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.
Original language | English |
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Pages (from-to) | 891-899 |
Number of pages | 9 |
Journal | Neuropharmacology |
Volume | 61 |
Issue number | 5-6 |
DOIs | |
Publication status | Published - Oct 2011 |
Bibliographical note
Funding Information:This work was supported by a grant from Forest Laboratories, Inc. ( MEM-TX-13 ), as well as the Canadian Institutes of Health Research ( MOP-44016 ). Author Pradeep Banerjee, from Forest Research Institute, Inc., contributed to study conception, preparation of protocols, data review and presentation, and manuscript preparation.
ASJC Scopus Subject Areas
- Pharmacology
- Cellular and Molecular Neuroscience
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't