The effects of N-methyl- D-aspartate receptor blockade with MK-801 upon the relationship between cerebral blood flow and glucose utilisation

Abstract

The local cerebral circulatory and metabolic effects of MK-801, a selective non-competitive N-methyl- D-aspartate receptor antagonist have been examined in conscious rats with quantitative autoradiographic techniques using [ 14C]iodoantipyrine and [ 14C]2-deoxyglucose as tracers. Local cerebral blood flow (CBF) and local cerebral glucose utilisation (GU) were measured in 41 discrete neuroanatomical loci using identical criteria for region of interest localisation. Animals received either saline or MK-801 (0.5 mg/kg in saline) intraveneously 10 min prior to the start of GU determination, or 15 min before the CBF measurement. MK-801 effects an immediate transient, elevation in mean arterial pressure (elevated by 30% from baseline) which returned rapidly to preinjection levels and a sustained moderate hypercapnia (arterial carbon dioxide tension increased by 16%) which persisted throughout the measurement periods. Statistically significant changes in GU were observed in 13 brain region structures after MK-801 administration. Glucose utilisation was significantly and markedly elevated with MK-801 in some limbic structures (particularly the hippocampus, posterior cingulate and entorhinal cortices), the inferior colliculus and most of the neocortex displayed moderate reductions in GU after MK-801 treatment. In the majority of brain regions (28 or the 41 studied), MK-801 minimally altered GU. There were widespread alterations in local CBF with MK-801 although in the majority of brain regions (24 of the 41 studied) there was no statistically significant alteration in CBF with MK-801. With one exception (the anterior thalamic nucleus), CBF was increased with MK-801 in all regions in which glucose use was elevated with the drug. In some brain regions (anterior and posterior cingulate cortices, visual cortex, caudate nucleus, frontal cortex and corpus callosum) with MK-801 treatment the relationship between local blood flow and glucose use differed from that observed in the same areas in control animals. In vehicle-treated animals, there was an excellent correlation between local CBF and GU. With MK-801 treatment, the correlation between local CBF and GU in animals treated with MK-801 was poorer and the mean ratio of local CBF to GU increased (vehicle treated: 1.86 ml/μmol, MK-801 treated: 2.42 ml/μmol). Thus, the putative anti-ischaemic agent, MK-801, can effect marked alterations in local CBF in normal, conscious rats.