CEREBRAL METABOLIC CHANGES INDUCED BY MK-801 - A 1D (PHOSPHORUS AND PROTON) AND 2D (PROTON) IN-VIVO NMR-SPECTROSCOPY STUDY

The dynamic effects of the non-competitive NMDA receptor antagonist, M K-801 on brain metabolism were investigated over 105 minutes in unanes thetized rats by proton and phosphorus NMR spectroscopy. MK-801 (0.5 a nd 5 mg/kg, i.p) induced no changes in intracellular pH, and in phosph ocreatine, ATP, and inorganic phosphate levels, indicating that the dr ug preserved energy and intracellular pH homeostasis. There were trans ient increases in lactate after both doses of MK-801, suggesting early activation of glycolysis, which was not immediately matched by enhanc ed oxidative metabolism or by enhanced brood flow. Thereafter, lactate control level was not restored after 0.5 mg/kg whereas it was restore d after 5 mg/kg in spite of a sustained metabolic activation. The low dose of MK-801 also caused a continuous decrease in cerebral aspartate level (-38%) which is thought to match the enhanced energy demand, wh ereas the high dose caused shorter and smaller changes. The intracereb ral glucose level rose after MK-801 injection, indicating that brain t issue had an adequate or even excessive supply of glucose. Glucose tim e course seemed to closely match the changes in blood flow elicited by MK-801. This is the first study giving the metabolic pattern of a pha rmacological activation. We demonstrate an excess of glycolysis over o xidative metabolism in the early time similar to that following physio logical and pathophysiological states such as photic stimulation and s eizures. The difference between the effects of the two doses of MK-801 suggests that the adjustment of cerebral metabolism to MK-801 activat ion is faster and greater with the high dose than with the low dose.