title: Effects of memantine and donepezil on cortical and hippocampal acetylcholine levels and object recognition memory in rats.
abstract: This preclinical study investigated the ability of memantine (MEM) to stimulate brain acetylcholine (ACh) release, potentially acting synergistically with donepezil (DON, an acetylcholinesterase inhibitor). Acute systemic administration of either MEM or DON to anesthetized rats caused dose-dependent increases of ACh levels in neocortex and hippocampus, and the combination of MEM (5 mg/kg) and DON (0.5 mg/kg) produced significantly greater increases than either drug alone. To determine whether ACh release correlated with cognitive improvement, rats with partial fimbria-fornix (FF) lesions were treated with acute or chronic MEM or DON. Acute MEM treatment significantly elevated baseline hippocampal ACh release but did not significantly improve task performance on a delayed non-match-to-sample (DNMS) task, whereas chronic MEM treatment significantly improved DNMS performance but only marginally elevated baseline ACh levels. Acute or chronic treatment with DON (in the presence of neostigmine to allow ACh collection) did not significantly improve DNMS performance or alter ACh release. In order to investigate the effect of adding MEM to ongoing DON therapy, lesioned rats pretreated with DON for 3 weeks were given a single intraperitoneal dose of MEM. MEM significantly elevated baseline hippocampal ACh levels, but did not significantly improve DNMS task scores compared to chronic DON-treated animals. These data indicate that MEM, in addition to acting as an NMDA receptor antagonist, can also augment ACh release; however, in this preclinical model, increased ACh levels did not directly correlate with improved cognitive performance.
authors.affiliation: A I Virtanen Institute, Department of Neurobiology, University of Eastern Finland, Kuopio, Finland. Jouni.Ihalainen@uef.fi
authors.forename: Jouni
authors.initials: J
authors.lastname: Ihalainen
authors.forename: Timo
authors.initials: T
authors.lastname: Sarajärvi
authors.forename: Doug
authors.initials: D
authors.lastname: Rasmusson
authors.forename: Susanna
authors.initials: S
authors.lastname: Kemppainen
authors.forename: Pekka
authors.initials: P
authors.lastname: Keski-Rahkonen
authors.forename: Marko
authors.initials: M
authors.lastname: Lehtonen
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Banerjee
authors.forename: Kazue
authors.initials: K
authors.lastname: Semba
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D020712:Fornix, Brain / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007189:Indans / Q000494:pharmacology*; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects* / Q000502:physiology
chemical_list: D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D000109:Acetylcholine; D008559:Memantine