The acute effects of MK-801 on cerebral blood flow and tissue partial pressures of oxygen and carbon dioxide in conscious and alpha-chloralose anaesthetized rats

The dynamic effects of the non-competitive N-methyl- d-aspartate receptor antagonist, MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo{ a,d}cyclohepten-5,10-imine], on cerebral blood flow and tissue partial pressures of oxygen and carbon dioxide were investigated in the striatal and occipital regions of conscious and anaesthetized rats by mass spectrometry. MK-801 (0.5 and 5 mg/kg, i.p.) induced a large increase in the blood flow of both cerebral regions of conscious rats, without significant changes in local tissue partial pressures of oxygen and carbon dioxide. The increase in cerebral blood flow was maximal within 30 min after injection. Its amplitude was independent of the dose of MK-801, but cerebral blood flow remained elevated for up to 4 h after 5 mg/kg MK-801, while it progressively decreased towards its basal level in rats given 0.5 mg/kg MK-801. The amplitude and time-course of the vascular changes were similar in the two cerebral regions studied. The difference in the changes in tissue partial pressure of oxygen induced by MK-801 and by a 6% CO 2 inhalation suggests that the MK-801-induced rise in cerebral blood flow in conscious rats is, at least partly, due to an increase in oxidative metabolism. In contrast, MK-801 induced either no changes or decreases in cerebral blood flow in alpha-chloralose-anaesthetized rats. The present results should be taken into account not only to determine the mechanisms by which N-methyl- d-aspartate receptor antagonists may exert their neuroprotective effects but also to further elucidate the sites of action of MK-801 in the central nervous system.