DESCRIPTION (provided by applicant): According to the CDC, cigarette smoking is associated with profound morbidity and mortality. In the United States alone, cigarette smoking is responsible for about 443,000 deaths per year and it costs the nation nearly $200 billion annually. About 20% of all adults smoke in the United States and by 12th grade, 42% of students report having smoked. Unfortunately, cigarette smoking is a disease of chronic relapse. Indeed, smokers will make as many as 20 quit attempts before they are successful and abstinence rates can be as low as 7%, even following nicotine replacement therapy (NRT) with the patch, gum, or nasal spray. As with other addictions, cue-induced craving contributes to relapse following a quit attempt. Along with cue-induced craving and relapse, addicts also suffer from drug-induced devaluation of natural rewards as evidenced by less responding for a sweet in rats and a weaker striatal response to monetary rewards in humans waiting to smoke. Indeed, those subjects (rats and humans) found least responsive to the natural reward are, in turn, most responsive to drug. Here we propose a novel alternative to the steady-state delivery of nicotine (i.e., to the standard patch), for the treatment of cigarette addiction. Specifically, we propose t use an oral film to treat smokers wishing to quit with random, rather than steady-state, delivery of nicotine prior to and following the quit date. On the basis of promising preclinical and clinica data, we hypothesize that, relative to steady state delivery, random nicotine delivery will be safe well-tolerated, and will facilitate smoking cessation, dissociation of nicotine-paired cues from drug, and a reduction in drug-induced devaluation of natural rewards. Specific Aim 1 will test the pharmacokinetics and safety of a range of doses of the nicotine film in human smokers. Specific Aim 2 will test whether smoking cessation is facilitated when human smokers are treated with random vs. steady-state delivery of nicotine before and after the quit date. Finally, Specific Aim 3 will use fMRI and published procedures to test whether random nicotine delivery also will reduce the neural (striatal) response to nicotine-paired cues and augment the neural response to an alternative monetary reward. If our random delivery hypothesis is confirmed, this novel approach will revolutionize treatment of substance abuse and addiction.

PUBLIC HEALTH RELEVANCE: Cigarette smoking costs 443,000 American lives and nearly $200 billion dollars annually. Despite the focus upon steady state delivery of nicotine (e.g., the patch), random delivery of drug reduces responding for drug and alcohol in rats and man. The present study, then, will use new NIDA-supported technology, behavioral assessment, and fMRI to test the hypothesis that random nicotine delivery will augment smoking cessation, reduce the striatal response to a nicotine-paired cue (i.e., a cigarette), and increase the striatal response o a natural reward (i.e., money). Confirmation of the hypothesis will have a large impact on the treatment of addiction.