The proposal will first determine the half-life, clearance and volume of distribution of cocaine in the pregnant guinea pig following intravenous injection during the last third of gestation. This pharmacokinetic data will be used to determine infusion rates for subcutaneous cocaine administration by osmotic pump. Clearance of cocaine in the dam will be verified during a subcutaneous infusion study. Cocaine and two of its metabolites, benzoylecgonine and norcocaine, will be determined by reverse phase, ion-pair high performance liquid chromatography (HPLC) with ultraviolet detection. Computerized gas chromatography/mass spectrometry will be used to check purity of standards and to supplement the HPLC analysis for identification of other metabolites. The ultimate aim of the proposal is to determine the effect of fetal cocaine exposure upon the neurological control of breathing in neonatal guinea pigs. Three doses of cocaine and a placebo treatment will be given intermittently by the intravenous route in four groups of animals and at a constant rate by the subcutaneous route of administration with an osmotic pump in another four groups. Assignment of treatments will be random allocation. Breathing will be assessed by a noninvasive plethysmographic method in conscious neonatal animals who have been exposed to cocaine or placebo treatment in utero. Neonatal ventilatory patterns will be analyzed while the animal breathes room air. Chemical control of breathing will be assessed by studying the breathing response of hypercapnea. Behavioral modulation of breathing will be evaluated as a function of electrocortical activity and sleep state. Physiological changes in neonatal breathing will be analyzed with respect to cocaine dose-response characteristics as well as to the route of cocaine administration. The breathing studies will be important for educating and counseling women of child bearing age and in caring for substance-abusing mothers and their infants. These studies are especially important since infants of substance-abusing mothers (ISAM) including cocaine-only users, have abnormal sleeping ventilatory patterns and may have an increased risk of sudden infant death syndrome (SIDS).
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