Drugs of abuse, including cocaine, are being used in increasing numbers by pregnant women. Accumulating evidence indicates that brain development may be particularly vulnerable. In a collaborative effort as part of this program project, our long-term goal is to define the molecular and structural changes that occur in the central nervous system of offspring following cocaine abuse during pregnancy. We will examine cocaine-induced changes in development in an effort to understand the functional consequences of the resulting defects. The animal model, using intravenous cocaine administration of pregnant rabbits, results in specific, long-term, anatomical and molecular changes. We have discovered marked defects in dendritic organization of cortical neurons in the anterior cingulate cortex, while sparing visual cortex. Altered properties of neuronal growth during corticogenesis may underlie this phenomenon. We will investigate potential mechanisms that underline the non-uniform changes in cortex, using a variety of technical strategies. In addition, we will initiate developmental studies on the striatum, which has been shown in this model to exhibit molecular changes that may cause specific behavioral anomalies. We propose three major aims to determine 1) the developmental onset and distribution of neurons exhibiting altered dendritic growth following prenatal cocaine exposure. Fetal cortical and striatal tissue is processed for immunocytochemistry and DiI filling of neurons to image dendritic organization with conventional and confocal microscopy; 2) the effects of prenatal cocaine exposure on intrinsic growth properties of cortical neurons. We will monitor process outgrowth of cultured neurons isolated from fetal cingulate, visual and striatal primordia at different times after cocaine exposure in utero, using immunocytochemistry and real-time video microscopy; 3) the effects of prenatal cocaine exposure on the responsiveness of cortical neurons to neurotransmitters that regulate process outgrowth. We will analyze the responsiveness of cultured neurons, exposed to cocaine in utero, to dopamine receptor manipulation. Assays of neurite outgrowth will be performed. We also will measure changes, in the cultured neurons, in dopamine receptor-G protein coupling, shown to be defective in vivo. Our model provides an opportunity to study the long-term effects, on brain structure-function, of altering mechanisms that control neural development. These and other investigations described in this PPG will provide important data for developing strategies of intervention once the child of drug abuse is born.
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