Transcript Functional Consequences of Prenatal Cocaine Exposure

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
[email protected]
Supported by:
•NIDA grant DA15502 (GS & PL)
•NICHD Core grant HD15052 (PL) - VKC
•NIDA F32 DA020981 (BT)
(COI- No Funding from Pharma)
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, 2008
Medical officials question arrest of pregnant patient
Officer says cocaine endangered fetus
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By CLAUDIA PINTO
Staff 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."
•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
3.5 fold increase in new use of antipsychotics for ADHD/conduct disorder
Research Informs The Way That We
Intervene!!!!!
Mental Health Disorders – A Neurodevelopmental Legacy?
Environmental
factors
Developmental disruption of 5-HT
function
- Gestational
malnutrition
Genetic
factors
- Autism hyperserotonemia
- SERT S/L
polymorphisms
- Drugs of abuse
- Maternal stress
Altered brain development
(e.g. circuits formation)
Altered adult brain
function
- MAO – 5-HT
metabolism
NEURON ARCHITECTURE: POLARIZED TO RECEIVE,
INTEGRATEAND SEND INFORMATION
Chemical Neurotransmission – the essence of
communication
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
2. Emerging clinical questions – does delineating such
shifts in developmental trajectory help predict features of
clinical populations?
e.g. – Executive function disruptions and interventions
What are the critical elements in
impacting developmental trajectory? –
Location, Timing and Bio-Activity
The Puzzle of Developmental Adaptation
t
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
Abuse Liability
Psychostimulants (cocaine, amphetamine)
Opioids (heroin, morphine)
Caffeine
Alcohol
Nicotine
Hallucinogenic drugs (LSD, MDMA)
Gambling
Sex
Video Games, etc…
control
on cocaine
www.drugabuse.gov
The Clinical Issue - Cocaine Use/Abuse During Pregnancy
• > 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.
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.
Model of Altered Regulation of Arousal
Prenatal Cocaine
Responsiveness
Control
Level of Arousal
adapted from Mayes, et al. (1998) Ann NY Acad Sci 846:126-143
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
Overview of Rabbit Model of In Utero Cocaine
• Administer 2-4 mg/kg cocaine (i.v.) to pregnant Dutch-Belted rabbits
• Examine offspring for structural, biochemical, and behavioral abnormalities
• Contrast DA-rich (ACC) and DA-poor (VC) cortical areas to evaluate specificity
Differentiation
eyes open
Proliferation
Postnatal Age
Gestational Age
0
weaning
20
10
Cocaine E8-E29
Cocaine E8-E25
Cocaine E16-E25
Cocaine E8-E15
30 1
10
20
60
Lack of Major Teratology in Offspring
• gestation duration
• maternal weight gain
• litter size
• birth weight
• survival
• postnatal growth
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
Functional Consequences of Prenatal Cocaine Exposure
loss of a psychostimulantinduced stereotypy (head bobbing)
Saline
Cocaine
Stanwood & Levitt (2004), Current Opinion in Pharmacology
Functional Consequences of Prenatal Cocaine Exposure
Why would DA responsiveness be blunted?
Cell Surface Binding (fmol / 103 cells)
Saline
Cocaine
160
SAL
COC
140
120
100
80
60
40
*
20
0
Stanwood & Levitt (2004), Current Opinion in Pharmacology
Stanwood & Levitt, 2007, Journal of Neuroscience, 27:152-7
Behavioral/Cognitive Alterations
1. No basal locomotor activity and simple response learning.
2. 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.
Condition Place Preference Experiment –
Prenatal Exposure to Cocaine Reduces
the Reinforcing Properties of Cocaine in Adult Offspring
percent increase in time spent on
cocaine-paired side
120
100
Cocaine
80
*
60
40
20
0
Prenatal Saline
Prenatal Cocaine
Thompson, Stanwood & Levitt, unpublished
Vehicle
Decreased Spontaneous
Alternation in Prenatal
Cocaine-Exposed Offspring
Y-Maze
… suggests effects on
attention/learning
Thompson et al, Behav Brain Res 2005
Functional Consequences of Prenatal
Cocaine Exposure – ( 9 yrs)
Singer et al J. Peds 153 (2008)
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;
fetal:maternal interactions;
brain architecture & chemistry)
Maternal Drug Abuse Policies
Policy Makers
(public perception; legality; child welfare)
•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
Thank You
kc.vanderbilt.edu
Research Informs The Way That We
Intervene!!!!!