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Contrasting Effects of D‐ and L‐( E )‐4‐(3‐Phospiono‐2‐ Propenyl) Piperazine‐2‐Carboxylic Acid as Anticonvulsants and as Inhibitors of Potassium‐Evoked Increases in Hippocampal Extracellular Glutamate and Aspartate Levels in Freely Moving Rats I
Author(s) -
Millan M. H.,
Chapman A. G.,
Meldrum B. S.
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.62010217.x
Subject(s) - extracellular , glutamate receptor , taurine , chemistry , glutamine , potassium , microdialysis , nmda receptor , pharmacology , glutamic acid , biochemistry , medicine , endocrinology , biology , amino acid , receptor , organic chemistry
Microdialysis experiments performed in the dorsal hippocampus of freely moving rats showed that L‐( E )‐ 4‐(3‐phosphono‐2‐propenyl) piperazine‐2‐carboxylic acid (L‐CPPene) is 10 times as potent as D‐CPPene in inhibiting potassium‐induced increases in extracellular levels of aspartate and glutamate. In control experiments, two 100 m M KCI stimuli (S1 and S2) applied for 10 min each (separated by a 40‐min recovery period) produced substantial (300–500%) increases in the extracellular levels of aspartate, glutamate, taurine, and GABA and a 50% decrease in the glutamine level. S2/S1 ratios in the control groups were 0.67 (aspartate), 0.78 (glutamate), 0.83 (GABA), and 0.85 (taurine). In the experimental groups, D‐ or L‐CPPene was applied via the probe during the second potassium stimulus (S2). L‐CPPene (25 or 250 μ M ) produced selective suppression of potassium‐induced increases of extracellular glutamate (S2/S1 ratio: 0.25) and aspartate (S2/S1 ratio: 0.20) levels, whereas 250 μ M D‐CPPene was required to inhibit the extracellular aspartate and glutamate increases. Neither enantiomer of CPPene affected the potassium‐induced increases of GABA and taurine or the decrease in extracellular glutamine concentration. An addtional study comparing the anticonvulsant potencies of D‐ and L‐CPPene was performed using audiogenic DBA/2 mice. The anticonvulsant potency of D‐CPPene, as assessed against sound‐induced seizures in DBA/2 mice, was an order of magnitude higher than that of L‐CPPene [ED 50 clonic phase (intraperitoneal, 45 min): 1.64 μmol/kg and 16.8 μmol/kg, respectively]. We attribute the anticonvulsant action of D‐CPPene to its antagonist action at the NMDA receptor. The selective inhibition by L‐CPPene of potassium‐induced increases in extracellular aspartate and glutamate levels is presumably due to an action on presynaptic glutamate receptors.