Epidemiologic data suggest that cocaine abuse is escalating at an alarming rate, with an increasing use among women of childbearing age. While the effects of this drug on the central nervous system and cardiovascular parameters in the adult subject have been investigated, there is a paucity of data in the fetus and newborn. Recent clinical evidence suggests that cocaine exposure to the fetus in-utero and the newborn can have profound effects on the central nervous system. It is known that cocaine causes a sympathetically mediated vasoconstriction by blocking presynaptic reuptake of the neurotransmitter, norepinephrine, resulting in an excess of this substance at postsynaptic receptor sites. Maternal administration of cocaine causes a decrease in uterine blood flow and may impair fetal oxygenation, resulting in fetal hypoxemia. Further, endogenous release of norepinephrine in the fetus and newborn potentiate the cardiovascular response to hypoxia. It is postulated that the severity and duration of the vasoconstrictor effect of cocaine will have a specific impact on brain cell membrane structure and function. The present studies investigate specific mechanisms of cocaine injury to the brain of the fetus and newborn by assessing the effect and mechanisms of action of cocaine on cerebral microcirculation, cerebral blood flow and oxygenation, and on brain cell membrane integrity. Measurement of cerebral blood flow and tissue oxygenation will be achieved using the radioactive microsphere technique; alterations of cerebral vascular resistance will be assessed using the cranial window technique. Measurement of cell membrane lipid peroxidation; sodium potassium ATPase activity and sodium potassium ATPase kinetic parameters will be used as indices of brain cell injury. Experimental protocols will be carried out on fetal and newborn lambs by investigating: (1) the relation of systemically administered cocaine on cerebral blood flow and oxygenation under normal acid-base balance and following asphyxia; (2) the effect of topically administered cocaine on cerebral vascular resistance and alteration of the blood-brain barrier; (3) the effect of sympathetic blockade or denervation on modulating the effect of cocaine; (4) the effect of chronic cocaine exposure on brain function in the developing fetus. These studies will lead to a better understanding of the mechanisms related to the susceptibility of the fetal and neonatal brain to alterations in brain tissue oxygen delivery effected by cocaine.
