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, MK-801 on brain metabolism were investigated over 105 minutes in unanesthetized rats by proton and phosphorus NMR spectroscopy. MK-801 (0.5 and 5 mg/kg, i.p) induced no changes in intracellular pH, and in phosphocreatine, ATP, and inorganic phosphate levels, indicating that the drug preserved energy and intracellular pH homeostasis. There were transient increases in lactate after both doses of MK-801, suggesting early activation of glycolysis, which was not immediately matched by enhanced oxidative metabolism or by enhanced blood flow. Thereafter, lactate control level was not restored after 0.5 mg/kg whereas it was restored 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, whereas the high dose caused shorter and smaller changes. The intracerebral glucose level rose after MK-801 injection, indicating that brain tissue had an adequate or even excessive supply of glucose. Glucose time 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 pharmacological activation. We demonstrate an excess of glycolysis over oxidative metabolism in the early time similar to that following physiological and pathophysiological states such as photic stimulation and seizures. The difference between the effects of the two doses of MK-801 suggests that the adjustment of cerebral metabolism to MK-801 activation is faster and greater with the high dose than with the low dose.
Laboratoire de Recherches Cérébrovasculaires, CNRS UA 641, Centre Universitaire Villemin, Université Paris VII, France.
I
I
Loubinoux
P
P
Meric
J
J
Borredon
J L
JL
Correze
B
B
Gillet
J C
JC
Beloeil
B
B
Tiffon
J
J
Mispelter
J M
JM
Lhoste
S
S
Jacques
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D010710:Phosphates / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism; D010758:Phosphorus; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013997:Time Factors
D010710:Phosphates; D016194:Receptors, N-Methyl-D-Aspartate; D010725:Phosphocreatine; D010758:Phosphorus; D001224:Aspartic Acid; D016291:Dizocilpine Maleate; C000179:N-acetylaspartate; D005947:Glucose