fg-9041 and 3-hydroxyaspartic-acid

Our previous studies have shown a local decrease in glutamate and aspartate levels during seizures, induced by picrotoxin microdialysis in the hippocampus of chronic freely moving rats. In this paper, we study the effect of continuous hippocampal microperfusion of the NMDA, AMPA and kainate glutamate receptor inhibitors 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (MK-801); 6,7-dinitroquinoxaline-2,3-dione (DNQX), and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466). We also examine the action of L(-)-threo-3-hydroxyaspartic acid (THA), a glutamate and aspartate reuptake blocker, on the modification of extracellular glutamate and aspartate levels induced by picrotoxin, using the microdialysis method in freely moving rats. We found that changes in extracellular hippocampal concentrations in both amino acids are prevented by NMDA, AMPA and kainate receptor inhibitors. Seizures elicited under DNQX also induce a transient increase in aspartate extracellular levels coincident with seizure time. L(-)-threo-3-hydroxyaspartic acid increased the basal extracellular concentrations of both amino acids, but did not prevent the seizure-related decrease. Our results suggest that glutamate, the major neurotransmitter at the synaptic level, may also play an important role in non-synaptic transmission during seizures.

Topics: Animals; Anti-Anxiety Agents; Aspartic Acid; Benzodiazepines; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Extracellular Space; Glutamic Acid; Hippocampus; Male; Microdialysis; Picrotoxin; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Seizures

Electrophysiological and pharmacological experiments suggest the presence of an electrogenic glutamate transporter in the motornervous system of the parasitic nematode Ascaris suum. This putative transporter occurs in hypodermis (a tissue in some respects analogous to glia) and in DE2 motorneurons, a dorsal excitatory motorneuron class which receives excitatory glutamatergic post-synaptic potentials. Glutamate application to hypodermis produced non-conductance mediated depolarizations that were smaller in amplitude and slower in rate of rise than DE2 responses where a glutamate-activated conductance occurs. The hypodermal response is sodium dependent and calcium independent. Excitatory amino acid ionotropic receptor agonists (kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid and N-methyl-D-aspartate) were ineffective in eliciting hypodermal responses. The ionotropic receptor antagonist, 6,7-dinitroquinoline-2,3-dione, had no effect on hypodermal glutamate responses. The L- and D-form of glutamate, aspartate and homocysteate produced hypodermal and DE2 depolarizations consistent with the pharmacological profile for glutamate transporters in other systems. Glutamate transport inhibitors (L-trans-pyrrolidine-2,4-dicarboxylate and beta-hydroxyaspartate) elicited electrogenic depolarizations in hypodermis and DE2. These results suggest that the hypodermal glutamate response has an electrogenic transporter component, while the DE2 response has 2 components, one conductance-mediated and the other due to an electrogenic transporter.

Topics: Amino Acid Transport System X-AG; Animals; Ascaris suum; Aspartic Acid; ATP-Binding Cassette Transporters; Biological Transport, Active; Calcium; Dose-Response Relationship, Drug; Electric Conductivity; Epithelium; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Amino Acids; Glutamic Acid; Kainic Acid; Membrane Potentials; Microelectrodes; Motor Neurons; Quinoxalines; Sodium

Neuron-enriched cultures from embryonic rat cerebral cortex were exposed to hypoxia and hypoglycemia, and the resulting cellular injury was quantified by measuring lactate dehydrogenase (LDH) release, which was maximal after 20-24 h. The increase in LDH release produced by hypoxia/hypoglycemia was prevented by N-methyl-D-aspartate (NMDA) antagonists, but not by three classes of drugs thought to modulate glutamate release: Ca2+ channel antagonists (nimodipine, omega-conotoxin GVIA, omega-agatoxin-IVA), KATP channel activators (cromakalim, diazoxide), and glutamate transport inhibitors (dihydrokainate, DL-threo-beta-hydroxyaspartate).

Topics: Animals; Aspartic Acid; Benzopyrans; Calcium Channel Blockers; Cell Hypoxia; Cells, Cultured; Cerebral Cortex; Cromakalim; Diazoxide; Embryo, Mammalian; Glutamates; Hypoglycemia; Kainic Acid; Kinetics; L-Lactate Dehydrogenase; Neurons; Potassium Channels; Pyrroles; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synapses; Synaptic Transmission; Time Factors