EEG seizure activity and behavioral neurotoxicity produced by (+)-MK801, but not the glycine site antagonist L-687,414, in the rat.
The objective of the present study was to compare the in vivo effects of the anticonvulsant/neuroprotective glycine-site partial agonists L-687,414 (3R-amino-1-hydroxy-4R-methylpyrrolidin-2-one) and (+)-HA966 (3-Amino-1-hydroxypyrrolidin-2-one) and the non-competitive N-methyl-D-aspartate (NMDA) antagonist (+)-MK801 on spontaneous cortical EEG activity and behavior in the unanesthetized rat. Comprehensive dose-response assessments demonstrated that acute i.v. injections of (+)-MK801 induced a behavioral neurotoxic syndrome comprised of head-weaving, ataxia, hyperlocomotion and myoclonic/clonic behaviors and associated with disruptions in normal EEG rhythms including paroxysmal EEG spike/wave complexes. Injections of (+)-HA966 produced behavioral sedation associated with high-amplitude, slow-wave synchronized EEG patterns; signs of ictal EEG activity were minimal (33% incidence) and only seen at the highest dose tested (100 mg/kg). Both (+)-MK801 and (+)-HA966 severely delayed the latency to slow-wave sleep (SWS). In contrast, the EEG dynamics and overt behavior associated with L687,414 were essentially indistinguishable from controls. There was no disruption in the latency to SWS and mild ataxia was evident only upon awakening. The calculated protective indices (EEG seizure ED50/anticonvulsant ED50) for (+)-MK801 and L-687,414 were 1.2 and > 4.5, respectively. The results of this study confirm that valuable pharmacological actions mediated via glycine site modulation of the NMDA receptor are possible without the clinical manifestation of unwanted neurotoxic side-effects.
Tortella
F C
FC
Department of Neuropharmacology, Walter Reed Army Institute of Research, Washington, DC 20307, USA.
Hill
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RG
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D004569:Electroencephalography / Q000187:drug effects*; D005069:Evaluation Studies as Topic; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D008297:Male; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C084173:L 687414; D016291:Dizocilpine Maleate; C001369:1-hydroxy-3-amino-2-pyrrolidone