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.