Effects of L-701,324, a high-affinity antagonist at the N-methyl-D-aspartate (NMDA) receptor glycine site, on the rat electroencephalogram

Abstract

L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy) phenyl-2-(1H)-quinolone) is a novel, orally active antagonist at the N-methyl-D-aspartate (NMDA) receptor glycine site. As NMDA receptor antagonism is generally associated with anaesthetic effects, we have examined the electroencephalographic alterations produced by doses of L-701,324 that effectively reduce NMDA-evoked responses in vivo. Microdialysis probes incorporating an electrode were implanted in the striatum of rats and perfused with artificial cerebrospinal fluid (ACSF). Under light halothane anaesthesia, 12 consecutive depolarizations were elicited by switching to ACSF containing 200 microM NMDA for 2 or 3 min, every 20 min. NMDA-evoked depolarizations 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 depolarizations, 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 Hz (low frequencies) and 6-21 Hz (high frequencies) did not change in the control group. At the higher dose of 10 mg kg-1 L-701,324 transiently increased the amplitude of low frequencies by around 20%. In contrast, both 5 and 10 mg kg-1 significantly reduced the high frequencies to around 70% of control, and this action was sustained with the higher dose. Analysis of the relative EEG power spectra confirmed a small, but persistent shift from high to low EEG frequencies. Our results suggest that L-701,324 slightly strengthened halothane anaesthesia at doses inhibiting effectively NMDA receptor function. Accordingly, the resulting anticonvulsant and neuroprotective actions of L-701,324 may not be associated with marked anaesthesia-like side-effects.

Kynurenine 3‐Hydroxylase Inhibition in Rats

“…The EEG data confirm this finding (i.e., lack of effect on NMDA receptor function), because the slight changes in cortical EEG that we observed (Fig. 5) do not correspond to those previously found with the high‐affinity antagonist of the NMDA receptor glycine site, L‐701,324 (Obrenovitch et al, 1997 a ). NMDA receptor block is known to potentiate halothane anaesthesia (McFarlane et al, 1995), and this was shown on the EEG in our previous study by an increase in low‐frequency amplitude and a reduction in the high‐frequency components (Obrenovitch et al, 1997 a ).…”

“…This concentration of NMDA was reduced to 150 μ M with urethane to minimise the occasional occurrence of spreading depression that had been observed with 200 μ M NMDA in preliminary experiments carried out with this anaesthetic (Saito et al, 1995). Using the same experimental procedure, inclusive of halothane anaesthesia, we previously demonstrated that known glycine‐site receptor antagonists (i.e., L‐701,324 and KYNA) inhibited the responses evoked by 2‐min perfusion of NMDA, in a concentration‐dependent manner (Obrenovitch et al, 1997 a ; Urenjak and Obrenovitch, 2000).…”

“…Two different anaesthetic agents were used for the two experimental series and, therefore, it is unlikely that the lack of effect of Ro 61‐8048 on NMDA‐induced depolarisations was due to anaesthesia. As in previous investigations (Obrenovitch et al, 1997 a , b ; Urenjak et al, 1997 a , b ), we used 200 μ M NMDA stimuli with halothane‐anaesthetised rats. This concentration of NMDA was reduced to 150 μ M with urethane to minimise the occasional occurrence of spreading depression that had been observed with 200 μ M NMDA in preliminary experiments carried out with this anaesthetic (Saito et al, 1995).…”

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

“…NMDA receptors participate in the development of the CNS (Colonnese et al, 2005;Colonnese and Constantine-Paton, 2006;Kelsch et al, 2012). In addition, overactivation of NMDA receptors can promote seizures and cell death (Choi, 1994;Rothman and Olney, 1995;Obrenovitch et al, 1997;Dirnagl et al, 1999;Yurkewicz et al, 2005), and NMDA receptor hypofunction is a leading hypothesis for schizophrenia (Coyle, 2012;Menniti et al, 2013). Thus, there is considerable interest in factors that control NMDA receptor expression and function.…”

A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder

“…NMDARs are Ca 2+ ‐permeable, voltage‐dependent receptors that mediate a slow synaptic current and are blocked by extracellular magnesium . The overactivation of NMDARs has been implicated in the induction of seizures and cell death, whereas hypofunction of this receptor may contribute to schizophrenia …”