NICOTINE and the BRAIN Wilson M. Compton, MD, MPE Deputy Director, U.S. National Institute on Drug Abuse

Tobacco is addictive because of the rewarding/reinforcing effects of nicotine (both positive and negative reward). Development is important. Adolescent exposure may be key to addiction. Electronic nicotine delivery systems (“E- cigarettes”) have both promise and concern. Summary “People smoke for nicotine but die from the tar.” (1976 Professor Michael Russell)

All Drugs Abused by Humans Raise Brain Dopamine Levels in the Nucleus Accumbens Nestler, Nature Neurosci, 2005 ` ` Time After Methamphetamine Dopamine (nM) METHAMPHETAMINE Dose (mg/kg IV) min hr Time After Nicotine % of Basal Release NICOTINE Di Chiara et al.

TYROSINE DA DOPA DA DA DA DA TYROSINE DA DOPA DA DA DA DA DA DA DA DA DA DA methylphenida te R R R R R R Self-Reports (0-10) Change in Dopamine Bmax/kd (Placebo - MP) “High” Increases in Dopamine are Associated with Perceived “High” raclopride DA Volkow et al., JPET 291(1): , NAcc VP REWARD

DARK SIDE OF ADDICTION

Biological Psychiatry Convergent Results Support CHRNA5/A3/B4 Gene Cluster Association with Nicotine DependenceMedialhabenula a5, a3,  4, have a high concentration in habenula and interpeduncular nucleus

Kimura et al., Nature Neuroscience Habenula neurons increased firing for NO REWARD and decreased firing for REWARD Dopamine neurons increased firing for REWARD and decreased firing for NO REWARD. HABENULA Habenula inhibits dopamine neurons Habenula communicates negative reward signals to dopamine neurons Habenula and Negative Reward

ACG OFC SCC Hipp NAcc VP Amyg REWARD INHIBITORY CONTROL INHIBITORY CONTROL MEMORY/ LEARNING MEMORY/ LEARNING EXECUTIVE FUNCTION EXECUTIVE FUNCTION PFC Becomes severely disrupted in ADDICTION MOTIVATION/ DRIVE MOTIVATION/ DRIVE The fine balance in connections that normally exists between brain areas active in reward, motivation, learning and memory, and inhibitory control

Tobacco is addictive because of the rewarding/reinforcing effects of nicotine (both positive and negative reward). Development is important. Adolescent exposure may be key to addiction. Electronic nicotine delivery systems (“E- cigarettes”) have both promise and concern. Summary

Highly Rewarding Effect of Nicotine/Acetaldehyde During Adolescence Belluzzi, et al., Neuropsychopharmacology, 2005 Apr;30(4):

Nicotine Up-regulates arc (gene involved in synaptic plasticity) in Adolescents but Not Adults T. L. Schochet, A. E. Kelley AND C. F. Landry Neuroscience 135 (2005) 285–297 Adolescent Adult

Source: Levine A. et al., Sci Transl Med

More Youth in USA Using E-Cigarettes Than Tobacco Cigs Monitoring the Future Study, University of Michigan Past Month Use of E-Cigs vs. Traditional Cigarettes in the 2014 Monitoring the Future Study of 8 th, 10 th and 12 th Grade Students in USA 8.1% 16.2% 17.1% 4.0% 7.2% 13.6%

Large Numbers of Youth in USA Using E-Cigarettes Without Prior Use of Tobacco Monitoring the Future Study, University of Michigan Past Month Use of E-Cigarettes Among Youth with/without Any Lifetime Use of Tobacco Cigarettes or Smokeless Tobacco in the 2014 Monitoring the Future Study of 8 th, 10 th and 12 th Grade Students in USA 36% 30% 21%

Tobacco is addictive because of the rewarding/reinforcing effects of nicotine (both positive and negative reward). Development is important. Adolescent exposure may be key to addiction. Electronic nicotine delivery systems (“E- cigarettes”) have both promise and concern. Summary

Electronic Nicotine Delivery Systems: “E-cigarettes” Slide Adapted from and Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA

Electronic Nicotine Delivery Systems: “E-cigarettes” Slide Adapted from and Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA

Device design influences nicotine yield… Data from Talih et al., under review. Slide Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA

Some Devices Do Not Deliver Nicotine to Naïve Users Vansickel et al., 2010 Note: 32 ECIG naïve cigarette smokers; 2, 10 puff bouts Tobacco cigarette Slide Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA

Data from Vansickel and Eissenberg, additional participants. BUT Some Devices Deliver Nicotine to Experienced Users Time (minutes) 10-PuffAd-Lib ng/ml Slide Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA

E-Cig Users Take Larger, Longer, Slower Puffs Tobacco cigarette data from Kleykamp et al., See also Farsalinos et al., 2013 (video recording of use) and Hua et al., 2012 (YouTube analysis). Slide Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA

22 Understanding Topography is Relevant to Health Slide Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA

Electronic Nicotine Delivery Systems: Promise or Peril? Promise: Promise: “If governments, parliaments, regulation agencies, and experts are able to restrain their yearning to restrict access to e-cigarettes, these products are likely to represent a revolution in public health.” Etter, Peril: Peril: “Urged on by myopic health professionals who seem to have lost any population health focus they might have had, this may become one of the biggest blunders of modern public health.” Chapman, Middle ground: Middle ground: “… [our responses to ECIGs] will provide the greatest public health benefit when they are proportional, based on evidence, and incorporate a rational appraisal of likely risks and benefits.” Hajek et al., in press. Slide Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA

Science is Essential to Inform Public Health Tobacco is addictive because of the rewarding/reinforcing effects of nicotine (both positive and negative reward). Development is important. Adolescent exposure may be key to addiction. Electronic nicotine delivery systems (“E- cigarettes”) have both promise and concern.