Translational Neuropsychopharmacology Research of Nicotine Addiction

Cigarette (henceforth nicotine) addiction is a chronic, relapsing brain disorder and remains
the leading preventable cause of death and disability in the US, costing nearly $200 billion
each year. Although ~20% of adults in the USA currently smoke, the majority want to quit. In
spite of the breadth of research focused on improving health outcomes and reducing the
societal burden caused by nicotine addiction, the majority of smokers who attempt to quit
will relapse. Nicotine withdrawal-related disturbances in executive function, negative affect
and reward processes compel a smoker to self-administer nicotine—each in turn representing
the loss of control to remain abstinent and risk factors for relapse. Thus, identifying the
effects of nicotine addiction on mechanisms of self-regulation, and the value of novel
medications for remediating dysregulated behavior are both needed in order to enhance
interventions for treating nicotine addiction. The preliminary data, along with the extant
literature, suggest that the maintenance of nicotine addiction is subserved by dysregulated
neural function in limbic-striatal and corticostriatal neural circuitry. While VRN may be
effective in treating limbic-striatal circuitry that is associated with promoting abstinence
and reducing acute withdrawal; NAC may be effective in treating corticostriatal circuitry
function that is associated with relapse vulnerability. Thus, the current proposal seeks to
investigate two medications (VRN & NAC), with potentially complementary effects on the two
different brain circuits— limbic-striatal (VRN) and corticostriatal (NAC) circuitry—and that
may therapeutically target two different phases in the recovery of nicotine addiction—the
promotion of abstinence (VRN) and relapse prevention (NAC). The placebo (PBO)-controlled
design in this proposal will allow the team to identify and translate between the
neurobiological substrates and the neurocognitive underpinnings of the effects of VRN+NAC on
smoking behavior in humans—thus, advancing the understanding of the pathophysiology of
nicotine addiction.

Inclusion Criteria:

1. Age 18 - 55

2. Right Handed

3. English fluency

4. 20/20 vision with corrective lenses.

5. Smoke ≥ 10 cigarettes/day for a minimum of two years and have an expired carbon
monoxide (CO) concentration of ≥ 10 ppm (to confirm inhalation).

6. Interest in quitting smoking or contemplating a quit attempt in the next 6 months

7. If female, agreement to use birth control

Exclusion Criteria:

1. Past head injury or primary neurological disorder associated with MRI abnormalities,
including dementia, MCI, brain tumors, epilepsy, Parkinson's disease, or demyelinating
diseases

2. Any physical or intellectual disability affecting completion of assessments

3. Any contraindication to MRI

4. Positive urine drug screen for illicit substances (such as marijuana or cocaine).

5. Current or past psychosis

6. Electroconvulsive therapy in last 6 months

7. Use of antidepressant medications or other psychotropic medications in the last month.

8. Positive urine pregnancy test or current breast feeding status