Distinctive acute brain damage involving limbic and related brain regions develops in adult rats following sustained limbic seizures induced by systemic administration of kainic acid or dipiperidinoethane (DPE) or by intra-amygdaloid injection of kainic acid or folic acid. This seizure-brain damage (S-BD) syndrome is of particular interest because it tends to parallel the type of seizures and brain damage seen in human temporal lobe epilepsy. We have observed that DPE induces the S-BD syndrome by systemic but not intra-mygdaloid injection, whereas an oxidized DPE derivative which structurally resembles the cholinergic agonist oxotremorine is effective when injected into the amygdala. Prompted by this finding, we injected known acetylcholine (ACh) agonists and cholinesterase (ChE) inhibitors into the rat amygdala and found that either class of agent reproduces this type of S-BD syndrome. These and related findings suggest that ACh mechanisms might have a more important role in human epilepsy and epileptic brain damage than has generally been appreciated.