Effect of donepezil hydrochloride (E2020) on extracellular acetylcholine concentration in the cerebral cortex of rats

Donepezil hydrochloride (donepezil), a potent and selective acetylcholinest erase inhibitor, has been developed for the treatment of Alzheimer's diseas e. We studied the effect of oral administration of this drug on the extrace llular acetylcholine (ACh) concentration in the cerebral cortex of rats usi ng microdialysis. We also observed fasciculation, a peripheral cholinergic sign induced by activation of neuromuscular transmission, after oral admini stration of the drug as an index of peripheral cholinergic activation. Othe r cholinesterase inhibitors, tacrine, ENA-713 and TAK-147, were used as ref erence drugs. Donepezil significantly and dose-dependently increased the ex tracellular ACh concentration in the rat cerebral cortex within the dose ra nge of 2.5-10 mg/kg. Tacrine, ENA-713 and TAK-147 also elevated the extrace llular concentration of ACh. The minimum effective doses of donepezil, tacr ine, ENA-713 and TAK-147 were less than or equal to 2.5, 10, 10 and less th an or equal to 10 mg/kg, respectively. Donepezil produced fasciculation at doses of 2.5 mg/kg and above, with a dose-dependent increase in incidence a nd intensity. The reference compounds also induced fasciculation in a dose- dependent manner. The threshold doses of tacrine, ENA-713 and TAK-147 for f asciculation were 5, 2.5 and 2.5 mg/kg, respectively. The values of the rat io of the minimum effective dose for the ACh-increasing action to that for the fasciculation-producing action were: donepezil, less than or equal to 1 ; tacrine, 2; ENA-713, 4; TAK-147, less than or equal to 4. These results i ndicate that orally administered donepezil has a potent and selective activ ity on the central cholinergic system.