Abstract
1. The role of glutamate in producing tissue damage during cerebral anoxia was investigated in brain slices using antagonists to the NMDA and AMPA receptor types. 2. Tissue function was assessed by field recordings of the synaptically evoked potentials elicited by stimulating the main afferent input to the olfactory cortex, the lateral olfactory tract. Anoxia was produced by bathing the slice in glucose-free solution equilibrated with 95% N2/5% CO2. 3. The amount of recovery of the evoked potential was inversely dependent on the period of anoxia and temperature: at 24 degrees C, 15 min of anoxia followed by reoxygenation produced a 14.6 +/- 4.1% recovery whereas there was no recovery at 35 degrees C. 4. Dizocilpine and ketamine had no effect on synaptic transmission in oxygenated media but following anoxia they produced an increased recovery of the responses: from 14.6 +/- 4.1% to 48.3 +/- 7.8% for dizocilpine (10 microM) and 21.6 +/- 7.7% to 87.2 +/- 7.1% for ketamine (200 microM); the tissue endurance to anoxia was increased by around 5 min. 5. Blockade of the AMPA receptors did not influence recovery in spite of the depressed synaptic transmission. A similar synaptic attenuation produced by lignocaine provided some increase in post-anoxic recovery. 6. The NMDA receptor antagonist, AP5, antagonized NMDA at 50 microM by 3.7 fold and at 200 microM by 15 fold but only 200 microM increased post-anoxic recovery. This suggests that a substantial degree of NMDA antagonist is required before anoxic tissue damage due to NMDA receptor activation can be nullified. The antagonist to the glycine binding site, 7-chlorokynurenic acid also increased recovery. 7. These in vitro experiments confirm the idea that NMDA receptor activation makes a substantial contribution to cerebral tissue damage and that this can be reduced by a substantial blockade of these receptors.