Glucocorticoids, the adrenocortical hormones secreted during stress, can be cumulatively toxic to hippocampal neurons, and this steroid-induced neuron loss has a role in functional impairments of the senescent hippocampus. The glucocorticoids, through their varied catabolic actions, appear to non-specifically induce metabolic vulnerability in the hippocampal neurons. As such, a wide variety of unrelated toxic insults which damage the hippocampus have their toxicity exacerbated by glucocorticoid treatment and attenuated by adrenalectomy. The present report demonstrates such a synergy between corticosterone (CORT), the species-specific glucocorticoid of rats, and 3-acetylpyridine (3-AP), a neurotoxic antimetabolite which inhibits ATP synthesis. When microinfused into Ammon's horn, 3-AP destroys dentate gyrus neurons preferentially. Administration of CORT at a concentration producing titers equivalent to those seen after prolonged stress, prior to and following 3-AP infusion, caused a 5-fold increase in the volume of hippocampal damage induced by the toxin. Conversely, adrenalectomy prior to microinfusion reduced the toxin's potency by more than 60%. Both the history of elevated CORT (i.e. prior to the 3-AP infusion) and the elevated CORT titers in the aftermath of the infusion contributed to the exaggerated damage. Finally, as little as 24 h of elevated CORT prior to and following the microinfusion could significantly potentiate toxin-induced damage. These studies present further evidence for CORT compromising the capacity of hippocampal neurons to survive a variety of toxic insults. Furthermore, the time-course of this effect suggests the relatively rapid metabolic actions of CORT as critical to this endangerment.