CONTINUOUS ADMINISTRATION OF THE GLUTAMATE UPTAKE INHIBITOR L-TRANS-PYRROLIDINE-2,4-DICARBOXYLATE PRODUCES STRIATAL LESION

This study examined the effects of chronic intrastriatal infusion of L -trans-pyrrolidine-2,4-dicarboxylate (PDC), a selective competitive in hibitor of high affinity glutamate transport systems, via osmotic mini pumps in rats. Injection of PDC at the rate of 25 nmol/h for 14 days c aused striatal lesion. Histological evaluation on frontal striatal sec tions showed that the lesion was circumscribed to a circular area show ing a dramatic neuronal loss accompanied by gliosis and representing 3 0% of the whole striatal surface at the level of the injection site. A total loss of neurons expressing glutamate decarboxylase (GAD67), enk ephalin or substance P mRNA was observed on a similar circular area, s uggesting degeneration of the two populations of striatal efferent neu rons. In the whole striatum outside the region devoided of hybridizati on signal, a selective 27% decrease in enkephalin mRNA expression occu rred, suggesting a higher sensitivity of enkephalin neurons versus sub stance P neurons to glutamate uptake-mediated alterations. Injection o f PDC at the rate of 25 nmol/h for 3 days produced striatal lesion of similar extent. In contrast, PDC at the rate of 5 nmol/h did not produ ce neuronal damage when administered over 14 days. This study provides new in vivo evidence that defective glutamate transport is one of the critical conditions that may give rise to toxicity of an endogenous t ransmitter system in the striatum, and may underlie neuronal death in neurodegenerative diseases. (C) 1997 Elsevier Science B.V.