AF64A (ethylcholine aziridinium ion), a cholinergic neurotoxin, selectively impairs working memory in a multiple...

The present study examined the nature of the cognitive deficits associated with a selective decrease of cholinergic activity in the hippocampus. Male Fischer rats were trained to perform a multiple component T-maze task which simultaneously assessed their ability to perform on the basis of trial-specific information (working memory) and trial-independent information (reference memory). Following 125 acquisition trials rats were bilaterally injected with AF64A (3 nmol/side) or artificial CSF into the lateral ventricles and allowed 14 days to recover before behavioral testing resumed. The controls rapidly returned to their preoperative level of performance on both components of the maze task. AF64A-treated animals were transiently impaired on the reference memory task. Their performance rapidly improved and they were performing at preoperative levels within 4 days of testing. In contrast, these animals exhibited a marked and long-lasting impairment in their performance of the working memory component. After behavioral testing was completed, neurochemical analysis revealed that AF64A produced a significant decrease in choline acetyltransferase (ChAT) activity in the hippocampus (43%) 42 days following surgery. This dosing regimen produced no alterations of striatal or cortical ChAT activity. These data suggest that alterations of hippocampal cholinergic activity severely impair an animal's ability to perform working memory tasks.