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Neurobiology of Tobacco Dependence

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Neurobiology of Tobacco Dependence Neurobiology of Tobacco Dependence Richard D. Hurt, M.D. Professor of Medicine Director, Nicotine Dependence Center Mayo Clinic http://ndc.mayo.edu © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED What we are up against! © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Cigarettes and Tobacco Dependence • Cigarette smoke – complex mixture of 7,000 chemicals with >60 known carcinogens • Most efficient delivery device for nicotine that exists- better than I.V. • Cigarette manufacturers modified cigarettes over the past decades to maximize nicotine delivery to the brain • High doses of arterial nicotine → upregulation of the nicotinic acetylcholine receptors • Genetic factors influence tobacco dependence • Left untreated 60% of smokers die from a tobacco-caused disease Hurt RD & Robertson© 2013 MAYO CR FOUNDATION JAMA 280:1173, FOR MEDICAL EDUCATION 1998 AND RESEARCH. ALL RIGHTS RESERVED Cigarette Smokers in the US • 88% of adult smokers began before age 18 • Each day >3800 teens have their 1st cigarette and >1000 become daily smokers • Causal relationship between tobacco company advertising and promotion and the initiation and progression of tobacco use in young people • In 2008 cigarette companies spent $9.8 billion on advertising and promotion which is 48% higher than in 1998 • 44% of adult smokers try to stop each year but <5% achieve long-term smoking abstinence USPHS Guideline© 2013 MAYO 2008; FOUNDATION US SurgeonFOR MEDICAL EDUCATION General AND RESEARCH. Report ALL 2012 RIGHTS RESERVED Dynamic Sequence of Gray Matter Maturation Over the Cortical Surface Source: Gogtay, Nitin et al. (2004) Proc. Natl. Acad. Sci. USA 101, 8174-8179 Copyright ©2004 by the National Academy of Sciences © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Maturation starts at the back of the brain ... and moves to the front Physical coordination, sensory processing Amygdala Motivation Cerebellum Emotion Nucleus Accumbens Judgment Notice: Judgment is last to develop! Prefrontal Cortex © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED • Why would anyone smoke with this hanging over their head? • It is in the brain! © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Nicotine • Not a carcinogen • Liquid in its native state • Distilled from burning tobacco and carried on tar droplets • Liquid nicotine plus entrained gas phase free nicotine • Only free (unprotonated) nicotine crosses biological membranes • Inhalation → peak arterial concentrations 2-4 X venous concentrations • Half-life 120 minutes © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Nicotinic Acetylcholine Receptors Unique in Biology • Up-regulated by high arterial doses of nicotine • Nicotine resets sensitivity of brain reward systems to ↑’d levels • Indelible “memory” of its effect on reward systems • Down-regulation takes months of smoking abstinence • This indelible “memory” evoked by external cues → craving Kenny, PJ and© 2013 Markou MAYO FOUNDATION A, Neuropsychopharm FOR MEDICAL EDUCATION AND RESEARCH. 31:1203, ALL RIGHTS 2005 RESERVED © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Perry, DC, et al. ©J 2013 Pharmacol MAYO FOUNDATION Exp FOR Ther MEDICAL, 289:1545, EDUCATION AND 1999 RESEARCH. ALL RIGHTS RESERVED Nicotine Withdrawal DSM-IV • Dysphoric or depressed mood • Insomnia • Irritability, frustration, or anger • Anxiety • Difficulty concentrating • Restlessness • Decreased heart rate • Increased appetite or weight gain © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Smoking Saturates Nicotinic Receptors • Radioligand allows for visualization of α4β2 nAChRs • Position Emission Tomography (PET) Scans • 11 smokers had 14 PET scan sessions • Smoked: none, 1 puff, 3 puffs, 1 cigarette or 2-3 cigarettes (satiety) Brody, A.L. Arch Gen Psychiatry. 63;907-915, 2006 © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Smoking Saturates Nicotinic Receptors MRI kBq/mL 9 0 0.0 Cigarette 0.1 Cigarette 0.3 Cigarette 1.0 Cigarette 3.0 Cigarette Nondisplaceable Brody, A.L. Arch Gen Psychiatry. 63;907-915, 2006 © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Effect of SHS on α4 β2 nAChR’s • 11 smokers and 13 nonsmokers: 1 hour SHS exposure in passenger seat of car • Smoker smoked mean 3.7 cigarettes during the hour • PET scans before and after SHS exposure • 19% occupancy of α4 β2 nAChR’s in smokers and nonsmokers • 23% ↑ craving in smokers after SHS exposure Brody AL.© et2013 alMAYO Arch FOUNDATION Gen FOR Psychiatry, MEDICAL EDUCATION May AND RESEARCH. 2011 ALL RIGHTS RESERVED One hour of moderate secondhand smoke (SHS) exposure leads to significant decreases in 2- [18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (also known as 2-[18F]fluoro-A-85380, or 2-FA) receptor binding in brain Brody, A. L. et al. Arch Gen Psychiatry 2011;0:archgenpsychiatry.2011.51v1-9. Copyright restrictions may apply. We believe the products we make are not injurious to health. We accept an interest in people’s health as a basic responsibility, paramount to every other consideration in our business. We always have and always will cooperate closely with those whose task it is to safeguard the public health. © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED …defend itself on three major fronts -- litigation, politics, and public opinion. -- creating doubt about the health charge without actually denying it © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED SMOKING AND HEALTH PROPOSAL What we want to do this morning is to take a summary look at the smoking and health question and then make a proposal to you for a B&W project to counter the anti-cigarette forces. © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Doubt is our product since it is the best means of competing with the “body of fact” that exists in the mind of the general public. © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED It is also the means of establishing a controversy. © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED The cigarette should be conceived not as a product but as a package. The product is nicotine. Think of the cigarette pack as a storage container for a day’s supply of nicotine: Think of the cigarette as a dispenser for a dose unit of nicotine: © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED What we need to know above all things is what constitutes the hold of smoking, that is, to understand addiction. © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED We believe that we have found possible reasonsExperiments for addiction have so farin two only other been phenomena carried out thatwith accompanyrats, but with steady these absorption it is found ofthat nicotine. certain rats become tolerant to repeated doses and after a while show the usual nicotine reactions but only on a very diminished scale. © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED There seems no doubt that the “kick” of a cigarette is due to the concentration of nicotine in the blood-stream…and this is a product of the quantity Nicotine of is nicotinein the smoke in the in smoke two forms and the as freespeed ofnicotine transfer base of (thinkthat nicotine of ammonia) from the and smoke as a to the bloodnicotine-stream. salt (think of ammonium chloride) and it is almost certain that the free nicotine base is absorbed faster into the blood-stream. © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Forms of Nicotine vs. pH © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED All evidence indicates that the relatively high smoke pH (high alkalinity) shown by Marlboro (and other Philip Morris brands) and Kool is deliberate and controlled. © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED Methods which may be used to increase smoke pH and/or nicotine “kick” include:…(3) use of alkaline additives, usually ammonia compounds, to the blend. © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED AT is the key to competing in smoke quality with PM worldwide. © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED “All work in this area should be directed towards providing consumer reassurance about cigarettes and the smoking habit.” “This can be provided in different ways, e.g., by claimed low deliveries, by the perception of low deliveries and by the perception of ‘mildness.’” © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED “People believe that cigarettes low in tar and nicotine have different ‘tobacco’ ingredients and different kinds of filters than other cigarettes.” “the tobacco is milder or a special mild blend, perhaps treated to remove tar and nicotine...” “Those who smoke low tar and nicotine cigarettes generally do so because they believe such cigarettes are ‘better for you.’” © 2013 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED “It
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