COADMINISTERED PENTOBARBITAL-ANESTHESIA POSTPONES BUT DOES NOT BLOCK THE MOTOR AND SLEEP EEG RESPONSES TO MK-801

In previous studies with Sprague-Dawley rats, we demonstrated that NMD A channel blockade during waking massively stimulates the delta (1-4 H z) EEG of non-rapid eye movement (NREM) sleep. However, non-competitiv e channel blockers also produce neurotoxicity that is manifested by po sterior cingulate vacuolization and heat shock protein production. The se neurotoxic effects can be blocked by coadministering gabaergic drug s, including barbiturates and benzodiazepines, with the MK-801. To det ermine whether delta stimulation by MK-801 would be similarly blocked, we administered an anesthetic dose (40 mg/kg) of pentobarbital follow ed immediately by 0.3 mg/kg of MK-801. Neither the MK-801 motor syndro me nor the NREM delta stimulation was blocked. When the rats recovered from nearly two hours of barbiturate anesthesia, they behaved as thou gh they had just received the MK-801 injection, exhibiting the typical motor syndrome, spikes in the waking EEG and strong stimulation of NR EM delta EEG. These findings support our previous evidence that NREM d elta stimulation by NMDA channel blockade does not depend on toxic bra in changes. They also raise interesting questions regarding the fate o f MK-801 during pentobarbital anesthesia. We propose that the drug is not metabolized during the period of anesthesia because it is sequeste red within the NMDA cation channel. However, neurons do not respond to the channel block because they have been rendered inert by the anesth esia. When the neurons emerge from anesthesia, the cascade of MK-801 e vents unfolds. This and other possible explanations can be tested expe rimentally. Establishing the fate of MK-801 during barbiturate anesthe sia could shed new light on the cellular processing of non-competitive NMDA channel blockers.