Stimulation and inhibition of N-methyl-D-aspartate receptors in rats: developing a seizure model.
OBJECTIVE
The objective of this study was to develop an experimental rat hippocampal seizure model based on the stimulatory effects of N-methyl-D-aspartate and to determine the inhibitory effects of MK-801 on N-methyl-D-aspartate-induced seizures.


METHODS
Two separate experiments were performed. In the first experiment chemitrode-implanted rats were injected intracranially with increasing doses (5, 10, 20, and 30 micrograms) of N-methyl-D-aspartate into the hippocampus. Various electrophysiologic and behavioral parameters were examined to determine the dose required to reliably elicit hippocampal seizure activity without having toxic effects on the rats. In the second experiment rats were given an intraperitoneal injection of MK-801 (0.5 or 1 mg/kg), followed 20 minutes later by an intracranial injection of N-methyl-D-aspartate (20 or 30 micrograms). The ability of MK-801 to suppress N-methyl-D-aspartate-induced seizure activity was assessed in this experiment.


RESULTS
Intrahippocampal injection of 20 micrograms of N-methyl-D-aspartate produced the shortest electrical seizure latency (193 +/- 72 seconds, p < 0.01). At this dose seizure was achieved in 80% (four of five of the animals, and the highest numbers of electrical seizures per animal were produced (2.2 +/- 0.8, p < 0.05). The group that received 30 micrograms of N-methyl-D-aspartate had a shorter latency, a longer duration of behavioral seizure and a higher number of behavioral seizures (p < 0.05). However, this group suffered a 60% (three of five) mortality rate. The addition of MK-801 significantly decreased the number of seizures per animal and the total seizure duration (p < 0.05). MK-801 also reduced the latency period.


CONCLUSIONS
Intracranial injection of 20 micrograms of N-methyl-D-aspartate produced reliable hippocampal seizure activity without mortality. MK-801 at a dose of 1 mg/kg injected intraperitoneally had significant inhibitory effects on this seizure model.
Department of Obstetrics and Gynecology, Wayne State University/Hutzel Hospital, Detroit, MI 48201.
M
M
Hallak
S M
SM
Irtenkauf
C A
CA
Janusz
D B
DB
Cotton
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy
D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate