PROJECT SUMMARY/ABSTRACT More than 50% of smokers attempt to quit smoking each year, but even with intensive treatment the overwhelming majority will return to smoking within six months. Given over 480,000 deaths each year in the United States alone are directly attributable to smoking, there is a tremendous need for improved smoking cessation interventions. β-adrenergic receptor antagonists have received substantial attention as a potential treatment for addiction across both pre-clinical and clinical models. Traditional smoking cessation medications are very effective for alleviating nicotine withdrawal but much less effective at addressing the influence of environmental cues on smoking behavior. One key advantage of β-adrenergic drugs is that they target a different mechanism than established treatments, acting to directly curb the influence of these environmental cues on smoking motivation. This creates the potential for adjuvant medication interventions, whereby β- adrenergic drugs are used in combination with medications targeting nicotine withdrawal to maximize potential efficacy. A recently completed study in our laboratory supports this idea, demonstrating that acute administration of propranolol reduces cue-provoked craving, suppresses neural response to smoking stimuli (e.g. cigarettes, lighters), and alters connectivity between key brain regions shown to mediate effects in pre- clinical models. This application seeks to expand upon this work by examining the impact of β-adrenergic drugs on neural and behavioral response to smoking cues in a larger sample using a design that enables examination of the effects of a β-adrenergic antagonist alone and in combination with an established smoking cessation medication targeting nicotine withdrawal. Adult cigarette smokers (N = 80) will systematically photograph their personal smoking contexts using procedures we have developed and validated. They will then undergo four functional magnetic resonance imaging (fMRI) scans during which they will be exposed to smoking stimuli, including images of their personal smoking contexts. Prior to each scan, they will receive either: 1) Nicotine Patch + β-Adrenergic Antagonist; 2) Placebo Patch + β-Adrenergic Antagonist; 3) Nicotine Patch + Placebo Drug; and 4) Placebo Patch + Placebo Drug. Analyses will examine the effects of these medications on craving and neural activation in response to smoking cues (Aim 1), as well as neural connectivity (Aim 2). In addition, an exploratory aim will examine whether observed effects are mediated by changes in cerebrovascular perfusion or neural connectivity at rest (Exploratory Aim 3). Results from this translational project will provide valuable information on the neural underpinnings of β-adrenergic medications. It will directly inform the development of a new line of pharmacological agents for smoking cessation and provide a deeper understanding of mechanisms that can be used to help refine future intervention protoc...