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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 [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) • April 24, 2008 Medical officials question arrest of pregnant patient Officer says cocaine endangered fetus • • • • • • 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!!!!!