title: Effects of rivastigmine and donepezil on brain acetylcholine levels in acetylcholinesterase-deficient mice.
abstract: OBJECTIVE
  Alzheimer s disease is characterized by a dysfunction of central cholinergic systems and is treated by inhibitors of acetylcholinesterase (AChE). This study tests the effect of two AChE inhibitors in therapeutic use, rivastigmine and donepezil, in mice that are devoid of AChE (AChE-/- mice). Rivastigmine is an inhibitor of both AChE and butyrylcholinesterase (BChE) whereas donepezil is a selective inhibitor of AChE.
  
  
  METHODS
  We have used in vivo microdialysis to investigate the effects of the two drugs on the extracellular concentration of acetylcholine (ACh) in the hippocampus of AChE-/- mice.
  
  
  RESULTS
  Extracellular ACh levels in the hippocampus were 30-fold elevated in AChE-/- mice compared to wild-type (AChE+/+) animals. Infusion of rivastigmine (1 and 10 microM) caused a further doubling of ACh levels in AChE-/- mice within 90-120 min. In contrast, infusion of donepezil (1 microM) did not affect hippocampal ACh levels in AChE-/- mice although it increased ACh levels more than twofold in wild-type mice.
  
  
  CONCLUSIONS
  In the absence of AChE, rivastigmine enhances the levels of extracellular ACh by inhibiting BChE. This finding may be of therapeutic relevance because BChE activity is preserved, but AChE activity is strongly decreased, in late-stage Alzheimer s disease.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, 1300 Coulter Dr, Amarillo, TX 79106, USA.
authors.forename: Runa S
authors.initials: RS
authors.lastname: Naik
authors.forename: Joachim
authors.initials: J
authors.lastname: Hartmann
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kiewert
authors.forename: Ellen G
authors.initials: EG
authors.lastname: Duysen
authors.forename: Oksana
authors.initials: O
authors.lastname: Lockridge
authors.forename: Jochen
authors.initials: J
authors.lastname: Klein
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000172:deficiency*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D000077265:Donepezil; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007189:Indans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D048448:Phenylcarbamates / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D000068836:Rivastigmine
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D048448:Phenylcarbamates; D010880:Piperidines; D000077265:Donepezil; D000110:Acetylcholinesterase; D000109:Acetylcholine; D000068836:Rivastigmine