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The ontogeny of ligand binding to N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) receptors and to the high affinity, sodium-dependent D-aspartate binding site in prenatal and postnatal ovine brains was studied using quantitative in vitro autoradiography. In general, the binding density for each of the excitatory amino acid receptors peaked during late prenatal and early postnatal development. In contrast, binding density for D-aspartate remained low during late prenatal and early postnatal development and peaked in the adult. These data suggest that an excess number of excitatory amino acid receptors and/or a relative deficiency of transporters may make the immature brain more vulnerable to the pathologic effects of glutamate and other related excitatory amino acids.

To assess if cocaine alters cerebral glucose metabolism in the fetus, we infused cocaine 0.6 mg/min intravenously to 6 of 13 fetal sheep for the 55 min prior to measurement of glucose utilization by an autoradiographic method. Overall, local cerebral glucose utilization (LCGU) was lower in cocaine-exposed fetuses than in 7 controls (P = 0.058). In the cocaine-exposed fetuses, 33 of 34 structures had lower mean LCGU than in the comparable structures of control fetuses. In addition, the autoradiographs in 4 of 6 cocaine-exposed fetuses revealed thin, dark lines of increased glucose utilization within the central white matter of some frontal gyri which were not seen in any of the 7 control fetuses. These lines were distributed similarly to ones seen earlier in severely hypoxic newborn lambs. In fetal lambs, cocaine resulted in a generalized decrease in LCGU and a specific increase in glucose utilization in parts of cortical white matter of the frontal gyri, possibly secondary to local ischemia.

The effect of cocaine on the behavioral state of six fetal sheep was studied during gestational ages between 128-135 days. Two to eight days after surgery, fetuses received either a continuous 60 min intravenous infusion of cocaine HCl (33.4 mg) or saline. The infusions were preceded and followed by control periods of 102 min. Cocaine induced a disruption in fetal behavioral state cyclicity and a decrease in the amount of time spent in rapid eye movement sleep (P < 0.01) and non-rapid eye movement sleep (P < 0.05) during the infusion, but not during the recovery period. Spectral amplitude of the electrocortical activity at all three cortical locations increased within most one-third octave bands between 0.8-4 Hz and decreased within most bands between 16-25 Hz (P < 0.05) compared to controls. There were no differences in spectral amplitude between pre- and post-cocaine periods at any location over the 25 frequency bands studied (P > 0.6) except for one frequency band centered at 12.5 Hz. The effects of a one hour cocaine infusion on fetal cortical electrical activity are diffuse, but short-lived, and occur independently of changes in fetal oxygenation.

Intrauterine cocaine exposure causes subtle neurologic abnormalities in human newborn infants; however, the mechanism for these abnormalities is not known. To investigate whether cocaine alters fetal behavioral state, the electrocortical, electro-ocular and neck muscle electrical activity was monitored in 7 chronically instrumented fetal sheep before and during both saline and cocaine HCl infusions directly to the fetus. Saline infusion to the fetus had no effect on the percentage of time spent in rapid eye movement sleep compared to no infusion (37.5 +/- 11.6% vs 46.3 +/- 4.6%, mean +/- SD, P greater than 0.1). Cocaine infusion directly to the fetus had no effect on fetal arterial pO2, but did increase mean arterial pressure from 53.6 +/- 15 mmHg to 61.0 +/- 21 mmHg (P less than 0.01). In addition, during cocaine infusion, the percentage of time spent in rapid eye movement sleep dropped to 3.9 +/- 5.1% (P less than 0.0001) and the average duration of rapid eye movement epochs decreased from 10.1 +/- 3.0 min precocaine infusion to 1.9 +/- 2.6 min during cocaine infusion (P less than 0.02). The influence of cocaine was noted in a frequency analysis of the electrocorticogram. The amplitude of the energy centered at 1 Hz during cocaine infusion (73.8 +/- 4.0 dB) was greater than the amplitude during rapid eye movement sleep (65.5 +/- 4.7 dB) and less than the amplitude during non-rapid eye movement periods (79.9 +/- 4.5 dB) (P = 0.01). Cocaine appears to alter fetal behavioral state directly and this may play a role in the abnormal behavior in newborn infants exposed to cocaine in utero.

To determine if hypoxemia altered local cerebral glucose utilization (LCGU) in newborn lambs, and where these alterations occurred, we measured LCGU using the 2-[14C]deoxyglucose [( 14C]DG) autoradiographic technique in lambs made hypoxemic by gradual reduction in inspired oxygen concentration. In 5 normoxemic control lambs, aged 3 days. LCGU of the cerebral cortex and white matter was higher than published values of LCGU in similar structures in near term normal fetuses and 2-4 times higher than reported values in normoxemic puppies. LCGU was highest in vestibular nuclei and auditory structures, followed by cerebellar nuclei, cerebral subcortical structures, and white matter. In 6 hypoxemic newborn lambs (paO2 14-18 torr) consistent increases in LCGU were noted only in the corona radiata compared to the values obtained in the normoxemic control lambs (36.5 +/- 8.1 vs. 23.9 +/- 1.7 mumol/100 per min, mean +/- S.D., P less than 0.02). This increase in LCGU in white matter was clearly noted in autoradiographs in which thin dark central regions within white matter often reached high into the gyri. In the hypoxic group. LCGU of the corona radiata superseded the value in many gray matter structures. In addition, patchy increases of [14C]DG utilization were present in the cerebral cortex of two hypoxemic lambs. Acute hypoxemia increases glucose utilization of the corona radiata to values equivalent to many gray matter structures, and leads to heterogeneous glucose metabolism in the cerebral cortex, but does not alter LCGU in other gray matter structures of newborn sheep.