OXIDANT STRESS AND COCAINE-INDUCED BRAIN INJURY IN UTERO

Rush University Medical Center, Chicago IL

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Abstract

DESCRIPTION (adapted from applicant's abstract): In previous research, the investigators have shown that fetal rat brain cocaine levels can vary by as much as 400 percent as a function of uterine position following a single injection to the dam. They hypothesized that fetuses exposed to low levels of cocaine as a result of their position in the uterus would be less likely to exhibit teratogenesis, resulting in greater variability in the experimental group, and increasing the likelihood of Type I (false negative) errors. This may explain why there is such an abundance of equivoval research reports with respect to animal studies. They subsequently demonstrated that prenatal exposure to cocaine produced reductions in CNS (striatal) and peripheral (carotid body) dopamine (DA) as well as the important DA developmental growth factor glial cell line-derived neurotrophic factor (GDNF) in a positionally-dependent fashion. Suprisingly, those fetuses with the lowest brain cocaine levels exhibited the most severe reductions in DA and GDNF. This led them to presume that cocaine was producing its effects through vasoconstriction which they confirmed by demonstrating that cocaine accentuates the cervical to ovarian gradient of vasoconstriction normally extant within the uterus. Based on all of these findings they have hypothesized that cocaine induced uteroplacental vasoconstriction (CIUV) leads to fetal oxidative stress, attenuating the production of GDNF which reduces the maturation and function of the mesencephalic DA system, the magnitude of which depends upon the fetus's relative uterine position. The current research was designed to determine if CIUV results in measurable oxidative stress in the fetus and whether these measures are correlated with striatal and carotid body alterations in GDNF and DA in a positionally-dependent fashion. The successful completion of these studies will allow them to clearly understand the role uterine position plays in the interpretation of animal data and whether CIUV produces damage to neuronal tissues that result in defined reductions in GDNF and DA. Only after such studies are completed can investigators make an informed judgement regarding the potential liability of prenatal cocaine exposure in animals and its importance in understanding the complex and subtle cognitive and behavioral deficits only now being observed in the rapidly maturing, prenatally cocaine-exposed, human populations.