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Central noradrenergic pathways are involved in stress-induced reinstatement to nicotine and in the prefrontal executive control of adaptive behaviors. We used a novel translational approach employing a validated laboratory analogue of stress-precipitated smoking, functional magnetic resonance imaging (fMRI), and a proof-of-concept treatment period to evaluate whether the noradrenergic \u03b12a agonist guanfacine (3\u2009mg\/day) versus placebo (0\u2009mg\/day) reduced stress-precipitated smoking in the laboratory, altered cortico-striatal activation during the Stroop cognitive-control task, and reduced smoking following a quit attempt. In nicotine-deprived smokers ( n=33), stress versus a neutral condition significantly decreased the latency to smoke, and increased tobacco craving, ad-libitum smoking, and systolic blood pressure in placebo-treated subjects, and these effects were absent or reduced in guanfacine-treated subjects. Following stress, placebo-treated subjects demonstrated decreased cortisol levels whereas guanfacine-treated subjects demonstrated increased levels. Guanfacine, compared with placebo, altered prefrontal activity during a cognitive-control task, and reduced cigarette use but did not increase complete abstinence during treatment. These preliminary laboratory, neuroimaging, and clinical outcome data were consistent and complementary and support further development of guanfacine for smoking cessation.<\/jats:p>","DOI":"10.1177\/0269881114562091","type":"journal-article","created":{"date-parts":[[2014,12,16]],"date-time":"2014-12-16T23:05:34Z","timestamp":1418771134000},"page":"300-311","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":64,"title":["A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation"],"prefix":"10.1177","volume":"29","author":[{"given":"Sherry A","family":"McKee","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA"},{"name":"Cancer Prevention and Control Research Program, Yale Cancer Center, New Haven, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc 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