Cocaine, a powerful stimulant with positive reinforcing actions, is used by a significant number of pregnant women. Very little is known about the disposition and pharmacodynamics of this drug during pregnancy, apart from the facts that it easily crosses the placenta and may cause intermittent intrauterine hypoxia, preterm labor, and possible long-term developmental problems. In this proposal we plan to use the pregnant ewe as a model to study certain features of cocaine use in pregnancy, including an extensive pharmacokinetic analysis of cocaine disposition in the ewe and fetus. Determinants of drug exposure to be studied will be i) maternal and fetal clearance, ii) dose; iii) route of administration (intravenous versus inhalation of volatilized free- base (crack) cocaine); iv) maternal and fetal plasma protein binding of cocaine; v) and formation and placental transfer of cocaine metabolites. We will compare plasma protein binding in ewe and fetal lamb with pregnant women and cord venous blood obtained at delivery. Correlations will be sought between the pharmacokinetics of cocaine and maternal and fetal cardiovascular response and blood gases, maternal and fetal plasma catecholamines, and fetal behavioral state. In view of the observations that maternally administered cocaine influences fetal development and neonatal behavior, we will determine local cerebral energy metabolism in fetal brain using the technique of (14C)-2-deoxyglucose utilization. Finally, we will determine how cardiovascular, neurophysiologic and neurochemical indexes of fetal and maternal health are altered by the simultaneous injection of cocaine and the inhalation of pyrolytic and combustion products of marijuana. The goals of this research are to describe the pharmacokinetics of cocaine in the maternal-fetal unit, and through pharmacodynamic analyses, to form a clearer understanding of the acute and chronic effects of cocaine on the function of the nervous systems of a special population at risk, fetuses in utero. This study will focus on basic mechanisms of action and effects and physiological hazards of cocaine use.
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