Nicotine, Tobacco and Brain Damage,

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Nicotine, Tobacco and Brain Damage, From the
Fetus to the Adolescent Finding the Smoking
Gun Theodore Slotkin, Ph.D. Dept. of
Pharmacology Cancer Biology Duke 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
1926 - dont be left out!
1929 - avoid getting fat
1932 - must be good for your health!
1942 - its patriotic to smoke!
1934 - cures depression and tiredness!
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U.S. Annual Figures for Maternal Cigarette Smoking
Overall US Rate 10-20 of all births

• 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

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
Nicotine in Fetus
Maternal-Fetal Unit
Hypoxia/Ischemia CO, HCN Anorexia
Effects on Fetal Brain General Development
Risky Behaviors Other drugs/alcohol Prenatal
Care Socioeconomic
Perinatal Morbidity/Mortality Growth
Retardation Behavioral Anomalies
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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 Rats
Matching Blood Nicotine Levels 6 mg/kg/day
1-2 packs 2 mg/kg/day 0.5-1 pack ETS amniotic
fluid nicotine active light smoker
Injection
Infusion
Threshold for Hypoxia/Ischemia
ETS exposure - inhalation chambers matching
nicotine, CO, particulates, etc
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Prenatal Nicotine Exposure Neonatal CNS Cell
Damage and Cell Deficits
Increased expression of p53 Constitutive
elevation of c-fos
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Prenatal Nicotine Exposure Impaired Neonatal
CNS Function
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Effects on CNS Development Below the Threshold
for Growth Impairment
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Neurotransmitter Signals Control Cell Fate
Nerve Terminal
Signaling Cascades
Nucleus
Receptors
??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
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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

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Effects During Neural Tube Stage but -- apparent
subsequent recovery!
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Hippocampus in Young Adulthood after Low-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 Birth
Lagercrantz Slotkin, Sci. Amer.,1986
Source 90 Adrenal 10 SNS
Interference with surge - cardiorespiratory
collapse
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Prenatal Nicotine Exposure Compromises the
Neonatal Response to Hypoxia
Same effect in controls with adrenalectomy or
adrenergic receptor blockade
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Subjects matched for age, parity, SES, PaO2,
PaCO2, pHa
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Nicotine Treatment accelerated adrenomedullary
development
Normal Development Direct response replaced by
reflex
Reflex response
Direct response
Direct response
Reflex response
Receptor imbalances ?cardiorespiratory
inhibition during hypoxia
Vulnerable Window
Increasing Age
Increasing Age
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Nicotine 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 gt Male
• Affective and Cognitive Components
• Vulnerable subset loss of autonomy with a few
  cigs
• also - 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
6 mg/kg/day adolescent rat 25 ng/ml
nonpregnant adult 100 ng/ml
posttreatment
Nicotine
PN30
PN47
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
effect _at_ 2 days same results for intermittent
exposure - daily injections

Other targets Serotonin - mood
appetite Immune Cardiac autonomic
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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 gt 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
the Response to Nicotine in Adolescence?
Nicotine
embryo implants
weaning PN21
birth GD22
posttreatment
Nicotine
PN30
PN47
50 60 75
4 Groups Vehicle/Vehicle
Nicotine/Vehicle
Vehicle/Nicotine Nicotine/Nicotine
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Prenatal Nicotine Blunts the Cholinergic
Response to Nicotine in Adolescence
Additional Enhanced neural damage/loss
Withdrawal ???synaptic activity
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Effects of Prenatal Nicotine Exposure on
Adolescent Nicotine Self-Administration
Withdrawal Triggers Elevated Consumption
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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
Brain to Nicotine Addiction in Adolescence
Mood Reward Learning Memory
ACh/Serotonin Dysfunction Emerging in Adolescence
Prenatal Nicotine
Reproduction
Higher Susceptibility of Adolescent Brain
Permanent Change?
Effects Relieved by Nicotine Intake BUT Relatively
Insensitive High Doses Required
CNS Damage to Pathways Mediating Mood,
Reward, Learning Memory
Profound Loss of Synaptic Activity on Withdrawal
- cognitive deficits, depression make quitting
difficult
Adolescent smoking is the cause of smoking
during pregnancy
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How Tobacco Companies Target Adolescents
Durant et al, Amer. J. Public Health, 1997
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Targeting Women Taking Aim at
Minorities Current Ads in Womens Magazines
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Medical Bias in Considering Tobacco a "Drug of
Abuse"
Pediatricians advise adolescents about tobacco
lt2 of visits
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