期刊
JOURNAL OF NEURAL TRANSMISSION
卷 109, 期 7-8, 页码 1067-1080出版社
SPRINGER-VERLAG WIEN
DOI: 10.1007/s007020200090
关键词
cholinesterase inhibitors; microdialysis; Alzheimer's disease; presynaptic autoreceptors; AFDX-384
The changes in extracellular acetylcholine levels were investigated by microdialysis in the cortex and hippocampus of aging rats after administration of metrifonate (80mg/kg), rivastigmine (0.75mg/kg), donepezil (1.5mg/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 muM) 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.
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