Effects of memantine and donepezil on object recognition memory and hippocampal acetylcholine levels in rats with cholinergic lesions

Abstract

The combination of donepezil (DON) and memantine (MEM) produces greater amelioration of Alzheimer's disease (AD) symptoms than DON treatment alone. We sought to elucidate mechanisms underlying that phenomenon.Rats with cholinergic denervation of the hippocampus (fornix lesion) were treated with DON (2.5 mg/kg/day), MEM (30 mg/kg/day), or placebo in drinking water for 3 weeks, then challenged with a single i.p. dose of MEM (5 mg/kg) or DON (2.5 mg/kg). In both treatment phases, animals were subjected to an object recognition task (ORT) and microdialysis measurements of hippocampal ACh levels. Cholinergic denervation was assessed by immunohistochemistry.Fornix lesions resulted in a loss of >50% cholinergic fibers and significantly impaired ORT performance. Three weeks of MEM treatment restored ORT performance and tended to increase ACh levels, whereas DON treatment produced no significant ORT improvement. The MEM challenge following DON or vehicle treatment significantly elevated ACh release, whereas the DON challenge did not affect ACh release. Both challenges improved ORT performance.Our data suggest that MEM restores recognition memory and increases hippocampal ACh release in ACh‐deficient rats. This latter effect, likely resulting from NMDA receptor antagonism, in addition to the normalization of glutamatergic transmission, may underlie the benefits of MEM in DON‐treated patients with AD.