Effects of donepezil treatment on rat nicotinic acetylcholine receptor levels in vivo and in vitro

Document Type

Article

Abstract

Research on acetylcholinesterase inhibitors (ChEIs) indicates that long term exposure increases the level of nicotinic acetylcholine receptors (nAChRs) but the effects of donepezil on nAChRs are not well studied. Therefore, we investigated the effects of sub-chronic donepezil administration on nAChRs in rats and rat pheochromocytoma PC-12 cells. Male Sprague Dawley rats were administered donepezil (0.7 and 2.4 μmoles/kg), nicotine (2.5 μmoles/kg) or saline subcutaneously twice daily for 14 days, PC-12 cells were incubated with 10-6 to 10-4 M donepezil for 72 hours and nAChR levels were determined by receptor binding assay using the nAChR ligands [ 3H]-epibatidine (EPI) for non-α7 nAChRs and [ 3H]-methyllyconitine (MLA) for α7 nAChRs. Chronic donepezil administration at 1.4 μmoles/kg/day and 4.8 μmoles/kg/day significantly increased [3H]-epibatidine binding in the cortex to 126 ± 1. 3% and 127 ± 3.2% of the saline control animals, respectively. [ 3H]-MLA binding in the cortex increased to 114 ± 4.4% and 124 ± 2.8% of the control group for the high and low dose groups, respectively. Hippocampal [3H]-EPI binding in the low dose and high dose groups significantly increased to 135 ± 3.6% and 125 ± 4.6% of the controls, respectively while there were no changes in the level of [ 3H]-MLA binding. In striatal homogenates, neither [3H] -EPI nor [3H]-MLA binding were significantly effected at either dose of donepezil. In PC-12 cells, [3H]-EPI binding was increased at the non-physiological 10-4 M concentration only. There was no effect of donepezil on [3H]-MLA binding at any concentration examined. These results indicate that donepezil increases cortical α7 and non-α7 nAChRs, hippocampal non-α7 nAChRs but does not influence striatal nAChR levels. Furthermore, the lack of an effect on the α7-nAChRs in PC-12 cells suggests that the increase in cortical α7 nAChRs may be an indirect effect of increased acetylcholine levels in vivo.

Publication Date

1-1-2003

Publication Title

Journal of Alzheimer's Disease

ISSN

13872877

Volume

5

Issue

6

First Page

429

Last Page

436

PubMed ID

14757932

Digital Object Identifier (DOI)

10.3233/jad-2003-5602

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