Time course of ethylcholine aziridinium ion (AF64A)-induced cholinotoxicity in vivo

The time course of the cholinotoxicity of ethylcholine aziridinium ion (AF64A) has been investigated. Rats were injected with AF64A (3 nmols/3 μ1/side, bilateral, i.e.v.) or with vehicle. One day to one year after treatment, the hippocampus, cortex and striatum were analyzed for the activity of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) and high-affinity transport of choline (HAChT). In addition, the release of K +-stimulated acetylcholine (ACh) from superfused slices of hippocampus was determined. The first parameter affected was high affinity transport of choline. One day after treatment with AF64A, the high affinity transport of choline in the hippocampus was reduced by 23%. This reduction was maximal one week after treatment (−67%) and persisted for at least 6 months. The high affinity transport of choline in the striatum and cortex was not altered by treatment with AF64A. The activity of ChAT and AChE in the hippocampus was reduced by 2 days after treatment with AF64A. These deficits persisted for at least 6 months (AChE) to 1 year (ChAT). The activity of ChAT and AChE in the cortex and striatum was minimally affected up to 1 year after treatment with AF64A, at which time significant reductions were noted. The release of ACh was affected 3 days after treatment with AF64A, and remained attenuated 6 months later. These data indicate that the cholinergic deficit caused by in vivo treatment with AF64A was first apparent at the level of high affinity uptake of choline in the hippocampus HAChT. Subsequently, the activity of ChAT and AChE and release of ACh in the hippocampus were affected. In contrast to these early effects, cholinergic parameters in the cortex and striatum were affected much later (1 year after treatment).