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Newborns delivered to cocaine-abusing mothers are often exposed to other concurrently consumed illicit drugs, which may alter the hemodynamic and cerebral response to cocaine. This study examined the interaction of ethanol, morphine or barbiturate with cocaine on mean arterial pressure (MAP), cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) in newborn pigs. CBF, CMRO2 and cerebral O2 extraction (CEO2) were measured before and 4 and 10 min after cocaine (1.5 mg/kg i.v.) was administered in piglets that were awake, or pretreated with morphine, ethanol or pentobarbital. In awake piglets, cocaine increased CMRO2 and CEO2 while it had no significant effect on CBF. Conversely, in morphine- and ethanol-pretreated piglets, cocaine decreased CMRO2, decreased CBF and had not effect on CEO2. In awake piglets, cocaine increased MAP, whereas in morphine- or ethanol-pretreated piglets, cocaine decreased MAP. In the pentobarbital group, cocaine had no effect. These data demonstrate that other drugs of abuse alter the hemodynamic and cerebral effects of cocaine in the immature animal and may contribute to the central nervous system abnormalities in 'crack babies'.

The effect of cocaine on brain cell membrane structure and function was studied in the fetal guinea pig. We tested the hypothesis that cocaine, a potent vasoconstrictor, would result in brain cell membrane dysfunction as determined by altered activity of Na+,K(+)-ATPase and the appearance of products of membrane lipid peroxidation (conjugated dienes (CD) and fluorescent compounds (FC)). A total of 14 pregnant guinea pigs were studied at term (60 days). One hour prior to delivery, the pregnant guinea pigs were divided into 3 groups as follows: cocaine, 30 mg/kg i.p., saline placebo i.p., or 7% FiO2 for 1 h. Following cocaine, brain Na+,K(+)-ATPase activity decreased (mean +/- S.D., 25.6 +/- 9.2 vs. 54.6 +/- 3.4 mumol Pi/mg protein/h, cocaine vs. control, respectively, P < 0.01) and was similar to the hypoxia group (21.9 +/- 2.8 mumol Pi/mg protein/h). The products of lipid peroxidation did not change significantly following cocaine whereas hypoxia resulted in a rise in CD from 0 to 0.175 +/- 0.015 mumol/g brain, control vs. hypoxia, (P < 0.01), and FC from 1.13 +/- 0.15 to 1.88 +/- 0.13 micrograms quinine sulfate/g brain, control vs. hypoxia, (P < 0.01). These data show that acute fetal cocaine exposure, unlike hypoxia alone, results in a significant decrease in Na+,(K+)-ATPase activity without a significant increase in the products of lipid peroxidation, suggesting the mechanism by which cocaine affects brain cell membrane integrity is distinct from hypoxia. Inhibition of the enzyme activity may be due to a direct action of cocaine on the enzyme or due to enzyme regulation by cocaine-induced alterations in neurotransmitters.

The present study examined the effects of acute cocaine administration on oxygen pressure in the vasculature of the cortex as well as on blood flow and extracellular levels of dopamine in the striatum of newborn piglets. The oxygen-dependent quenching of phosphorescence was used to continuously monitor oxygen pressure in the vasculature of the cortex. Following acute cocaine injection (1.5 mg/kg iv) the cortical oxygen pressure rapidly decreased from 36.3 +/- 1.2 to 32.9 +/- 1.4 Torr and remained at the lower level during the 120 min of postinjection period during which measurements were made. Blood flow in striatum, as determined by laser Doppler, was decreased by 8-10% at 5 min after injection of cocaine. This decrease in blood flow was statistically significant up to 40 min postinjection. Extracellular dopamine, measured using in vivo microdialysis, showed a large increase after cocaine injection. The dopamine level increased from 14 +/- 7 to 88 +/- 21 pmol/ml by 15 min after drug administration, then decreased to 45 +/- 11 pmol/ml and remained stable for the 120 min post-injection period. The mechanism(s) by which the increase in the extracellular level of dopamine occurred may include a direct effect of cocaine on the dopamine transporter and/or an indirect effect due to the decrease in cerebral oxygenation and blood flow. The increase in extracellular dopamine can be responsible for several alterations in neuronal metabolism with potentially deleterious effects on neuronal function.

Cocaine abuse by pregnant women is often associated with neurological injury in the newborn. To explore a vascular-related mechanism of injury, we investigated the effect of cocaine on the cerebral circulation in newborn pigs. During normoxic conditions, cocaine administration (1.5 mg/kg i.v.), resulting in peak plasma cocaine levels on the order of 10(-6) M, decreased cerebral blood flow (CBF) by 14%, as measured by the tracer microsphere method. To elicit the mechanisms by which cocaine decreased CBF, closed cranial windows were placed and the diameter of pial arterioles was measured by intravital microscopy while cocaine (10(-6) M) was applied onto the cortical surface. Topically applied cocaine decreased pial arteriolar diameter by 9%. Vasoconstriction induced by topically applied cocaine was blocked by tetrodotoxin (10(-7) M, Na+ channel blocker), whereas phentolamine (10(-5) M, noradrenergic receptor blocker) had no effect on the arteriolar response to cocaine, which suggested that cocaine effected constriction by an anesthetic and not a sympathomimetic mechanism. To evaluate this hypothesis further, cerebral vessels in the right hemibrain were sympathetically denervated while those in the left hemibrain remained innervated. During normoxia, cocaine (1.5 mg/kg i.v.) decreased CBF equally in both hemibrains, confirming the non-sympathomimetic mechanism. During asphyxia, cocaine administration attenuated cerebral hyperemia in both hemibrains, but in innervated more than in denervated, indicating that anesthetic and sympathomimetic vasoconstriction occurred during asphyxia. We conclude that cocaine constricts the immature cerebrovasculature and decreases CBF by an anesthetic mechanism during normoxic conditions and by both sympathomimetic and anesthetic mechanisms during asphyxia.

We examined the effect of cocaine and several of its metabolites on cerebral arterioles in newborn pigs and evaluated the sympathomimetic properties of each of the compounds as a vasoactive mechanism. After piglets were equipped with closed cranial windows, compounds were suffused over the brain surface and pial arteriolar diameter (base line, approximately 100 microns) was recorded. Cocaine, cocaethylene, norcocaine, ecogonine, benzoylecgonine and ecgonine methylester each caused a dose-dependent (10(-8) M to 10(-4) M) decrease in pial arteriolar diameter: maximum percent reductions in diameter induced by each compound (10(-4) M) were, respectively, 12 +/- 1, 12 +/- 2, 11 +/- 1, 7 +/- 1, 7 +/- 2 and 5 +/- 1. In analyzing the dose-response curves, cocaethylene was the most potent vasoconstrictor, followed by cocaine, norcocaine and then ecogonine, benzoylecgonine and ecgonine methylester. Cerebral vasoconstriction induced by topically applied norepinephrine was enhanced by cocaine, norcocaine and cocaethylene, but not by the other three metabolites. Topical application of phentolamine failed to block vasoconstriction elicited by cocaine or its metabolites, although it did block vasoconstriction elicited by norepinephrine. These observations indicate that cocaine and its metabolites constrict the immature cerebrovasculature by a non-sympathomimetic mechanism.

The present study investigated the effect of cocaine (COC) on cerebral circulation (CBF) and oxidative metabolism (CMRO2) in the newborn piglet and aimed to relate pharmacokinetics of cocaine to cerebrovascular effects. COC decreased CBF and CMRO2 from 75 to 64 and 4.27 to 3.91 ml/min/100 g, respectively, at 4 min with reduced flow to all brain regions (p < 0.05) which returned to baseline by 10 min. COC was rapidly metabolized with a t1/2 of 43 min and peak plasma concentration of 1,172 ng/ml. Norcocaine (NOR) appeared in plasma and CSF within 3 min of cocaine administration and remained elevated for the duration of the study along with COC in the CSF. These data show that the timing of the peak plasma COC level is associated with maximal decreased CBF. Further, the stable elevated level of COC and NOR in the CSF suggests that biotransformation does not occur in the brain. As a result, accumulation of these drugs may occur in the brain with successive COC use and affect the developing CNS in a deleterious manner.

The effect of prenatal cocaine on acoustic sensorineural reactivity was assessed using reflex modification procedures in infants born to mothers with cocaine abuse (C-exposed). Reflex modification was tested using a controlled eyeblink-eliciting tap to the glabella presented either alone or with a 90-dB SPL tone. The results from 19 C-exposed infants were compared to 19 healthy matched drug-free infants. ANOVA comparison of the two groups showed C-exposed infants were more reactive in general, as indicated by a larger glabellar reflex, and more responsive to auditory stimuli, as indicated by an increased blink when the tone accompanied the tap (p less than 0.05). These data suggest that in utero cocaine exposure may have a direct effect on sensorineural processing and may place these infants at risk for cognitive and/or neurological sequelae.