Effect of subchronic administration of metrifonate, rivastigmine and donepezil on brain acetylcholine in aged F344 rats

• Published in: Journal of Neural Transmission Vol. 109; no. 7-8; pp. 1067 - 1080
• Main Authors: SCALI, C, CASAMENTI, F, BELLUCCI, A, COSTAGLI, C, SCHMIDT, B, PEPEU, G
• Format: Journal Article
• Language: English
• Published: Wien Springer 01-07-2002; New York, NY Springer Nature B.V
• Subjects: Acetylcholine - metabolism; Aging - metabolism; Animals; Biological and medical sciences; Body Weight - drug effects; Brain - drug effects; Brain - metabolism; Carbamates - administration & dosage; Carbamates - pharmacology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cholinesterase Inhibitors - administration & dosage; Cholinesterase Inhibitors - pharmacology; Cholinesterases - metabolism; Development. Senescence. Regeneration. Transplantation; Drug Administration Schedule; Fundamental and applied biological sciences. Psychology; Hippocampus - drug effects; Hippocampus - metabolism; Indans - administration & dosage; Indans - pharmacology; Male; Muscarinic Antagonists - pharmacology; Phenylcarbamates; Piperidines - administration & dosage; Piperidines - pharmacology; Pirenzepine - analogs & derivatives; Pirenzepine - pharmacology; Rats; Rats, Inbred F344; Rivastigmine; Trichlorfon - administration & dosage; Trichlorfon - pharmacology; Vertebrates: nervous system and sense organs; Senescence; Rat; Enzyme; Alzheimer disease; Rodentia; Central nervous system; Enzyme inhibitor; Esterases; Cholinesterase; Carboxylic ester hydrolases; Vertebrata; Mammalia; Hydrolases; Acetylcholine; Brain (vertebrata)
• ISSN: 0300-9564; 1435-1463
• DOI: 10.1007/s007020200090

The changes in extracellular acetylcholine levels were investigated by microdialysis in the cortex and hippocampus of aging rats after administration of metrifonate (80 mg/kg), rivastigmine (0.75 mg/kg), donepezil (1.5 mg/kg) or vehicle for 21 days (twice daily p.o.). Eighteen h after the last administration, cholinesterase inhibition was 85, 52 and 39% after metrifonate, rivastigmine and donepezil, respectively, and was accompanied by 988, 590 and 75% increase in cortical acetylcholine level. In the hippocampus, metrifonate and rivastigmine brought about a 169 and 108% increase in acetylcholine levels. A challenge dose of metrifonate, rivastigmine and donepezil was followed by a further increase in cortical and hippocampal acetylcholine levels. The retrograde perfusion of the M(2)-M(4) receptor antagonist AFDX-384 (10 microM) induced a 500 and 300% increase in cortical and hippocampal acetylcholine release, in control and rivastigmine-treated rats, respectively, no increase in metrifonate-treated rats, and a 210% increase in donepezil-treated rats. In conclusion, chronic treatment of aging rats with metrifonate, rivastigmine and donepezil induces a long-lasting increase in acetylcholine levels, and reveals marked differences between the three drugs.