This positron emission tomography (PET) study examines the effects of 24 hours abstinence from smoking on return to availability of neuronal nicotinic receptors in slow and fast metabolizers of nicotine.

The nicotine metabolite ratio (NMR), a stable marker of nicotine clearance rate, is a robust predictor of smoking relapse. Individuals who are fast nicotine metabolizers have higher rates of relapse, compared to slow metabolizers, on nicotine replacement or placebo treatment. Nicotine exerts its reinforcing properties, in part, by binding to α4β2* nicotinic acetylcholine receptors (nAChRs) in the brain. The α4β2* nAChRs are abundant and have high affinity for nicotine relative to other nAChR subtypes. The goal of this project is to identify abstinence-induced changes in neuronal nicotinic receptor availability that may underlie risk for smoking relapse.

The investigators propose to utilize positron emission tomography (PET) imaging to examine the association of variation in nicotine metabolism with return to availability of α4β2* nAChRs during early abstinence. The investigators will measure α4β2* receptor availability using the PET radio-ligand 2-[18F]FA, administered with bolus injection, on two separate occasions: during smoking as usual and after 24 hours of abstinence. The proposed study will help us understand the neurochemical mechanisms that underlie the higher risk of relapse among faster nicotine metabolizers, thereby pointing to potential targets for tailored therapy for these smokers at increased risk.

In addition, the investigators will invite six subjects who have completed the two PET scans described above to complete a third PET scan. During this third PET scan, the investigators plan to measure α4β2* receptor availability using the PET radio-ligand 2-[18F]FA, administered as bolus plus constant infusion after 24 hours of abstinence. The purpose will be to compare α4β2* nAChR binding potential data from the bolus 2-[18F]FA infusion protocol used in the main study to the bolus plus constant infusion protocol used in this third PET scan.

The protocol of this third PET scan will help the investigators demonstrate the feasibility at the University of Pennsylvania of administering the radiotracer as a bolus plus constant infusion, and the feasibility of scanning for two hours (versus one hour in the current protocol) paradigm. This data is important pilot data for future NIH grant submissions using this radiotracer.

Inclusion Criteria:

1. Ages 18 to 65 years old.
2. Smoke 10 cigarettes per day for the previous 6 months.
3. Weigh less than 300lbs (due to limitations of the PET and MRI scanners).

Exclusion Criteria:

1. Smoking behavior:

   1. Current enrollment or plans to enroll in a smoking cessation program, or use other smoking cessation medications in the next 2 months.
   2. Provide a CO reading of less than 10 ppm at medical screening.

2. Alcohol/Drugs:

   1. History of substance abuse and/or currently receiving treatment for substance abuse (e.g., alcohol, opioids, cocaine, marijuana, or stimulants).
   2. Positive drug screen at any of the sessions (see page 8 for list of drugs and/or contra-indicated medications).
   3. Current alcohol consumption that exceeds 25 standard drinks/week.
   4. Providing a breath alcohol concentration (BrAC) reading of greater than or equal to 0.01 at any session.

3. Medical:

   1. Women who are pregnant, planning a pregnancy, or lactating; all female subjects shall undergo a serum pregnancy test at the medical screening session and urine pregnancy tests at the two PET scans and MRI scan.
   2. Women of child-bearing age must agree in writing to use an approved method of contraception or agree to abstain from sexual intercourse
   3. History or current diagnosis of the following psychiatric diagnoses identified by the MINI (Mini International Neuropsychiatric Interview) such as psychosis, bipolar disorder, schizophrenia, major current depression, or any Axis 1 disorder
   4. Self-report of serious or unstable disease within the past 6 months (e.g., cancer [except melanoma], HIV/AIDS, stroke, angina, coronary disease, heart attack).
   5. History of epilepsy or a seizure disorder.
   6. Any medical or neurological condition that might interfere with the distribution of the radiotracer as determined by the study M.D.

4. Medication:

   a. Current use or recent discontinuation (within last 14-days) of the following medications:

   • Any form of smoking cessation medication (Zyban, Wellbutrin, Wellbutrin SR, Chantix, NRT);
   • Recent (within last 14 days) or planned use of psychotropic medications (anti-psychotics, anti-depressants, anti-anxiety, anti-panic medications, mood stabilizers, opioids, and stimulants).
   • Participants shall be instructed to refrain from using any study prohibited drugs (note - participants are allowed to take prescription medicines not in the exclusion list) throughout their participation in the study.

5. Imaging-Related Exclusion Criteria:

   1. Self-reported history of head trauma or brain (or CNS) tumor.
   2. Self-reported history of claustrophobia (contraindicated for PET and MRI).
   3. Having a cochlear implant or wearing bilateral hearing aids.
   4. Self-reported use of pacemakers, certain metallic implants, or presence of metal in the eye as contraindicated for MRI.
   5. History of gunshot wound.
   6. Circumstances or conditions that may interfere with magnetic resonance imaging (MRI)
   7. Inability to complete the baseline study procedures within four hours and/or correctly, as determined by the PI.

20 adult, non-treatment seeking smokers, reporting consumption of greater than/equal to 10 cigarettes per day for at least 6 months will be the target population for the study. Participants will first be screened over the phone and then complete an in-person medical screen to ensure final eligibility. Enrolled participants will complete 2 PET scans and an MRI scan.

6 smokers who have completed the study and have agreed to be re-contacted for future studies will be invited to participate in an additional procedure. Participants will be screened over the phone and complete an in-person medical screen to ensure final eligibility. Enrolled participants will complete 1 PET scan.