ACCUMULATION OF EXTRACELLULAR GLUTAMATE BY INHIBITION OF ITS UPTAKE IS NOT SUFFICIENT FOR INDUCING NEURONAL DAMAGE - AN IN-VIVO MICRODIALYSIS STUDY

It is well documented that neurons exposed to high concentrations of e xcitatory amino acids, such as glutamate and aspartate, degenerate and die. The clearance of these amino acids from the synaptic cleft depen ds mainly on their transport by high-affinity sodium-dependent carrier s. Using microdialysis in vivo and HPLC analysis, we have studied the effect of the administration of inhibitors of the glutamate transporte r (L-trans-pyrrolidine-2,4-dicarboxylate and dihydrokainate) on the ex tracellular concentration of endogenous amino acids in the rat striatu m. In addition, we have analyzed whether the changes observed in the c oncentration of glutamate and aspartate were injurious to striatal cel ls. Neuronal damage was assessed by biochemical determination of choli ne acetyltransferase and glutamate decarboxylase activities, 7 days af ter the microdialysis procedure, In other experiments, pyrrolidine dic arboxylate and dihydrokainate, as well as two other inhibitors of the glutamate carrier, DL-threo-beta-hydroxyaspartate and L-aspartate-beta -hydroxamate, were microinjected into the striatum, and neuronal damag e was assessed, both biochemically and histologically, 7 or 14 days af ter the injection. Dihydrokainate and pyrrolidine dicarboxylate produc ed a similar remarkable increase in the concentration of extracellular aspartate and glutamate. However, the former induced also notable ele vations in the concentration of other amino acids. Clear neuronal dama ge was observed only after dihydrokainate administration, which was pa rtially prevented by intraperitoneal injection of (+)d-methy-10,11-dih ydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate or by intrastriata l coinjection of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (f) quinoxalin e. No cell damage was observed with the other three glutamate carrier inhibitors used. It is concluded that an increased extracellular gluta mate level in vivo due to dysfunction of its transporter is not suffic ient for inducing neuronal damage. The neurotoxic effects of dihydroka inate could be explained by direct activation of glutamate postsynapti c receptors, an effect not shared by the other inhibitors used.