Glucocorticoids Exacerbate Kainic Acid–Induced Extracellular Accumulation of Excitatory Amino Acids in the Rat Hippocampus


Address correspondence and reprint requests to Dr. R. M. Sapolsky at Department of Biological Sciences, Stanford University, Stanford, CA 94305, U.S.A.


Abstract: Glucocorticoids (GCs) compromise the ability of hippocampal neurons to survive various insults, and do so, at least in part, by exacerbating steps in the glutamate/N-methyl-D-aspartate (NMDA)/calcium cascade of damage. As evidence, GCs impair uptake of glutamate by hippocampal astrocytes, the GC endangerment of the hippocampus is NMDA receptor dependent, and GCs exacerbate kainic acid (KA)-induced calcium mobilization. These observations predict that GCs should also exacerbate KA-induced accumulation of extracellular glutamate and aspartate. To test this, adrenalectomized rats were given replacement GCs in either the low or high physiological range. Three days later, rats were anesthetized and 1 mM KA was infused through a dialysis probe placed in the dorsal hippocampus. Extracellular amino acid concentrations in the dialysate were then assessed by HPLC. After KA infusion, high-GC rats (30 ± 3 μg/dl) had significantly elevated concentrations of glutamate and aspartate compared with low-GC rats (all <0.95 μg/dl). The glutamate accumulation was due to GCs raising pre-KA concentrations, whereas the aspartate accumulation was due to GCs exacerbating the KA-induced rise. Glutamine concentrations were unaffected by KA, whereas the high-GC regimen elevated glutamine concentrations both before and after KA. Taurine concentrations rose after infusion of KA, but were unaffected by GC regime, whereas alanine concentrations were unaffected by either manipulation. Serine concentrations were unaffected by KA, but were depressed both before and after KA in high-GC rats. The high-GC effects on glutamate, aspartate, and serine concentrations could be reversed by supplementing rats with the sugar mannose; this agrees with prior observations that GC endangerment of the hippocampus and GC exacerbation of other steps in the glutamate/NMDA/calcium cascade are reversible with energy supplementation. A variety of steps are suggested by which GCs, exerting their known disruptive effects on hippocampal energetics, could cause excessive accumulation of extracellular glutamate and aspartate during neurological insults and thus exacerbate the subsequent toxicity.