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Effects on Cholinergic Markers in Rat Brain and Blood after Short and Prolonged Administration of Donepezil

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Abstract

Donepezil is a selective inhibitor of acetylcholinesterase (AChE) clinically used for treating Alzheimer’s disease. Cholinergic effects after short-term exposure of donepezil (up to 12 h) have been extensively studied in rats, but few have addressed the potential long-term effects. After 14 days administration (1×3 mg/kg, decapitation 4 h after the last injection) the cerebral acetylcholine level was increased by 35% and the AChE activity was decreased by 66% and 32% in brain and blood, respectively. No change was detected in choline acetyltransferase activity, or the levels of vesicular acetylcholine transporter, choline transporter, or muscarinic receptors. Expression of various cholinergic genes was unaffected. Preliminary results of AChE activity in human blood showed 60–97% and 43–89% of pre-exposed level after one and three days of donepezil administration (5 mg daily), respectively. In conclusion, donepezil exposure in rats at doses that do not inhibit brain AChE continuously during the day, will not lead to tolerance development.

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Abbreviations

AChE:

acetylcholinesterase

ACh:

acetylcholine

AD:

Alzheimer’s disease

ChAT:

choline acetyltransferase

CHT:

choline transporter

mAChR:

muscarinic acetylcholine receptor

PET:

positron emission tomography

QNB:

quinuclidinyl benzilate

VAChT:

vesicular acetylcholine transporter

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Authors and Affiliations

  1. Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1112, N-0317, Oslo, Norway

    Kristin Huse Haug, Inger Lise Bogen & Ivar Walaas

  2. Molecular Neurobiology Research Group, Faculty of Medicine, University of Oslo, Oslo, Norway

    Kristin Huse Haug, Inger Lise Bogen, Ivar Walaas & Frode Fonnum

  3. Institute of Oral Biology, University of Oslo, Oslo, Norway

    Harald Osmundsen

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  1. Kristin Huse Haug
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  2. Inger Lise Bogen
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  3. Harald Osmundsen
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  4. Ivar Walaas
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  5. Frode Fonnum
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Correspondence to Kristin Huse Haug.

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Haug, K.H., Bogen, I.L., Osmundsen, H. et al. Effects on Cholinergic Markers in Rat Brain and Blood after Short and Prolonged Administration of Donepezil. Neurochem Res 30, 1511–1520 (2005). https://doi.org/10.1007/s11064-005-8828-6

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