The%20Intersection%20of%20Developmental%20Neurobiology%20and%20Developmental%20Neurotoxicology:%20Opportunities%20in%20Translational%20Neuroscience

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The Intersection of Developmental Neurobiology
and Developmental Neurotoxicology Opportunities
in Translational Neuroscience Pat Levitt,
Ph.D. Vanderbilt Kennedy Center Zilkha
Neurogenetic Institute, Keck School of Medicine
of USC pat.levitt_at_vanderbilt.edu
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• Supported by
• NIDA grant DA15502 (GS PL)
• NICHD Core grant HD15052 (PL) - VKC
• NIDA F32 DA020981 (BT)

(COI- No Funding from Pharma)
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Lab Dan Campbell Kathie Eagleson Aurea
Pimenta Alexandre Bonnin Masaaki Torii Barbara
Thompson Elizabeth Hammock Shenfeng Qiu Melinda
Arnett Matt Judson Mica Bergman Phil
Gorrindo Elizabeth Catania Chris Svitek Shaine
Jones Lisa McFayden-Ketchum Donte Smith Kate
Spencer Paula Woods Deborah Gregory Li Zhang
Collaborators Tony Persico (Campus
Bio-Medico) Jim Sutcliffe Gregg Stanwood Karoly
Mirnics (Vanderbilt) Jurgen Bolz (Univ Jena) Judy
Cameron (Oregon Primate Center) Pat Card (Univ
Pittsburgh) Dan Geschwind (UCLA) Michael
Meaney Danielle Champagne (McGill) Lique
Coolen (Univ Western Ontario) Margaret Bauman Tim
Buie Jim Perrin (MGH-Ladders)
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• April 24, 2008Medical officials question
  arrest of pregnant patientOfficer says cocaine
  endangered fetusBy CLAUDIA PINTOStaff Writer
• Demetria Jones was 7 months pregnant and gripped
  by chest pain when she went to Williamson Medical
  Center for help.
• After routine blood tests indicated she had
  cocaine in her system, the expectant mother was
  arrested and taken to jail.
• And because of that, this medical-turned-legal
  case may have implications beyond what happened
  to just one woman. Some health-care officials
  fear the February arrest and Jones' possible
  conviction could cause other pregnant women who
  use drugs to go without medical care for fear of
  being tested and then arrested.
• "This sends the message to pregnant women Don't
  seek emergency medical care. Don't trust law
  enforcement. Don't seek prenatal medical care,"
  said Dr. Carolyn Szetela, an assistant professor
  of professional and medical education at Meharry
  Medical College.
• Others argue that society is obliged to protect
  unborn children and that the case was handled as
  it should have been.
• "If she used cocaine, she put her baby in
  jeopardy," said Brian Harris, president of
  Tennessee Right to Life. "It is child abuse. It
  certainly is."

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• Memory deficits
• Hyperactivity
• Inability to manage money
• Immature social behavior
• Poor impulse control

• Attention deficits
• Difficulty with abstract concepts
• Poor problem solving skills
• Lack of control over emotions
• Poor judgement

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3.5 fold increase in new use of antipsychotics
for ADHD/conduct disorder
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Research Informs The Way That We Intervene!!!!!
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Mental Health Disorders A Neurodevelopmental
Legacy?

• Autism - hyperserotonemia
• SERT S/L polymorphisms
• MAO 5-HT metabolism

• Gestational malnutrition
• Drugs of abuse
• Maternal stress

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NEURON ARCHITECTURE POLARIZED TO RECEIVE,
INTEGRATEAND SEND INFORMATION
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Chemical Neurotransmission the essence of
communication
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1. What is most informative from basic research
on the neurodevelopmental consequences of
exposure to toxic environments?
fundamental shift in brain architecture/chemistry
and neurodevelopmental trajectory

1. Emerging clinical questions does delineating
   such shifts in developmental trajectory help
   predict features of clinical populations?

e.g. Executive function disruptions and
interventions
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What are the critical elements in impacting
developmental trajectory? Location, Timing
and Bio-Activity
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The Puzzle of Developmental Adaptation
t
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One Example - Effects of Prenatal Cocaine
Clinical Impact -

• Increased impulsivity, irritability
• Altered arousal and autonomic regulation
• Attenuated startle response
• Decreased executive functioning
• Increased risk (2-fold) of developmental delay
• Increased risk for ADHD and ODD

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Abuse Liability
Psychostimulants (cocaine, amphetamine) Opioids
(heroin, morphine) Caffeine Alcohol Nicotine H
allucinogenic drugs (LSD, MDMA) Gambling Sex Vi
deo Games, etc
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control
on cocaine
www.drugabuse.gov
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The Clinical Issue - Cocaine Use/Abuse During
Pregnancy

• gt 1 of mothers have used cocaine during
  pregnancy.
• In the mid-1980s, the overall rate was 3-5,
  with some
• populations having an incidence of up to 20.
• Evidence of drug abuse during pregnancy is less
  likely to be
• reported by private clinics whose patients
  tend to be
• middle-class and Caucasian, but drug abuse
  seems equally
• common across all racial and socioeconomic
  groups.
• Even today, it is estimated that there are
  12,000 new births of
• in utero cocaine-exposed children each year.

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Effects of Prenatal Cocaine Clinical Studies
Depiction of crack babies misleading
Alterations in cognitive and emotional
development after moderate use

• Increased irritability, impulsivity
• Altered arousal, autonomic regulation, and
• stress responses
• Decreased attentiveness (errors of omission)
• Decreased executive functioning

But most studies are confounded by polydrug use,
prenatal care, nutrition, etc.
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Model of Altered Regulation of Arousal
adapted from Mayes, et al. (1998) Ann NY Acad Sci
846126-143
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Confounding Factors in Estimating the Effects
of Cocaine Abuse During Pregnancy on Offspring
JAMA, 2001, 285 1613-25

• Maternal nutrition

• Prenatal care

• Polydrug abuse nicotine, alcohol, opiates

• Postnatal environment

necessity of good animal models
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Overview of Rabbit Model of In Utero Cocaine
Differentiation
eyes open
Proliferation
weaning
Postnatal Age
Gestational Age
20
30
1
10
20
60
0
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Cocaine E8-E29
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Lack of Major Teratology in Offspring

• gestation duration
• maternal weight gain
• litter size
• birth weight
• survival
• postnatal growth

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Consequences of Prenatal Cocaine Exposure
specific features of cortical pyramidal cells
(left) and interneurons (right) are permanently
altered
Saline
Cocaine
ACC
Str
Stanwood Levitt (2004), Current Opinion in
Pharmacology
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Functional Consequences of Prenatal Cocaine
Exposure
loss of a psychostimulant- induced stereotypy
(head bobbing)
Saline
Cocaine
Stanwood Levitt (2004), Current Opinion in
Pharmacology
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Functional Consequences of Prenatal Cocaine
Exposure
Why would DA responsiveness be blunted?
Saline
Cocaine
Stanwood Levitt (2004), Current Opinion in
Pharmacology Stanwood Levitt, 2007, Journal of
Neuroscience, 27152-7
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Behavioral/Cognitive Alterations

• No basal locomotor activity and simple response
  learning.
• Decreased induction of locomotion and
  stereotypies
• by stimulants.
• 3. Decreased rate of acquisition of more
  complicated learning
• tasks (differential conditioning models).
• 4. Decreased performance in spontaneous
  alternation task.

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Condition Place Preference Experiment Prenatal
Exposure to Cocaine Reduces the Reinforcing
Properties of Cocaine in Adult Offspring
Vehicle
Cocaine
Thompson, Stanwood Levitt, unpublished
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Decreased Spontaneous Alternation in
Prenatal Cocaine-Exposed Offspring
Y-Maze
suggests effects on attention/learning
Thompson et al, Behav Brain Res 2005
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Functional Consequences of Prenatal Cocaine
Exposure ( 9 yrs)
Singer et al J. Peds 153 (2008)
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Closing the Gap Using What We Know To Inform
What We Do
Factors that Influence Policy Decisions
Strategies to Affect Public Policy

• Develop simplifying frames of factors that
• impact child development
• (Drugs Stress Nutrition)

Public/Media Perception (free will legality
excesses)
What Science Tells Us (maternal
health fetalmaternal interactions brain
architecture chemistry)
Maternal Drug Abuse Policies

• Develop key working partnerships
• (National Conference of State Legislatures
• Childhood-Focused Private Foundations)
• Engage scientists in providing impartial
  testimony
• What science tells us Just the facts
• Scientists work with print and video media to
  tell a core story
• of the impact of drugs of abuse on fetal
  development

Policy Makers (public perception legality child
welfare)
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Thank You
kc.vanderbilt.edu
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Research Informs The Way That We Intervene!!!!!