COCAINE--EFFECT ON FETAL BRAIN METABOLISM AND FUNCTION

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DESCRIPTION: (Applicant's Abstract) Cocaine use by pregnant women remains a major public health issue. Recent reports reveal that 10-15% of neonates from inner city populations have been exposed to cocaine in-utero. Although we now know much about the physiological effects of a single dose of cocaine in both the mother and the fetus, virtually nothing is known about these effects when cocaine has been administered as it usually is in pregnancy, that is repetitively over a prolonged period of time. We are proposing studies designed to examine the effects of repeated exposures to cocaine on the developing brain. Specifically, we will study the circulation and metabolism of the fetal brain chronically exposed to cocaine, alterations in fetal behavioral state induced by this exposure, and alterations in neural receptors known to be important in cocaine's neuropharmacology. The objectives of this proposal are threefold. First, using the pregnant sheep as a model, we will determine the effects of chronic cocaine administration on some important maternal and fetal basal physiological parameters. Cocaine will be administered daily to the ewe over the 2nd half of pregnancy after which we will study maternal blood pressure, heart rate and uterine blood flow as well as fetal blood pressure, heart rate, behavioral state, hypothalamic-pituitary-adrenal axis hormones and cerebral and myocardial blood flow and oxidative metabolism during a resting, non-stress condition. In addition, using the same animal model, we will study local cerebral glucose utilization in the fetus as a marker for functional central nervous system alterations. Second, we will determine if the fetus develops tolerance to cocaine as determined by the physiological responses to cocaine administered as a novel, first time exposure versus cocaine exposure for a significant duration of fetal life. Further, we will determine if cocaine metabolism and clearance and plasma catecholamine concentrations following cocaine are altered in these animals compared to animals receiving their first exposure to the drug. Third, we will determine the effects of repetitive cocaine exposure on the density and distribution of neural receptors in the fetus known to be either directly or indirectly affected by cocaine; specifically dopamine D1 and D2 receptors, dopamine reuptake sites, and NMDA and non-NMDA glutamate receptors.