6-cyano-7-nitroquinoxaline-2-3-dione and 5-7-dichlorokynurenic-acid

We examined the effects of blockers of N-methyl-D-asparate (NMDA) and +/- -alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors on the maintenance of self-sustaining status epilepticus (SSSE) induced in rats by brief intermittent electrical stimulation of the perforant path (PPS). Blocking of NMDA receptor at the PCP site by MK-801 (0.5 mg/kg, i.p.) or ketamine (10 mg/kg, i.p.) as well as at the glycine allosteric site by intrahippocampal 5,7-dichlorokynurenic acid (5,7-DCK, 10 nmol), rapidly and irreversibly aborted both behavioral and electrographic manifestation of SSS. Intrahippocampal injection of the AMPA/kainate receptor blocker 6-cyano7-nitroquinixaline-3-dione (CNQX, 10 nmol) transiently suppressed seizures, which reappeared 4-5 h later. We suggest that the maintenance phase of SSSE depends on activation of NMDA receptors and that NMDA receptor blockers may be a promising class of compounds for the treatment of status epilepticus.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Anticonvulsants; Disease Models, Animal; Dizocilpine Maleate; Electric Stimulation; Excitatory Amino Acid Antagonists; Hippocampus; Ketamine; Kynurenic Acid; Male; Perforant Pathway; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Status Epilepticus

Field excitatory postsynaptic potentials (EPSPs) were recorded in the CA1 region of hippocampal slices from 12-18-day-old rats. The isolated N-methyl-D-aspartate (NMDA) receptor mediated field EPSP as well as the composite field EPSP of both NMDA and alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptor mediated components were obtained in low Mg2+ solutions with 10 microM or 1 microM of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively. The isolated AMPA receptor mediated field EPSP was obtained either in normal Mg2+ solution or in a low Mg2+ solution in the presence of the NMDA receptor antagonist D-2-amino-5-phosphonopentanoic acid. The waveforms of the field EPSPs were studied and the effect of long-term depression (LTD) on these waveforms was compared with the effects of several pharmacological agents that attenuate the synaptic efficacy. It was shown that LTD occurred without changes in the waveforms of isolated AMPA and NMDA EPSPs. Reducing the number of release sites by lowering the stimulus strength or reducing the probability of transmitter release by an adenosine agonist N6-cyclohexyl-adenosine both mimicked the LTD-induced changes. Partial blockade of the AMPA receptors was also without effect on the waveforms of isolated AMPA EPSPs. In contrast, partial blockade of the NMDA receptors in several different ways resulted in waveform changes. A similar result could be inferred from experiments using composite field EPSPs. The synaptic attenuation caused by a partial blockade of NMDA receptors therefore appears to differ mechanistically from that involved in LTD, arguing against a postsynaptic locus of the modification involved in LTD. However, directly testing for alterations in transmitter release using the open channel blocker of NMDA receptors MK-801 failed in revealing such presynaptic changes during LTD. Our results therefore suggest that LTD might be due to a coordinated pre- and postsynaptic change instead of distinct pre- or postsynaptic modifications.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dizocilpine Maleate; Evoked Potentials; Excitatory Amino Acid Antagonists; Hippocampus; Kynurenic Acid; Male; Neuronal Plasticity; Neurotransmitter Agents; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Receptors, Presynaptic; Synapses