Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats

Eur J Pharmacol. 1999 Sep 10;380(2-3):101-7. doi: 10.1016/s0014-2999(99)00545-2.


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.

MeSH terms

  • Acetylcholine / metabolism*
  • Acetylcholinesterase / drug effects
  • Acetylcholinesterase / metabolism
  • Administration, Oral
  • Animals
  • Brain / drug effects
  • Brain / enzymology
  • Brain / metabolism
  • Carbamates / metabolism
  • Carbamates / pharmacology
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology*
  • Donepezil
  • Dose-Response Relationship, Drug
  • Extracellular Space / drug effects
  • Extracellular Space / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Indans / metabolism
  • Indans / pharmacology*
  • Male
  • Phenylcarbamates*
  • Piperidines / metabolism
  • Piperidines / pharmacology*
  • Rats
  • Rats, Wistar
  • Rivastigmine
  • Tacrine / metabolism
  • Tacrine / pharmacology


  • Carbamates
  • Cholinesterase Inhibitors
  • Indans
  • Phenylcarbamates
  • Piperidines
  • Tacrine
  • Donepezil
  • Acetylcholinesterase
  • Acetylcholine
  • Rivastigmine