Nicotine, Tobacco and Brain Damage, Nicotine, Tobacco and Brain Damage, From the Fetus to the Adolescent: From the Fetus to the Adolescent: Finding the Smoking Gun Finding the Smoking Gun Theodore Slotkin, Ph.D. Theodore Slotkin, Ph.D. Dept. of Pharmacology & Cancer Biology Dept. of Pharmacology & Cancer Biology Duke University Medical Center Duke University Medical Center Research Support: NIH DA14247 and the Philip Morris External Research Program
37
Embed
Nicotine, Tobacco and Brain Damage, From the Fetus to the Adolescent: Finding the Smoking Gun Theodore Slotkin, Ph.D. Dept. of Pharmacology & Cancer Biology.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Nicotine, Tobacco and Brain Damage,Nicotine, Tobacco and Brain Damage,From the Fetus to the Adolescent:From the Fetus to the Adolescent:
Finding the Smoking GunFinding the Smoking Gun
Theodore Slotkin, Ph.D.Theodore Slotkin, Ph.D.
Dept. of Pharmacology & Cancer BiologyDept. of Pharmacology & Cancer Biology
Duke University Medical CenterDuke University Medical Center
Research Support: NIH DA14247 and the Philip Morris External Research Program
Carrie Nation (WCTU founder) - 1890s
These tobacco users transmit nervous diseases, epilepsy, weakened constitutions, depraved appetites and deformities of all kinds to their offspring.
The tobacco user can never be the father of a healthy child.
ETS exposure!
Recruiting Women Smokers - the Origin of the Problem
1932 - must be good for your
health!
1942 - it’s
patriotic to smoke!
1929 - avoid getting fat
1926 - don’t be left out!
1934 - cures depression and tiredness!
U.S. Annual Figures for Maternal Cigarette SmokingU.S. Annual Figures for Maternal Cigarette Smoking
Greater Sensitivity of ACh and Serotonin systems• enhanced onset of nAChR upregulation and greater persistence• persistent deficiency in synaptic activity - ACh and Serotonin• exquisite sensitivity - down to level of ‘chipper’ or ETS
Cell damage• loss of synaptic function• brain areas involved in learning and memory, mood
Sex selectivity: effects on females > males (also true for adolescent smokers)
Conclusion: There is a biological basis for the susceptibility of the adolescent
brain to nicotine addiction
Does Prenatal Nicotine Exposure Alter theResponse to Nicotine in Adolescence?
embryo implants
birthGD22
weaningPN21
Nicotine
PN30 PN47
posttreatment
Nicotine
50 60 75+
4 Groups: Vehicle/Vehicle Nicotine/Vehicle
Vehicle/Nicotine Nicotine/Nicotine
-20
0
20
40
60
80
Prenatal Adolescent Prenatal+Adolescent
nAChR Binding in Midbrain
PN45PN50PN60PN75
Per
cent
cha
nge
from
con
trol
ANOVA: Rx, p < 0.0001; Rx x Age, p < 0.0001
*
*
*
**
*
Control vs. Adolescent, p < 0.0001Prenatal vs. Adolescent, p < 0.0001
Prenatal vs. [Prenatal+Adolescent], p < 0.002Adolescent vs. [Prenatal+Adolescent], p < 0.0001
-20
-10
0
10
20
30
40
Norepinephrine Release By AcuteNicotine Challenge on Postnatal Day 30
ControlNicotine (p < 0.0005)
Forebrain
Pe
rcen
t R
ele
ase
d
Midbrain Hippo-campus
Fetal Treatment
Prenatal Nicotine Blunts the Cholinergic Responseto Nicotine in Adolescence
Additional: Enhanced neural damage/loss
Withdrawal synaptic activity
Effects of Prenatal Nicotine Exposure on Adolescent NicotineSelf-Administration — Withdrawal Triggers Elevated Consumption
0
2
4
6
8
10
12
14
16
18
Infusionsper
Session
1 2 3 4 Nic Phase No Access Reinstatement MAOI Phase
Week
Nicotine Self-Administration after Prenatal Nicotine Exposure
Prenatal Nicotine
Control
p<0.05
p<0.05
Prenatal ± Adolescent Nicotine: A Model for the Effects of Maternal Smoking During Pregnancy
On Subsequent Smoking in Offspring
Animal Studies:• adolescent brain shows high sensitivity to nicotine stimulation
• profound neurochemical effects associated with withdrawal in adolescence
• prenatal nicotine produces ACh, 5HT deficits that emerge in adolescence
• prenatal nicotine desensitizes nAChR, necessitating high doses for stimulation
• prenatal nicotine worsens withdrawal from adolescent nicotine
Human Studies:Jacobsen, Slotkin, Westerveld,
Mencl & Pugh, 2006
which suggested
How Prenatal Nicotine Exposure Predisposes the Brainto Nicotine Addiction in Adolescence
Prenatal Nicotine ACh/Serotonin DysfunctionEmerging in Adolescence
MoodReward
Learning & Memory
Effects Relievedby Nicotine Intake
BUTRelatively InsensitiveHigh Doses Required
Higher Susceptibilityof Adolescent Brain
CNS Damageto Pathways Mediating
Mood, Reward,Learning & Memory
Profound Loss ofSynaptic Activityon Withdrawal -
cognitive deficits,depression make
quitting difficult
Permanent Change?
Reproduction
Adolescent smoking is the “cause”
of smoking during pregnancy
How Tobacco Companies Target AdolescentsDurant et al, Amer. J. Public Health, 1997
0
5
10
15
20
25
30
MTV VH1 CMT BET
Per
cen
t
By Network
0
5
10
15
20
25
30
Rap Rock AdultContemp
Country R&B
Pe
rce
nt
By Genre / Target Group
Pre-TeenTeen Adult
Targeting Women — Taking Aim at MinoritiesCurrent Ads in Women’s Magazines
Medical Bias in Considering Tobacco a "Drug of Abuse"
0
100
200
300
400
500
Drug Abuse Alcohol Tobacco
US Annual Deaths (thousands)
McGinnis & Foege, 1999
0
20
40
60
80
100
per
cen
t o
f su
bst
ance
abu
se p
ages
Drug Abuse Alcohol Tobacco
Ginzel, 1985
Medical Textbook Coverageof Substance Abuse
Pediatricians advise adolescents about tobacco <2% of visits