Effect of the subchronic treatment with the acetylcholinesterase inhibitor heptastigmine on central cholinergic transmission and memory impairment in aged rats.

The effect of subchronic administration of the acetylcholinesterase (AChE) inhibitor heptastigmine (HEP 0.6 mg/kg s.c. daily for 15 days) was investigated on cortical extracellular acetylcholine (ACh) levels and on memory function in aged male rats (26 months old at the beginning of the experiments) using microdialysis and behavioural techniques. Twenty-four hours after the last treatment, cortical ACh levels were significantly higher in rats subchronically treated with HEP than in rats treated with saline and AChE activity was still inhibited in cortex, hippocampus and striatum. The injection of a challenge dose of HEP (0.6 mg/kg s.c.) 24 h after the last treatment produced a faster and a more sustained increase of ACh in the cortex of subchronically treated rats compared to those repeatedly injected with saline. However, the maximum increase of ACh levels after injection of the challenge was comparable in both groups. In an object recognition test in which the pretest and test phase were spaced by 45 days, HEP prevented the deterioration of spatial memory occurring during this period, but had no effect on non-spatial memory. The present results suggest that moderate inhibition of brain AChE is able to maintain high levels of cortical extracellular ACh in aged rats and that this increase matches facilitatory effect of HEP on spatial memory.