Glucocorticoids (GCs) disrupt the energy metabolism of neurons of the hippocampus, and thus leave them more vulnerable to a variety of damaging metabolic insults. In this manner, GCs appear to influence the rate of hippocampal neuron loss during aging in the rat, as well as the severity of hippocampal damage following hypoxia-ischemia or seizure. These GC actions could be secondary to their multitudinous peripheral actions. The present report, however, suggests that GCs directly endanger hippocampal neurons. Glucocorticoid-induced sensitization of neurons to damaging toxins was demonstrated in vitro. The viability of primary cultures of dispersed fetal rat hippocampal neurons was assessed following exposure to a variety of neurotoxins. Prior incubation of the cultures with the rodent-typical GC, corticosterone, significantly decreased neuronal viability in the face of the toxins. Such compounds included the glutaminergic excitotoxin kainic acid, the antimetabolite 3-acetylpyridine and the superoxide radical generator paraquat. As little as 10(-9) M corticosterone could potentiate damage, a concentration equivalent to low basal values in vivo. Higher concentrations of corticosterone could potentiate damage even further; these corticosterone concentrations were not themselves damaging. Administration of glucose increased neuronal viability in the face of the GC/toxin combination, without increasing viability following toxin alone. This suggests that a critical feature of the action of GCs on neurons might be the inhibition of glucose utilization (which is a hallmark of peripheral GC action).