title: Elevation of dopamine induced by cigarette smoking: novel insights from a [11C]-+-PHNO PET study in humans.
abstract: Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine's addictive potential. Here, we used PET and [(11)C]-(+)-PHNO ([(11)C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases [(11)C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent [(11)C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [(11)C]-(+)-PHNO binding in D2 and D3-rich areas (-12.0 and -15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [(11)C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission.
authors: 1] Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments, Centre for Addiction and Mental Health, Toronto, ON, Canada [3] Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada [4] Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada [5] Department of Pharmacology, University of Toronto, Toronto, ON, Canada [6] Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada [7] Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
authors: Bernard
authors: B
authors: Le Foll
authors: Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Mihail
authors: M
authors: Guranda
authors: 1] Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada [3] Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Alan A
authors: AA
authors: Wilson
authors: 1] Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Sylvain
authors: S
authors: Houle
authors: 1] Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Pablo M
authors: PM
authors: Rusjan
authors: Biobehavioural Addictions and Concurrent Disorders Laboratory (BACDRL), Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Victoria C
authors: VC
authors: Wing
authors: 1] Department of Pharmacology, University of Toronto, Toronto, ON, Canada [2] Clinical Neuroscience Program, Centre for Addiction and Mental Health, Toronto, ON, Canada [3] Addiction Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Laurie
authors: L
authors: Zawertailo
authors: Clinical Neuroscience Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Usoa
authors: U
authors: Busto
authors: 1] Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada [2] Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada [3] Clinical Neuroscience Program, Centre for Addiction and Mental Health, Toronto, ON, Canada [4] Addiction Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Peter
authors: P
authors: Selby
authors: Department of Psychiatry and Behavioral Sciences, University of California at Los Angeles (UCLA), Los Angeles, CA, USA.
authors: Arthur L
authors: AL
authors: Brody
authors: 1] Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada [2] Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada [3] Biobehavioural Addictions and Concurrent Disorders Laboratory (BACDRL), Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Tony P
authors: TP
authors: George
authors: 1] Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada [3] Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada [4] Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada [5] Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors: Isabelle
authors: I
authors: Boileau
mesh_terms: D000328:Adult; D002250:Carbon Radioisotopes / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods; D050637:Receptors, Dopamine D3 / Q000096:biosynthesis / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D050637:Receptors, Dopamine D3
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