CONTRASTING EFFECTS OF D- AND -4-(3-PHOSPHONO-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

Microdialysis experiments performed in the dorsal hippocampus of freel y moving rats showed that L-(E)4-(3-phosphono-2-propenyl)piperazine-2- c acid (L-CPPene) is 10 times as potent as D-CPPene in inhibiting pota ssium-induced increases in extracellular levels of aspartate and gluta mate. In control experiments, two 100 mM KCl stimuli(S1 and S2) applie d for 10 min each (separated by a 40-min recovery period) produced sub stantial (300-500%) increases in the extracellular levels of aspartate , glutamate, taurine, and GABA and a 50% decrease in the glutamine lev el. S2/S1 ratios in the control groups were 0.67 (aspartate), 0.78 (gl utamate), 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 mu M) produced selective suppressio n of potassium-induced increases of extracellular glutamate (S2/S1 rat io: 0.25) and aspartate (S2/ S1 ratio: 0.20) levels, whereas 250 mu M D-CPPene was required to inhibit the extracellular aspartate and gluta mate increases. Neither enantiomer of CPPene affected the potassium-in duced increases of GABA and taurine or the decrease in extracellular g lutamine concentration. An additional study comparing the anticonvulsa nt potencies of D-and L-CPPene was performed using audiogenic DBA/2 mi ce. 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 mu mol/kg and 16.8 mu mol/kg, respectively]. We attribute the anticonv ulsant action of D-CPPene to its antagonist action at the NMDA recepto r. 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.