title: Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats.
abstract: The effects of oral administration of the centrally acting acetylcholinesterase (AChE) inhibitors, donepezil hydrochloride (donepezil: E2020: (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride), tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and ENA-713 (rivastigmine: (S)-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate), which have been developed for the treatment of Alzheimer's disease, on the extracellular acetylcholine concentration in the hippocampus of rats were evaluated by using a microdialysis technique without adding cholinesterase inhibitor to the perfusion solution. We also compared the inhibition of brain AChE and the brain concentrations of these drugs. Donepezil at 2.5 mg/kg and tacrine at 5 mg/kg showed significant effects for more than 6 h. At these doses, the maximum increases were observed at about 1.5 h after administration of donepezil, and at about 2 h with tacrine, and were 499% and 422% of the pre-level, respectively. ENA-713 produced significant effects at doses of 0.625, 1.25 and 2.5 mg/kg, which lasted for about 1, 2 and 4 h, respectively. The maximum increases produced by these doses at about 0.5 h after administration were 190, 346 and 458% of the pre-level, respectively. The time courses of brain AChE inhibition with donepezil at 2.5 mg/kg, tacrine at 10 mg/kg and ENA-713 at 2.5 mg/kg were mirror images of the extracellular acetylcholine-increasing action at the same doses. The time courses of the brain concentrations of drugs after oral administration of donepezil at 2.5 mg/kg and tacrine at 10 mg/kg were consistent with those of brain AChE inhibition at the same doses, and there was a linear relation between these parameters. Brain concentration of ENA-713 at 2.5 mg/kg was below the limit of quantification at all time points measured. These results suggest that oral administration of donepezil, tacrine and ENA-713 increases acetylcholine concentration in the synaptic cleft of the hippocampus mostly through AChE inhibition, and that donepezil has a more potent activity than tacrine and a longer-lasting effect than ENA-713 on the central cholinergic system.
authors.affiliation: Tsukuba Research Laboratories, Eisai, Ibaraki, Japan. t-kosasa@hhc.eisai.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Kosasa
authors.forename: Y
authors.initials: Y
authors.lastname: Kuriya
authors.forename: K
authors.initials: K
authors.lastname: Matsui
authors.forename: Y
authors.initials: Y
authors.lastname: Yamanishi
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002219:Carbamates / Q000378:metabolism / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007189:Indans / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D048448:Phenylcarbamates; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000068836:Rivastigmine; D013619:Tacrine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007189:Indans; D048448:Phenylcarbamates; D010880:Piperidines; D013619:Tacrine; D000077265:Donepezil; D000110:Acetylcholinesterase; D000109:Acetylcholine; D000068836:Rivastigmine