Gestational exposure to drugs of abuse is the single largest preventable cause of developmental compromise of infants in America today. Despite intense effort clinical progress has been slow in ascertaining the specific neurodevelopmental effects of these drugs on the children of drug-abusing mothers. Rodent models have been particularly informative regarding mechanisms underlying the acute and chronic actions of drugs of abuse. A number of animal models of developmental drug exposure suggest that cocaine may act as a behavioral teratogen, a drug capable of altering fetal brain development and subsequent function. Over the past eight years we have developed a model of transpiacental cocaine exposure in mice, and have been able to identify, and for certain outcomes separate the role of cocaine and cocaine-induced malnutrition in impairing fetal brain growth and development. Cocaine exposure in utero results in specific behavioral, anatomical and biochemical changes in mouse pups, many of which persist into adulthood. Among the reproducible changes that we observe in exposed mice that are specifically attributable to cocaine are: 1) disruptions in neuronal migration and subsequent development of cortical brain structures; 2) delayed maturation of cortical neurons utilizing the neurotransmitter GABA; 3) a persistent decrease in coupling of Dl -like receptors and their Gscoupled signals in striatum and neocortex; and 4) a persistent increase in the functional coupling of the 5-HT 1 A autoreceptor on neurons in the Dorsal Raphe. We propose a series of experiments to confirm and extend these findings characterizing specific neuroanatomical, pharmnacological, and molecular consequences induced by prenatal cocaine in particular cortical and subcortical brain structures in juvenile and adult mice. These include:
Specific Aim 1) quantitative neuroanatomic studies to more accurately characterize neuropathologic changes, and in particular delayed postnatal maturation of GABAergic cells;
Specific Aim 2) vitro receptor competition studies and cyclase assays to identify impaired functional coqpling of forebrain Di-like signal transduction;
and Specific Aim 3) in vitro receptor competition studies and [35s]GTPyS assays to identify enhanced functional coupling of 5-HT1A autoreceptors on neurons in the Dorsal Raphe. It is hoped that our animal work may lead to identification of relevant, selective therapeutic interventions which can be utilized in clinical settings to ameliorate the toxicity, or to improve the neurodevelopmental outcome of children whose brain development is compromised following in utero cocaine exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA008648-07
Application #
6515513
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Riddle, Robert D
Project Start
1995-02-01
Project End
2004-04-30
Budget Start
2002-05-20
Budget End
2003-04-30
Support Year
7
Fiscal Year
2002
Total Cost
$323,888
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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