The specific aims of this proposal are to 1) define the pharmacokinetics (PK) of heroin and its metabolites in the maternal-fetal unit (MFU); 2) compare the effects of acute heroin and methadone exposure on fetal behavior and cerebral metabolism; 3) investigate the development of tolerance and dependence to the effect of methadone on fetal behavior upon chronic exposure; 4) define the effect of methadone and morphine on fetal breathing movements, and study the breathing pattern and sleep pattern of neonates who have been chronically exposed to methadone throughout the 3rd trimester. These objectives can only be fulfilled by using the chronic fetal lamb model. These objectives can only be fulfilled by using the chronic fetal lamb model. Heroin will be infused to both mother and fetus, and maternal and fetal steady state plasma concentrations of heroin, acetylmorphine and morphine determined using HPLC. Placental and fetal clearances of heroin will be determined at 3 gestational ages. The effect of heroin and methadone of fetal cerebral metabolism will be evaluated by their effects on the extraction of oxygen and glucose by the fetal brain. This will be accomplished with indwelling catheters in the brachiocephalic artery and sagittal sinus. The effects of acute and chronic heroin and methadone exposure on fetal behavior will be interpreted from intrauterine recordings of electrocortical activity, eye movements, body movements, breathing movements, blood pressure and heart rate. Fetal behavior will be differentiated into quiet sleep, rapid eye movement sleep and wakefulness according to established criteria. The proposed studies will provide the first available data on the PK of heroin and its metabolites in the MFU, and together with the pharmacodynamic (PD) studies, will indicate whether differences in PK and/or PD can explain the difference in neonatal outcome between heroin-dependent and methadone-maintained infants. These studies will also provide unique data on the effects of acute and chronic narcotics exposure on fetal behavior and cerebral metabolism. New information can be obtained on the relationship between CNS function and metabolism, and on the phenomena of tolerance and dependence to narcotics in the fetus. These studies will help in the understanding of the increased incidence of neurological and behavioral disturbances, and sudden infant death syndrome reported in children who have been exposed to narcotics in utero.
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