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![Page 1: Nicotine, Tobacco and Brain Damage, From the Fetus to the Adolescent: Finding the Smoking Gun Theodore Slotkin, Ph.D. Dept. of Pharmacology & Cancer Biology.](https://reader036.fdocuments.us/reader036/viewer/2022062516/56649dd05503460f94ac58ee/html5/thumbnails/1.jpg)
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
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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!
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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!
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U.S. Annual Figures for Maternal Cigarette SmokingU.S. Annual Figures for Maternal Cigarette Smoking
•Spontaneous abortions: 19,000 - 141,000•Low Birthweight: 32,000 - 61,000•Neonatal ICU Admissions: 14,000 - 26,000•Perinatal Deaths: 1,900 - 4,800
•50-500% Increased Incidence of:•SIDS•Learning Disorders•ADHD•Disruptive Behaviors
Overall US Rate: 10-20% of all births
DiFranza et al, J. Fam. Pract. 1995
ETS exposure: part of the continuum of adverse effects
Fetal nicotine range ≈ 10-30% of active smoking
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Maternal Cigarette Smoking
Effects on Fetal BrainGeneral Development
Hypoxia/IschemiaCO, HCNAnorexia
Maternal-Fetal UnitNicotine in Fetus
Perinatal Morbidity/MortalityGrowth RetardationBehavioral Anomalies
Risky Behaviors:Other drugs/alcohol
Prenatal CareSocioeconomic
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Why Do We Need Animal Models?Why Do We Need Animal Models?
• Proof of cause-and-effect
• Rational approach to regulating ETS exposure (biomarker)
• Use of NRT in pregnancy
• Framework for understanding onset of addiction in adolescence
• Point to new outcomes to be studied in humans
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Fetal Nicotine Exposure in RatsFetal Nicotine Exposure in Rats
Time
Blo
od
Lev
el
Time
Blo
od
Lev
el
Threshold forHypoxia/Ischemia
Injection Infusion
ETS exposure - inhalation chambers matching nicotine, CO, particulates, etc
Matching Blood Nicotine Levels: 6 mg/kg/day ≈ 1-2 packs; 2 mg/kg/day ≈ 0.5-1 packETS amniotic fluid nicotine ≈ active light smoker
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Prenatal Nicotine Exposure: Neonatal CNS Cell Damage and Cell Deficits
Increased expression of p53Constitutive elevation of c-fos
100
120
140
160
180
per
cen
t co
ntr
ol
200
2 4 7 10 14
Postnatal Age (days)
ODC Activity
Forebrain (p < 0.01)Cerebellum (p < 0.01)
-40
-30
-20
-10
0
per
cen
t ch
ang
e fr
om
co
ntr
ol
10
2 4 7 10 14
Postnatal Age (days)
DNA Content
Forebrain (p < 0.01)Cerebellum (p < 0.01)
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Prenatal Nicotine Exposure: Impaired Neonatal CNS Function
-20
-10
0
10
20
30
40
ForebrainP
erc
en
t R
ele
as
ed
Midbrain Hippo-campus
Norepinephrine Release By AcuteNicotine Challenge on Postnatal Day 30
ControlNicotine (p < 0.0005)
Fetal Treatment
50
60
70
80
90
100
110
120
130
140
0 10 20
Effects of Prenatal Nicotineon Norepinephrine Contentand Turnover in Forebrain
*
30
per
cen
t co
ntr
ol
40
Postnatal Age (days)
*50
Content: CON > NIC, p < 0.01; NIC x Age, p < 0.01Turnover: CON > NIC, p < 0.01; NIC x Age, p < 0.01
60
Content
*
***
*
Turnover *
*
*
50
75
100
125
0 10 20 30 40
per
cen
t co
ntr
ol
50
ANOVA:CON > NIC, p < 0.0001NIC age, p < 0.0005
*
Postnatal Age (days)
Effects of Prenatal Nicotine Exposure on
Hippocampus [3H]Hemicholinium-3 Binding
**
*
* *
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Effects on CNS Development Belowthe Threshold for Growth Impairment
-40
-20
0
20
40
per
cen
t ch
ang
e
60
2 10
ODC
7Postnatal Age (days)
Biomarkers
10 20
DNA
42 7
NETurnover
42 6050
60
70
80
90
100
110
120
130
140
0 10 20
Body and Tissue Weights
30 40
per
cen
t co
ntr
ol
50Postnatal Age (days)
60 70
BodyForebrainBrainstemCerebellum
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Neurotransmitter Signals Control Cell FateNeurotransmitter Signals Control Cell Fate
NerveTerminal
Receptors
SignalingCascades Nucleus
Gene Transcription
Replicate Differentiate Grow Die Learn
The same neurotransmitter may be used for multiple decisions
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Prenatal Nicotine Preempts the Natural Trophic Role of ACh by Stimulating ACh Receptors
0
20
40
60
80
100
120
0 10 20 30 40 50
Forebrain: Ratio of Choline Uptake toCholine Acetyltransferase Activity
*
CON
rati
o
NIC
Postnatal Age (days)
*CON > NIC, p < 0.01
NIC x Age interaction, p < 0.01
100
110
120
130
140
150
6 mg/kg/day 2 mg/kg/day
per
cen
t co
ntr
ol
*CON < NIC, p < 0.01
[3H]Nicotine Binding to Receptorsin Fetal Brain on Gestational Day 18
*
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Nicotine Inhibits DNA Synthesis in Developing Brain Through Effects on Nicotinic Receptors
•2 µg to CNS - same effect
•blocked by nAChR antagonists
•effect mediated by nAChRs in culture
-80
-60
-40
-20
0
20
GD18 PN3 PN10
BrainstemForebrainCerebellum
*
pe
rce
nt
ch
an
ge
*
CON > NIC, p < 0.001Nic x Region interaction, p < 0.01
Age
* * * *
*
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Effects During Neural Tube Stagebut -- apparent subsequent recovery!
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Hippocampus in Young Adulthood afterLow-Dose Prenatal Nicotine Exposure in vivo
dentate gyrus
reduced cell size
increased cell packing density
increased numbers of glial cells
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Prenatal Nicotine Exposure in Rhesus Monkeys:nAChR Upregulation Enhanced by Supposed Ameliorative Therapies
Choline or Vitamin C double the nicotine concentration in amniotic fluid!
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Perinatal ETS exposure in Rhesus Monkeys:nAChR Upregulation ≈ Nicotine
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Nicotine is a Neuroteratogen
• Cell damage and deficits in cell number
• Impaired synaptic activity
• Receptor-Mediated, therefore low threshold
• Affects Cell Replication/Differentiation Switchover
• Initiates the Program for Cell Death
• Morphological changes subtle but detectable in adulthood
Does altered neurochemistry account for functional deficits?
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Catecholamine Surge at BirthLagercrantz & Slotkin, Sci. Amer.,1986
0 10 20 30 40 50
Catecholamines (nM)
Infants at Birth
Pheochromocytoma
Women During Delivery
Heavy Exercise
Sauna
Adults at Rest
Interference with surge - cardiorespiratory collapse
Source90% Adrenal10% SNS
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Prenatal Nicotine Exposure Compromises the Neonatal Response to Hypoxia
0
5
10
15
20
25
30
Per
cen
t M
ort
alit
y60 minutes
Mortality During 5% O2
Exposure on Postnatal Day 1
Control
75 minutes
p < 0.007
p < 0.004
Nicotine
0
10
20
30
40
50
NE
Per
cen
tag
e S
ecre
ted
Epi Total
*
Adrenal Catecholamine SecretionCaused by 5% O
2 for 75 minutes
**
ANOVA: CON > NIC (p < 0.004)
ControlNicotine
Same effect in controls with adrenalectomy or adrenergic receptor blockade
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Subjects matched for:Subjects matched for:age, parity, SES, Page, parity, SES, PaaOO22, , PPaaCOCO22, pH, pHaa
0
1000
2000
3000
4000
5000
6000
7000
8000
Norepinephrine Epinephrine
Catecholamines in Umbilical ArterialBlood at Delivery, Before the First BreathANOVA: Non-smoker > Smoker, p < 0.05
Non-smoker (21)Smoker (20)
0
100
200
300
400
500
600
700
800
No
rep
ine
ph
rin
e (
pg
/ml)
Measure
Ep
ine
ph
rin
e (
pg
/ml)
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Directresponse
Reflex response
Increasing Age
Normal Development: Direct response replaced by reflex
Directresponse
Reflex response
Increasing Age
Nicotine Treatment: accelerated adrenomedullary development
VulnerableWindow
Receptor imbalancescardiorespiratory
inhibition during hypoxia
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Nicotine is a NeuroteratogenNicotine is a Neuroteratogen
• Causal relationship between smoking, SIDS, ADHD, etc
• Effects shared by ETS in a dose-response continuum
• Caution in using NRT in pregnancy (is it even effective?)
• formulation and pharmacokinetic issues
• Interaction with OTC nutritional supplements
Brain development continues into adolescence
How does the adolescent brain respond to nicotine?
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Adolescent Smoking
Nearly all smokers begin as adolescents
75% become daily smokers by 20 y.o.
Higher daily consumption, lower quit rate
Female > Male
Affective and Cognitive Components
Vulnerable subset: loss of autonomy with a few cigsalso - greater withdrawal problems
Relationship to maternal smoking during pregnancy?
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Brain Development Continues into Adolescence:So Does the Developmental Neurotoxicity of Nicotine
-20
-10
0
10
20
30
40
during Rx 1 month post Rx
Midbrain Nicotinic Receptor Upregulation
adolescentadult
% c
ha
ng
e f
rom
co
ntr
ol
adolescent > adult, p < 0.001
*
*
-60
-40
-20
0
20
60 75 60 50 60 45 80
Hippocampus — Adolescent Females
% c
ha
ng
e f
rom
co
ntr
ol
* * *
* *
*
*
Synaptic ActivityMarkers
membraneprotein
p53mRNA
HC-3Binding
NEturnover
DamageMarkers
6 mg/kg/day: adolescent rat 25 ng/ml; nonpregnant adult 100 ng/ml
PN30 PN47
posttreatment
Nicotine
50 60 75+
Significant effects at 2.5 ng/ml ≈2 cigs per day or ETS!!!
Effects with little as 2 days of exposure
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Adolescent Nicotine Effects - Low Threshold!!0.6 mg/kg/day ≈ 2.5 ng/ml = 2 cigs/day ≈ ETS
Other targets: Serotonin - mood & appetite
ImmuneCardiac autonomic
effect @ 2 days
same results for
intermittent exposure -
daily injections
*
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Adolescent Nicotine Effects
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
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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
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-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
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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
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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
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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
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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
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Targeting Women — Taking Aim at MinoritiesCurrent Ads in Women’s Magazines
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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
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0
20
40
60
80
'90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02
Rev
iew
s'9
0-'9
7
Rev
iew
s'9
8-'0
2
Annual Publications — Fetal or Neonatal Development
CocaineNicotine
No.
of
Pub
licat
ions
Source: Medline