EFFECTS OF L-701,324, A HIGH-AFFINITY ANTAGONIST AT THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR GLYCINE SITE, ON THE RAT ELECTROENCEPHALOGRAM

L-701,324 ro-4-hydroxy-3-(3-phenoxy)phenyl-2-(1H)-quinolone) is a nove l, orally active antagonist at the N-methyl-D-aspartate (NMDA) recepto r glycine site. As NMDA receptor antagonism is generally associated wi th anaesthetic effects, we have examined the electroencephalographic a lterations produced by doses of L-701,324 that effectively reduce NMDA -evoked responses in vivo. Microdialysis probes incorporating an elect rode were implanted in the striatum of rats and perfused with artifici al cerebrospinal fluid (ACSF). Under light halothane anaesthesia, 12 c onsecutive depolarizations were elicited by switching to ACSF containi ng 200 mu M NMDA for 2 or 3 min, every 20 min. NMDA-evoked depolarizat ions and EEG were recorded with the microdialysis electrode. L-701,324 (5 or 10 mg kg(-1) i.v.) or vehicle were administered 5 min after the 3rd NMDA stimulus. L-701,324 dose-dependently inhibited NMDA-evoked d epolarizations, with 10 mg kg(-1) reducing these responses by 50 % for at least 3 h. The average amplitude of the EEG in the window 0.25-6 H z (low frequencies) and 6-21 Hz (high frequencies) did not change in t he control group. At the higher dose of 10 mg kg(-1) L-701,324 transie ntly increased the amplitude of low frequencies by around 20 %. In con trast, both 5 and 10 mg kg(-1) significantly reduced the high frequenc ies to around 70 % of control, and this action was sustained with the higher dose. Analysis of the relative EEG power spectra confirmed a sm all, but persistent shift from high to low EEG frequencies. Our result s suggest that L-701,324 slightly strengthened halothane anaesthesia a t doses inhibiting effectively NMDA receptor function. Accordingly, th e resulting anticonvulsant and neuroprotective actions of L-701,324 ma y not be associated with marked anaesthesia-like side-effects.