ACUTE AND LONG-LASTING EFFECTS OF NEONATAL HYPOXIA ON (-3-[I-125]MK-801 BINDING TO NMDA BRAIN RECEPTORS())

The NMDA receptor subtype is the major excitatory mediator for glutama te neurotoxicity. To assess its participation in the noxious effects o f postnatal hypoxia, we have characterized the binding of the ionophor ic marker of NMDA receptor, dizocilpine (MK-801). Binding of (+)-3-[I- 125]MK-801 to NMDA brain receptors under nonequilibrium conditions was quantified by in vitro autoradiography in rats exposed to hypoxia ind uced by 93% N-2/6.5% O-2 exposure for 70 min on Postnatal Day 4. Acute and long-lasting effects were investigated at 4 h after injury and on Postnatal Day 40. At the acute stage, a transient decrease in binding was found in several specific brain areas, hypothalamus, amygdaloid n uclei, entorhinal cortex, perirhinal cortex, and hippocampus, and no d ifferences were found in temporal cortex, thalamus, and geniculate nuc leus, when compared to sham-treated animals. At this early age, there was no increase of binding when slices from both groups were incubated in the presence of glutamate and glycine (Glu/Gly), positive alloster ic modulators of MK-801 binding. In the 40-day-old brains, the binding to the NMDA receptors of hypoxia-treated animals was not different wi th respect to controls in most of the areas studied, but the Glu/Gly s timulation of binding in hypoxic rats showed a reduced, or absent, res ponse to the allosteric modulators. In contrast, control rats showed a remarkable increase of the specific binding induced by the presence o f the modulators in the incubation buffer. Binding of(+)-3-[I-125]MK-8 01 was also performed at a higher concentration to clarify whether the altered response to Glu/Gly may be due to differences in the number o f channels; however, the density of NMDA receptors at this concentrati on was similar in both control and hypoxia-treated rats. We conclude t hat the effect of exposure of newborn rats to hypoxia can generate acu te and long-lasting effects on the NMDA receptor. The deleterious acti on of this kind of nora on the CNS could be exerted by interference wi th normal glutamatergic transmission and hence over normal growth andd evelopment. (C) 1997 Academic Press.