INHIBITION OF GLUTAMATE UPTAKE WITH L-TRANS-PYRROLIDINE-2,4-DICARBOXYLATE POTENTIATES GLUTAMATE TOXICITY IN PRIMARY HIPPOCAMPAL CULTURES

Sodium-dependent, high-affinity glutamate transport is generally assum ed to limit the toxicity of glutamate in vivo and in vitro, but there is very little direct evidence to support this hypothesis. In the pres ent study, the effects of the specific uptake inhibitor L-trans-pyrrol idine-2,4-dicarboxylate on the toxicity and clearance of glutamate wer e examined in hippocampal neuronal cultures. At a concentration that w as not toxic by itself, L-trans-pyrrolidine-2,4-dicarboxylate increase d the toxicity of glutamate approximately fivefold and slowed the clea rance of glutamate from the extracellular space. This toxicity was alm ost completely blocked by the N-methyl-D-aspartate receptor antagonist , D-2-amino-5-phosphonopentanoate. These studies provide direct eviden ce that sodium-dependent, high-affinity glutamate transport limits glu tamate toxicity in vitro.