PHYSIOLOGICAL ELEVATIONS OF GLUCOCORTICOIDS POTENTIATE GLUTAMATE ACCUMULATION IN THE HIPPOCAMPUS

Glucocorticoids (GCs) are secreted during stress and can damage the hi ppocampus over the course of aging and impair the capacity of hippocam pal neurons to survive excitotoxic insults. Using microdialysis, we ha ve previously observed that GCs augment the extracellular accumulation of glutamate and aspartate in the hippocampus following kainic acid-i nduced seizures. In that study, adrenalectomized rats maintained on mi nimal GC concentrations were compared with those exposed to GCs elevat ed to near-pharmacological levels. We wished to gain insight into the physiological relevance of these observations. Thus, we have examined the effects of GCs over the normal physiological range on glutamate an d aspartate profiles; this was done by implanting adrenalectomized rat s with GC-secreting pellets, which produce stable and controllable cir culating GC concentrations. We observe that incremental increases in G C concentrations cause incremental increases in glutamate accumulation before the kainic acid insult, as well as in the magnitude of the glu tamate response to kainic acid. Elevating GC concentrations from the c ircadian trough to peak doubled cumulative glutamate accumulation, whe reas a rise into the stress range caused a fourfold increase in accumu lation. Similar, although smaller, effects also occurred with aspartat e accumulation (as well as with taurine but not glutamine accumulation ). These data show that the highly elevated GC concentrations that acc ompany neurological insults such as seizure or hypoxia-ischemia will g reatly exacerbate the glutamate accumulation at that time. Furthermore , stress levels of GCs augmented glutamate accumulation even in the ab sence of an excitotoxic insult, perhaps explaining how sustained stres s itself damages the hippocampus. Finally, even the moderately elevate d basal GC concentrations that typically occur in aged rats augmented glutamate accumulation, perhaps explaining how GCs damage the hippocam pus over the course of normal aging.