title: A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation.
abstract: Stress and prefrontal cognitive dysfunction have key roles in driving smoking; however, there are no therapeutics for smoking cessation that attenuate the effects of stress on smoking and enhance cognition. 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 α2a agonist guanfacine (3 mg/day) versus placebo (0 mg/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.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Cancer Prevention and Control Research Program, Yale Cancer Center, New Haven, CT, USA sherry.mckee@yale.edu.
authors.forename: Sherry A
authors.initials: SA
authors.lastname: McKee
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Marc N
authors.initials: MN
authors.lastname: Potenza
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Hedy
authors.initials: H
authors.lastname: Kober
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Sofuoglu
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Amy F T
authors.initials: AF
authors.lastname: Arnsten
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Weinberger
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ashare
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Rajita
authors.initials: R
authors.lastname: Sinha
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D016316:Guanfacine / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000378:metabolism; D012907:Smoking / Q000523:psychology; D016540:Smoking Cessation / Q000379:methods*; D000074606:Smoking Prevention; D013315:Stress, Psychological / Q000150:complications / Q000188:drug therapy; D055815:Young Adult
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D016316:Guanfacine; D006854:Hydrocortisone
keywords: Guanfacine; Stroop; ad-libitum smoking; craving; fMRI; lapse; smoking cessation; stress