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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.
Citation preview
NICOTINE and the BRAIN
Wilson M. Compton, MD, MPEDeputy 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
Dop
amin
e (n
M)
METHAMPHETAMINE2000
1500
1000
500
0
512.5
Dose (mg/kg IV)
0 20 40 60 80min
0
100
150
200
250
0 1 2 3 hrTime After Nicotine
% o
f Bas
al R
elea
se NICOTINE
Di Chiara et al.
TYROSINE
DA
DOPA
DA
DA
DA
DA
TYROSINE
DA
DOPA
DA
DA
DA
DADA DA DA
DADADA methyl pheni date
RRRRRR
-10 0 10 20 30 40-202468
10
Self-
Repo
rts(0
-10)
Change in DopamineBmax/kd (Placebo - MP)
“High”
Increases in Dopamine are Associated with Perceived “High”
racloprideraclopride
DA DA
Volkow et al., JPET 291(1):409-415, 1999.
NAcc VPREWARD
DARK SIDE OF ADDICTION
Biological Psychiatry
Convergent Results Support CHRNA5/A3/B4
Gene Cluster Association with Nicotine Dependence
Medial habenula
a5, a3, 4, have a high concentration in habenula and interpeduncular nucleus
Kimura et al., Nature Neuroscience 2007.
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 neuronsHabenula communicates negative reward signals to dopamine neurons
Habenula and Negative Reward
ACG
OFCSCC
Hipp
NAccVP
Amyg
REWARDINHIBITORY CONTROL
MEMORY/LEARNING
EXECUTIVEFUNCTION
PFC
Becomes severely disrupted in ADDICTION
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
0 1 2 3 4 5
Test Day
Nic/Acet 30/16 µg (N = 6)Acet 16 µg (N = 6)Nic 30 µg (N = 10)Saline µg (N = 8)
P90 Males
*
****
****
0
10
20
30
40
0 1 2 3 4 5
Test Day
Mea
n Se
lf-In
ject
ions
(N
ose-
poke
s in
3 h
r) Nic/Acet 30/16 µg (N=11)Acet 16 µg (N = 8)Nic 30 µg (N=9)Saline 100 µl (N=7)
P27 Males
Belluzzi, et al., Neuropsychopharmacology, 2005 Apr;30(4):705-12.
Nicotine Up-regulates arc (gene involved in synaptic plasticity) in
Adolescents but Not Adults
T. L. Schochet, A. E. Kelley AND C. F. LandryNeuroscience 135 (2005) 285–297
Adolescent Adult
Source: Levine A. et al., Sci Transl Med. 2011.
More Youth in USA Using E-Cigarettes Than Tobacco Cigs
Monitoring the Future Study, University of Michigan
8th Grade 10th Grade 12th Grade0
2
4
6
8
10
12
14
16
18
Tobacco CigarettesE-Cigarettes
Past Month Use of E-Cigs vs. Traditional Cigarettes in the 2014 Monitoring the Future Study of 8th, 10th and 12th 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
8th Grade 10th Grade 12th Grade0
2
4
6
8
10
12
14
16
18
20
E-Cigs OnlyE-Cigs and Any Lifetime Tobacco
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 8th, 10th and 12th 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.
Profile Puff duration Flow rate Liquid nicotine Voltage Nicotine yield(sec) (ml/sec) (mg/ml) (v) (mg, 15 puffs)
Tobacco cigarette smoker 2 33.3 18 3.3 0.11 ± 0.02Tobacco cigarette smoker 2 33.3 18 5.2 0.64 ± 0.10
Slide Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA
Some Devices Do Not Deliver Nicotine to Naïve Users
Vansickel et al., 2010Note: 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, 2013 + additional participants.
BUT Some Devices Deliver Nicotine to Experienced Users
Mean plasma nicotine (N=13)
-5 5 15 30 45 60 750
5
10
15
20
25
Time (minutes)10-Puff Ad-Lib
ng/m
l
Slide Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA
E-Cig Users Take Larger, Longer, Slower Puffs
Tobacco cigarette data from Kleykamp et al., 2008.See also Farsalinos et al., 2013 (video recording of use) and Hua et al., 2012 (YouTube analysis).
UserPuff parameter ECIG (N=13) Tobacco (N=123)Number 10.1 ± 0.28* 10.8 ± 4.12IPI (sec) 24.9 ± 1.52* 21.7 ± 10.47Volume (ml) 107.9 ± 56.24 51.3 ± 19.23Duration (sec) 4.6 ± 1.36 1.4 ± 0.38Flow (ml/sec) 23.3 ± 9.50 37.8 ± 9.66
Slide Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA
22
Understanding Topography is Relevant to Health
Product A
Puffing intensity, Zp
Des
ign
effic
acy,
Zd Product B
unsafetargetineffective
Nicotine flux (mg/s)
Product C
Slide Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA
Electronic Nicotine Delivery Systems: Promise or Peril?• 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, 2013.
• 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, 2013.
• 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.
