Scali C, Casamenti F, Bellucci A, Costagli C, Schmidt B, Pepeu G
Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, I-50139 Florence, Italy.
J Neural Transm (Vienna). 2002 Jul;109(7-8):1067-80. 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.
采用微透析法研究了在衰老大鼠皮层和海马中，给予敌百虫（80毫克/千克）、卡巴拉汀（0.75毫克/千克）、多奈哌齐（1.5毫克/千克）或赋形剂21天（每日口服两次）后细胞外乙酰胆碱水平的变化。末次给药18小时后，敌百虫、卡巴拉汀和多奈哌齐后的胆碱酯酶抑制率分别为85%、52%和39%，同时皮层乙酰胆碱水平分别升高988%、590%和75%。在海马中，敌百虫和卡巴拉汀使乙酰胆碱水平分别升高169%和108%。给予敌百虫、卡巴拉汀和多奈哌齐的激发剂量后，皮层和海马乙酰胆碱水平进一步升高。在对照大鼠和卡巴拉汀治疗的大鼠中，M(2)-M(4)受体拮抗剂AFDX-384（10微摩尔）的逆行灌注分别使皮层和海马乙酰胆碱释放增加500%和300%，在敌百虫治疗的大鼠中无增加，在多奈哌齐治疗的大鼠中增加210%。总之，用敌百虫、卡巴拉汀和多奈哌齐对衰老大鼠进行长期治疗可使乙酰胆碱水平长期升高，并揭示了这三种药物之间的显著差异。
