of Living Scale (SILS) which correlates with the
Wechsler Adult Intelligence Scale-Revised (WAIS-R) Estimated IQ Test (administered at
the medical screening visit).

- Experience of dizziness or lightheadedness upon standing on a daily basis.

- Lifetime history of stroke.

fMRI Exclusion Criteria:

- Self-reported history of claustrophobia.

- Left-handedness.

- Color blindness.

- Any impairment preventing subjects from using response pad necessary for cognitive
testing.

- Circumstances or conditions that may interfere with magnetic resonance imaging (MRI).

- Having a cochlear implant or wearing bilateral hearing aids.

- Self-reported history of head trauma (including being knocked unconscious for 3
minutes or greater and diagnosis of a concussion) or CNS tumor.

- Self-reported use of pacemakers, certain metallic implants, or presence of metal in
the eye as contraindicated for MRI.

- History of gunshot wound.

- Weight greater than 300lbs. at medical screening or either testing day.

- Completion of cognitive testing in study #810493 or #811325 within the last 6 months.

Genetic Profile Exclusion Criteria:

- In order to balance the distribution of males and females, some participants who meet
genotype and other eligibility criteria may not be enrolled in the study.

General Exclusion Criteria:

- Any medical condition or concomitant medication that could compromise subject safety
or treatment, as determined by the Principal Investigator and/or Study Physician.

- Inability to provide informed consent or complete any of the study tasks as
determined by the Principal Investigator and/or Study Physician.