L. Massieu et al., ACCUMULATION OF EXTRACELLULAR GLUTAMATE BY INHIBITION OF ITS UPTAKE IS NOT SUFFICIENT FOR INDUCING NEURONAL DAMAGE - AN IN-VIVO MICRODIALYSIS STUDY, Journal of neurochemistry, 64(5), 1995, pp. 2262-2272
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.