Cocaine exacerbates hypoxia-induced cell damage in the developing brain: effects on ornithine decarboxylase activity and protein synthesis.
The immature brain is resistant to cell damage from hypoxia, such as that experienced during parturition. Because cocaine causes cerebral ischemia, we examined whether cocaine interferes with this resistance. On postnatal days 1, 4 or 8, neonatal rats were given an acute injection of saline or cocaine (30 mg/kg s.c.) and were then exposed to 7% O2 for 2 h. At the end of the exposure period, activity of ornithine decarboxylase (ODC), an enzymatic marker for activation of cell damage/repair, was assessed in different brain regions. Across all ages and regions, cocaine by itself suppressed ODC, reflecting reduced cell metabolism in the face of ischemia; the protein synthetic rate, assessed with [3H]leucine incorporation, was largely preserved during the drug insult. On postnatal day 1, hypoxia alone also led to a reduction in forebrain ODC as part of the protective metabolic response, with preservation of protein synthesis despite restricted oxygen availability. However, when cocaine and hypoxia were combined, ODC was induced and protein synthesis fell, indicating the onset of cell damage. By 4 days of age, brain maturation produced a change in the metabolic response to hypoxia alone, characterized by ODC induction; when cocaine was present, the response to hypoxia was exacerbated. At 8 days of age, neonatal brain again showed ODC induction with hypoxia, but in this case, cocaine pretreatment reduced the effect on ODC. Measurements of the patterns of protein synthesis during and after hypoxia indicated that cocaine pretreatment was enhancing the cell damage component of the response (increased protein synthesis during hypoxia) and reducing the cell repair component (decreased ability to induce ODC). In contrast to the interaction of acute cocaine with hypoxia, chronic prenatal treatment with cocaine did not elicit exacerbation of the cell damage markers during a subsequent exposure to postnatal hypoxia; worsening of hypoxic cell injury thus occurs only when cocaine is present concurrently with the hypoxia, as would be expected from direct ischemic actions of cocaine. Enhanced sensitivity to hypoxia-induced brain cell damage could be an important contributing factor to the net effects of cocaine on brain development in light of the acute ischemia associated with 'crack' cocaine smoking, hypoxia/ischemia from cigarette smoking, or hypoxia during parturition.
Spraggins
Y R
YR
Department of Pharmacology, Duke University Medical Center, Durham, N.C. 27710.
Seidler
F J
FJ
Slotkin
T A
TA
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005865:Gestational Age; D000860:Hypoxia / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D009419:Nerve Tissue Proteins; D009955:Ornithine Decarboxylase; D007930:Leucine; D003042:Cocaine