| Despite over twenty years of research, it is still not clear how cocaine damages the developing brain. This thesis examined the contribution of hypoxic mechanisms in neurotoxicity resulting from prenatal cocaine and ethanol exposure. Cocaine has been shown to cause vasoconstriction of the uterine vasculature as well as act directly within the CNS. I hypothesized that fetuses exposed to cocaine would demonstrate changes in immediate early gene expression, reactive oxygen species and cell death similar to those exposed to perinatal asphyxia. Pregnant rats were exposed to a cocaine binge and the pups extracted by C-section. The offspring's brains were analyzed by immunocytochemical assays measuring known indicators of synaptic activity (c-Fos), oxidative stress (nitrotyrosine) and apoptosis (cleaved caspase-3). In these pups, all three indices of neurotoxicity exhibited marked similarities to data collected from pups exposed to perinatal asphyxia.; I then used three separate exposure models to isolate the direct and indirect, hypoxic mechanisms of prenatal cocaine exposure, where I proposed that hypoxic mechanisms would cause more neurotoxicity than cocaine's direct effects. A model of intrauterine position cocaine exposure was used to separate the direct and indirect effects of the drug within the same litter. The degree of vasoconstriction is different within the uterine horn so that the fetuses located distally to the cervix receive less cocaine than the proximally located fetuses. Moreover, the intrauterine differences in the amount of hypoxia and cocaine concentration experienced by the developing pups were assessed by the above measures. Additionally, the indirect (hypoxic) and direct effects of prenatal cocaine were modeled with either intrauterine vasoconstriction via phenylephrine or postnatal cocaine. The result of high cleaved caspase-3 immunoreactivity in the phenylephrine-exposed pups and little immunoreactivity in the postnatal cocaine-exposed pups gives further evidence that hypoxia is a significant mechanism of toxicity in prenatal cocaine exposure.; Pregnant rats were exposed to a combination of ethanol and cocaine, as well as cocaine alone and ethanol alone. The offspring's brains were analyzed by immunocytochemical and biochemical assays measuring indicators of cell activity (Fos) and toxicity (cleaved caspase-3). The significance of additional hypoxia in fetuses exposed to drugs was evaluated: concurrent exposure increased transcription factor induction the striatum, however, there was no additional cell death in any brain region analyzed. (Abstract shortened by UMI.)... |
