Several lines of evidence suggest that abstinence-induced problems with attention and hyperactivity/impulse control may be important targets for pharmacological smoking cessation treatment. Atomoxetine is a norepinephrine reuptake inhibitor with low abuse potential that was recently FDA approved for the treatment of inattention and hyperactive/impulsivity symptoms in adults and children with attention deficit hyperactivity disorder. In an effort to evaluate novel and safe medications for tobacco dependence treatment, we propose a short-term human behavioral pharmacology study to evaluate the effects of atomoxetine on early abstinence symptoms and smoking behaviors. Study hypotheses will be tested using a within-subject model of brief abstinence and relapse designed by Stitzer and colleagues. Following brief treatment with oral atomoxetine 1.2 mg/kg (or placebo) and monitored abstinence from smoking, 100 smokers will be exposed to a """"""""programmed"""""""" smoking lapse designed to simulate the common lapses that smokers have during a quit attempt. They will then be instructed to attempt to refrain from smoking in their natural environments, and smoking behavior will be recorded and biochemically verified for the next 5 days. Following a medication wash-out period, the sequence will be repeated with atomoxetine or PLA (order counterbalanced between subjects). The primary outcome will be smoking behavior following the brief abstinence period and programmed smoking lapse. Secondary outcomes include abstinence-induced symptoms, with an emphasis on self-report and performance measures of inattention, concentration, and impulse control and the subjective rewarding effects of the lapse cigarette. In exploratory analyses, we will test whether inherited variation in genes in the norepinephrine pathway, the primary target of atomoxetine, modify therapeutic response. The long-term objective of this research is to identify new harmacotherapies for smoking cessation and to develop treatment paradigms that can be readily translated to clinical trials and patient care settings.

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