Effects of ABT-089 on Smoking Abstinence Symptoms and Reward

Inclusion Criteria. Eligible subjects will be: 1. Male and female smokers who are between 18 and 65 years of age and self-report smoking at least 10 cigarettes (menthol and/or non-menthol) per day for at least the last 6 months. 2. Healthy as determined by the Study Physician, based on relevant medical history, physical examination (including vitals), and basic screening tests (CBC, CHEM7, AST/ALT). 3. Smokers who wish to quit smoking in the next 2-6 months (treatment-seeking), because our prior work suggests that motivated subjects are more sensitive to medication effects on smoking behavior. Using a scale from 0 to 100 (100, being extremely interested), subjects must rate their interest in quitting smoking within the next 6 months greater than 50. 4. Able to communicate fluently in English (speaking, writing, and reading). 5. Plan to live in the area for the next 2 months. 6. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent and HIPAA form. Exclusion Criteria. Subjects who self-report and/or present with the following criteria will not be eligible to participate in the study: 1. Smoking behavior. 1. Current enrollment or firm plans to quit smoking and/or enroll in a smoking cessation program within the next 2 months. 2. Current and/or anticipated use of any nicotine substitutes and/or smoking cessation treatments/medications within the next 2 months. 3. Provide a Carbon Monoxide (CO) reading less than 11 parts per million (ppm) at Intake. 4. Provide a CO reading of 10 ppm or greater at either Testing Visit (Days 6 and 37). If the CO reading is greater than or equal to 10 ppm, but there is a 50% reduction from the CO reading collected at the Baseline/Period 1 Medication Pick-Up Visit, this will be sufficient and the subject may continue as scheduled. 5. Self-report smoking during the mandatory abstinence period at either Testing Visit (Days 6 and 37). 6. Regular use of chewing tobacco or snus. 2. Alcohol/Drugs. 1. History of substance abuse in the past 6 months and/or currently receiving treatment for substance abuse (e.g., alcohol, opioids, cocaine, marijuana, or stimulants). Subjects reporting a history of substance abuse must be in remission at least 6 months or greater. 2. Current alcohol consumption that exceeds 25 standard drinks/week. 3. Provide a breath alcohol concentration (BrAC) reading of greater than or equal to 0.01 at Intake, Baseline/Period 1 Medication Pick-Up, or Testing Visits (Days 6 and 37). 4. A positive urine drug screen for cocaine, PCP, amphetamines, methamphetamines, tricyclic antidepressants, opiates, methadone, benzodiazepines, and/or barbiturates at Intake, Baseline/Period 1 Medication Pick-Up, Period 2 Medication Pick-Up, and Observation Visits on Days 10 and 41. 3. Medical. 1. Women who are pregnant, planning a pregnancy, and/or breast feeding. All female subjects will undergo a urine pregnancy test at Intake, after which only females determined to be of childbearing potential will complete a urine pregnancy test at Baseline/Period 1 Medication Pick-Up, Period 2 Medication Pick-Up, and Observation Visits on Days 10 and 41. By signing the combined consent and HIPAA form, women of childbearing potential agree to use an approved method of contraception during the study. 2. Men who do not agree to use an approved method of contraception during the study. Men who are sexually active must be surgically sterile (vasectomy) or using a barrier method (condom) of birth control for the duration of the study. By signing the combined consent and HIPAA form, men agree to use an approved method of contraception. 3. Current treatment of cancer or diagnosed with cancer (except basal cell carcinoma) in the past 6 months. 4. Any impairment including, but not limited to, visual, physical, and/or neurological impairments preventing neurocognitive task performance. 5. Color blindness. 6. History of brain injury. 7. History of epilepsy or a seizure disorder. 8. Low or borderline intellectual functioning - determined by receiving a score of less than 90 on the Shipley Institute of Living Scale (SILS, administered at Intake), which correlates with the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Estimated IQ Test. 9. Serious or unstable disease within the past 6 months (i.e., heart disease, liver/kidney failure). 10. Recent history (last 6 months) of abnormal heart rhythms, tachycardia, and/or cardiovascular disease (stroke, angina, heart attack) may result in ineligibility. These conditions will be evaluated on a case-by-case basis by the Study Physician. 11. Clinically significant abnormalities determined by physical examination and collection of vital signs at Intake. Abnormalities will be assessed by the Study Physician and eligibility will be determined on a case-by-case basis. 12. Uncontrolled hypertension (Systolic Blood Pressure \[SBP\] greater than or equal to 160 mmHg and/or Diastolic Blood Pressure \[DBP\] greater than or equal to 100 mmHg). 13. Heart rate/pulse greater than or equal to 110 beats per minute (bpm). 14. Clinically significant abnormalities in clinical chemistry (CBC, CHEM7, and AST/ALT). Results greater than 20% outside of normal range will be evaluated for clinical significance by the Study Physician and eligibility will be determined on a case-by-case basis. 15. Inability to provide an assessable blood sample for basic screening tests (CBC, CHEM7, and AST/ALT) at Intake. 4. Psychiatric. As determined by self-report, the Mini International Neuropsychiatric Interview (MINI), and/or Columbia-Suicide Severity Rating Scale (C-SSRS): 1. Any suicide risk score on the MINI. 2. Current (past month) suicidal ideation or lifetime suicidal behavior on the C-SSRS. 3. Lifetime history or current diagnosis of psychosis, bipolar disorder, and/or schizophrenia. 4. Current diagnosis of major depression and/or recurrent major depression. Persons with a history of a single episode of major depression, in remission for 6 months or longer, are eligible provided they are not excluded based on medications (see Medication Exclusion Criteria). 5. Current or past hypomanic/manic episode. 6. History or current diagnosis of posttraumatic stress disorder (PTSD). 7. Prior or current diagnosis of attention deficit hyperactivity disorder (ADHD). 5. Medication. 1. Current use or recent discontinuation (within the last 14 days at the time of Intake) of: * Smoking cessation medication (e.g., Zyban, Wellbutrin, Wellbutrin SR, Chantix). * Anti-anxiety or panic disorder medications. * Anti-psychotic medications. * Medications used to treat depression (e.g., Wellbutrin, MAOIs, SSRIS, tricyclic antidepressants). * Prescription stimulants (e.g., Provigil, Ritalin, Adderall). * Systemic corticosteroids. 2. Current use of: * Nicotine replacement therapy (NRT). 3. Daily use of: * Opiate-containing medications for chronic pain. * Inhaled corticosteroids.