This study will evaluate effects of treatment with varenicline, a smoking cessation drug, on the dopaminergic system by using Positron Emission Tomography (PET) imaging with new radioligand, [11C]-(+)-PHNO. The investigators primary hypothesis is that chronic varenicline administration will increase dopamine (DA) receptors levels ([11C](+)PHNO) within the human brain.

Subjects will undergo a pre-treatment PET and MRI scans for baseline [11C](+)PHNO measures on Day 1. Subjects will subsequently be provided an initial 2-week supply of study medications (varenicline) and directions for use. Any adverse events, compliance to medication and smoking patterns will be noted during these two weeks. Varenicline will be used at the same dosage regimen as used for smoking cessation. After subjects go through a post-treatment PET and MRI scans on Day 10, they will be instructed to set up a quit date. There will then be follow-up visits every 2 weeks for the duration of the medication phase (3 months total) and a visit at 6 months follow-up.

Inclusion Criteria:

• Subjects will be nicotine dependent, males and females of any ethnic origin between 21 and 45 years old.
• Meet DSM-IV criteria for nicotine dependence,
• Smoke ≥10 cigarettes/day, Baseline FTND score ≥4, CO level ≥10 and are motivated to quit within 30 days of initial intake.
• Treatment seeking smokers that are willing to use varenicline as a treatment approach for their smoking cessation attempt
• No previous use of medication for smoking cessation in previous month prior inclusion.

Exclusion Criteria:

• Pregnancy (a urine pregnancy test will be performed before each PET in women)
• Trying to become pregnant or breastfeeding;
• Have abused alcohol or other drugs of abuse (cocaine, opiates, benzodiazepines, etc) in 3 months prior to randomization.
• Presence of metal objects in the body (e.g. some artificial joints, bone pins, surgical clips, skull plate, certain part of dental braces) or implanted electronic devices (e.g. cardiac pacemaker, neurostimulator), that preclude safe MR scanning.
• Claustrophobia.
• Cardiovascular or cerebrovascular diseases.
• Major psychiatric disorders including mood, anxiety or psychotic disorders with historical evidence of suicidal or homicidal behaviour.
• History of or current neurological illnesses including seizure disorders, migraine, multiple sclerosis, movement disorders, head trauma, CVA or CNS tumor. Gross structural brain abnormalities as revealed by T1 weighted images.
• Current use or use during the previous month of medication that may affect the CNS at the time of scanning (including illicit and non-illicit psychoactive drugs).
• Learning disability, amnesia or other conditions that impede memory and attention.
• Allergy to varenicline.
• Renal insufficiency.
• Use of other smoking cessation aids